Neurobehavioral consequences of small molecule-drug immunosuppression

Neuropharmacology xxx (2014) 1e11

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Invited review

Neurobehavioral consequences of small molecule-drug immunosuppression € sche a, *, Karin Weissenborn b, Uwe Christians c, Oliver Witzke d, Katharina Bo Harald Engler a, Manfred Schedlowski a, Martin Hadamitzky a a

Institute of Medical Psychology and Behavioral Immunobiology, University Hospital, Essen, University of Duisburg-Essen, Hufelandstrasse 55, 45122 Essen, Germany Department of Neurology, Hannover Medical School, 30625 Hannover, Germany c Department of Anesthesiology, University of Colorado School of Medicine, Aurora, CO 80045, USA d Department of Nephrology, University Hospital Essen, University of Duisburg-Essen, 45122 Essen, Germany b

a r t i c l e i n f o

a b s t r a c t

Article history: Available online xxx

60 years after the first successful kidney transplantation in humans, transplant patients have decent survival rates owing to a broad spectrum of immunosuppressive medication available today. Not only transplant patients, but also patients with inflammatory autoimmune diseases or cancer benefit from these life-saving immunosuppressive and anti-proliferative medications. However, this success is gained with the disadvantage of neuropsychological disturbances and mental health problems such as depression, anxiety and impaired quality of life after long-term treatment with immunosuppressive drugs. So far, surprisingly little is known about unwanted neuropsychological side effects of immunosuppressants and anti-proliferative drugs from the group of so called small molecule-drugs. This is partly due to the fact that it is difficult to disentangle whether and to what extent the observed neuropsychiatric disturbances are a direct result of the patient's medical history or of the immunosuppressive treatment. Thus, here we summarize experimental as well as clinical data of mammalian and human studies, with the focus on selected small-molecule drugs that are frequently employed in solid organ transplantation, autoimmune disorders or cancer therapy and their effects on neuropsychological functions, mood, and behavior. These data reveal the necessity to develop immunosuppressive and antiproliferative drugs inducing fewer or no unwanted neuropsychological side effects, thereby increasing the quality of life in patients requiring long term immunosuppressive treatment. This article is part of a Special Issue entitled ‘Neuroimmunology and Synaptic Function’. © 2014 Elsevier Ltd. All rights reserved.

Keywords: Immunotherapeutic drugs Neuropsychiatric complications Affective disorders Anxiety Depression

1. Introduction Since the first renal transplantation in 1954 between identical twins (Merill, 1956), immunosuppressive drugs have been widely employed to prevent graft rejection. The continuous treatment with immunosuppressive drugs is an inevitable prerequisite for long term transplant survival (Halloran, 2004; Miller, 1996). However, the dark side of this success is the fact that all immunosuppressive drugs induce unwanted toxic side effects including impaired functions of the central nervous system (CNS). These

* Corresponding author. Tel.: þ49 201 723 4749; fax: þ49 201 723 5948. € sche), martin. E-mail addresses: [email protected] (K. Bo [email protected] (M. Hadamitzky).

partially severe neurological manifestations (Hotson and Pedley, 1976; Palmer and Toto, 1991) include seizures, disturbances of consciousness, neurocognitive dysfunctions such as learning and memory deficiencies, depression, or psychotic disorders (Bronster et al., 1994; Saner et al., 2007). Neurological complications commonly follow liver transplantation and are a significant source of morbidity and mortality in transplant recipients (Saner et al., 2007; Stein et al., 1992). Encephalopathy is the most common CNS complication after liver transplantation, with multiple causes: anoxia, primary graft nonfunctioning, renal failure, rejection, sepsis, and drugs (Bronster et al., 2000, 1994). In adult lung transplantation patients, neurological complications affect 92% of patients within 10 years, severe in 31% of cases. Most common are perioperative stroke and encephalopathy (Mateen et al., 2010). These previously described

http://dx.doi.org/10.1016/j.neuropharm.2014.12.008 0028-3908/© 2014 Elsevier Ltd. All rights reserved.

€ sche, K., et al., Neurobehavioral consequences of small molecule-drug immunosuppression, Please cite this article in press as: Bo Neuropharmacology (2014), http://dx.doi.org/10.1016/j.neuropharm.2014.12.008

€ sche, K., et al., Neurobehavioral consequences of small molecule-drug immunosuppression, Please cite this article in press as: Bo Neuropharmacology (2014), http://dx.doi.org/10.1016/j.neuropharm.2014.12.008

Table 1 Overview of drug description, mechanism of action, therapeutic use and influences on CNS/behavior. Drug

Description

Mechanism of action

Therapeutic use

Influences on the CNS/behavior of experimental animals

Influences on the CNS/behavior of humans

Cyclosporine A (CsA)

Calcineurin Inhibitor (CNI)

CsA acts as an inhibitor of calcineurin preventing the dephosphorylation of NFAT and its transfer to the nucleus (Tedesco and Haragsim, 2012)

Prevention of graft rejection in kidney, liver and heart transplantation Rheumatoid Arthritis (RA)

Induced anxiety- and depressionlike behaviors in rats through diminished calcineurin activity in the amygdala (Mineur et al., 2014)

Psoriasis

Induced depressive-like behavior in rats by blocking of the mTOR signaling pathway (Yu et al., 2013) cf. CsA

Increased incidence rate of developing affective or anxiety symptoms such as disorientation, depression, aggression, paranoia, and apathy (Chang et al., 2001; de Groen et al., 1987; Kahan, 1994; Kahan et al., 1987; Lang et al., 2009; Lindenfeld et al., 2004b) cf. CsA

Tacrolimus (TAC, FK506)

CNI

Sirolimus (rapamycin) Everolimus Temsirolimus

Mammalian target of rapamycin (mTOR) inhibitor

TAC interacts with FKBP12 to form a calcineurin-blocking complex (Halloran, 2004) Sirolimus forms a complex with the FK binding protein 12 (FKBP12) that in turn inhibits mTOR and interleukin-2-driven T-cell proliferation (Guertin and Sabatini, 2009)

Liver- and kidney transplantation

Widely used as an immunosuppressant in organ transplantation

Elevated EEG and cFOS expression in the amygdala and increased anxiety-like behavior in rats (Hadamitzky et al., 2014)

Cancer therapy

In mice, sirolimus can result in abnormal sensorimotor milestones, motor abnormalities and increased anxiety-related behaviors, both in early postnatal development and during adult stages (Tsai et al., 2013; Yu et al., 2013)

Mycophenolate mofetil (MMF)

MMF is the morpholinoethylester of mycophenolic acid (MPA)

MPA inhibits the proliferation and clonal expansion of both B and T cells (Mele and Halloran, 2000)

MMF is usually given in combination with cyclosporine or corticosteroids after kidney, heart or liver transplantation

Leflunomide

Disease-modifying antirheumatic drug (DMARD) Pyrimidine synthesis inhibitor

RA Off-label use as an immunosuppressant

Azathioprine

DMARD

Two possible mechanisms of action (Ruckemann et al., 1998) - reversible inhibition of dihydroorotate dehydrogenasea - inhibition of tyrosine kinases Inhibits purine synthesis through its metabolite, 6-mercaptopurine; Inhibits the proliferation of B and T lymphocytes; Reduces antibody production (Lindenfeld et al., 2004b)

Interruption of DNA synthesis (Barnhart et al., 2001)

Used in low doses for the treatment of immune-mediated disorders such as RA

Methotrexate (MTX)

Anti-folate, anti-neoplastic drug

The prescribing information for MMF reports depression as an adverse event Case report: 64-year-old woman developed a severe depressive disorder after the start of therapy (Draper, 2008) Less mental health impairment than otherwise treated groups (Pinho de Oliveira Ribeiro et al., 2013)

RA Used in renal homo-transplantation to prevent graft rejection

Combination therapy (CMF; cyclophosphamide, MTX, and 5Fluorouracil) in cancer patients

Temsirolimus (CCI-779) in tumor therapy induced symptoms of bipolar disorder patients without a medical history of neuropsychiatric complications (Raymond et al., 2004)

Long-lasting cognitive dysfunctions in rats (Fardell et al., 2010; Seigers and Fardell, 2011; Seigers et al., 2008, 2009, 2010) Decreased hippocampal cell proliferation and white matter density (Seigers et al., 2009) Increased freezing during test of fear conditioning (Gandal et al., 2008)

Normal (age-appropriate) mental development in babies exposed to azathioprine in utero and via breastfeeding in a long-term followup study (Angelberger et al., 2011) DMARDs in general: prevalence of depressive and anxiety disorders (14e47 % compared to general population) (Pinho de Oliveira Ribeiro et al., 2013) Mild or even major CNS symptoms (Gonzalez-Suarez et al., 2014; Kivity et al., 2014; Wernick and Smith, 1989) CMF has been shown to be associated with severe, long lasting cognitive impairment (Kreukels et al., 2005; Schagen et al., 1999)

€ sche, K., et al., Neurobehavioral consequences of small molecule-drug immunosuppression, Please cite this article in press as: Bo Neuropharmacology (2014), http://dx.doi.org/10.1016/j.neuropharm.2014.12.008

Fingolimod (FTY720)

Cyclophosphamide

a

Cytotoxic agent

DHODH ¼ a key enzyme in pyrimidine synthesis.

Inhibits the egress of T cells out of lymph nodes (Brinkmann et al., 2002) Prodrug; activated by enzymatic and chemical activation (Emadi et al., 2009)

Multiple sclerosis Used in phase III trials in renal transplantation Autoimmune disorders (e.g. MS) Diverse Cancers, cf. methotrexate in CMF Bone marrow transplantation

Depression is found as a side effect in 1e10 % of patients cf. methotrexate in CMF

cf. methotrexate in CMF

AC: No effect on anxiety behavior (Konat et al., 2008); impaired contextual fear memory, but no effect on cued-fear or acquisition of fear response (Macleod et al., 2007); In mice, no impairment in contextual-fear conditioning or memory ability (Fremouw et al., 2012) Cyclophosphamide alone: no cognitive impairment (Lee et al., 2006); Impaired inhibitory avoidance, but no effect on anxiety behavior (Reiriz et al., 2006) Impaired passive avoidance learning and memory ability (Yang et al., 2010) Acute reduction of survival of newly born hippocampal cells; no long-term effect on spatial working memory or hippocampal proliferation (Lyons et al., 2011) Impairment of cognitive ability (Christie et al., 2012)

FAC: Decline in cognitive function (Wefel et al., 2010) AC: Transient decline in a range of cognitive domains (Jansen et al., 2011) CTC, FEC, CMF: Improvement of cognitive dysfunction at 4 years post-therapy (Schagen et al., 2002) Cyclophosphamide alone: Confusional state (SPC) Occasionally occurring peripheral neuropathy, polyneuropathy, neuralgia (SPC) Improvement of cognitive function in MS patients (Weiner and Cohen, 2002; Zephir et al., 2005)

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complications may be a direct consequence of transplantation itself, but they might also be caused by immunosuppressive medication. Accordingly, it is not surprising that treatment with immunosupressants is considered a crucial factor for the development of neuropsychiatric disturbances (Tombazzi et al., 2006). Although it has already been shown that anti-viral treatment with cytokines in patients with hepatitis or cancer (Capuron et al., 2001; Miller et al., 2008; Musselman et al., 2001), or immunosuppression with calcineurin inhibitors (CNIs) can have severe effects on the patients' mental health (Lang et al., 2009), little is known about the effects of other small molecule-drugs on mood, cognition and behavior. The major groups of small molecule-drugs include immunophilin-binding drugs, inhibitors of nucleotide synthesis, anti-metabolites and sphingosin-1P (S1P)-receptor antagonists (Halloran, 2004). In spite of the increasing specificity of new small molecule-drugs, the complexity of interacting and overlapping molecular pathways that are involved in each biological pathway are not completely understood (Haley, 2012). In general, it remains difficult to distinguish the neuropsychological side effects of the specific medication from the symptom cluster induced by the diseases themselves. Immunosuppressive therapy, for example in cancer, leads to sickness behavior suggesting that treatment and/or cancer itself are perturbing central neuronal function (Dantzer et al., 2012). Immunosuppressive or anti-proliferative small drugs are also employed in autoimmune diseases, such as rheumatoid arthritis (RA), psoriasis or multiple sclerosis (MS). Since RA, for example, can cause severe persistent pain and a decreased quality of life, it might be possible that the occurrence or worsening of an already existing depression is increased by the course of the disease itself (Gettings, 2010; Pinho de Oliveira Ribeiro et al., 2013). Thus, it will be of importance in future studies to analyze the neurobiological mechanisms underlying neuropsychological symptoms in any specific disease compared to drug effects (Kim et al., 2012). Immunosuppressive therapeutics include small-molecule drugs, depleting and nondepleting protein drugs (polyclonal and monoclonal antibodies), fusion proteins, intravenous immune globulin, and glucocorticoids. Due to this broad range of compounds, this review focuses on the group of small molecule-drugs as classified in Halloran (2004). We here try to provide a comprehensive overview on what is known regarding the effects of small molecule-drugs in human patients and, if available, in experimental animals, employed in transplantation medicine, certain autoimmune diseases, and cancer treatment on mood, cognition and behavior (Table 1). 2. Mechanisms of action and therapeutic use of small molecule-drugs and their effects on CNS and neuropsychological functions 2.1. Immunophilin binding drugs: mechanisms of action and therapeutic use The cyclophilin binding substance cyclosporine A (CsA) acts as an inhibitor of calcineurin, which, in its active form, dephosphorylates the nuclear factor of activated T-lymphocytes (NFAT). CsA prevents the dephosphorylation of NFAT, its transfer to the nucleus (Tedesco and Haragsim, 2012), and its ability to initiate transcription of interleukin-2 (IL-2), interferon-gamma (IFN-g) and related genes (Batiuk and Halloran, 1997). CsA is approved for the prevention of graft rejection in kidney, liver and heart transplantation as well as for treatment of rheumatoid arthritis and psoriasis (Lindenfeld et al., 2004a). In addition to CsA, Tacrolimus (TAC, FK506) is approved as a CNI for liver- and kidney transplantation (Taylor et al., 2001). Its mechanism of action is similar to CsA, however TAC interacts with a different immunophilin, the

FK506-binding protein FKBP12, to form a complex capable of blocking calcineurin activity, as well (Halloran, 2004). 2.1.1. Immunophilin binding drugs: effects on CNS and neuropsychological functions in humans Clinical evidence indicates that treatment with immunosuppressive drugs such as CsA or TAC is accompanied by an increased incidence of neuropsychiatric side effects such as disorientation, depression, aggression, paranoia, and apathy (Chang et al., 2001; de Groen et al., 1987; Kahan, 1994; Kahan et al., 1987; Lang et al., 2009; Lindenfeld et al., 2004a). Calcineurin inhibition by CsA and TAC alters sympathetic outflow, which may play a role in the mediation of neurotoxic and hypertensive adverse events (Bechstein, 2000). Despite their lipophilic nature, CsA and TAC do not easily cross the bloodebrain barrier and enter brain tissue, except in high doses and chronic administration, for example after transplantation (Borlongan et al., 2002). CsA appears to enhance nitric oxide production, which may cause dysfunction of the bloodebrain barrier; high exposure to CsA after intravenous (i.v.) administration may lead to endothelial damage and vasogenic edema. Therefore, one possible entry is at the capillary level where injured endothelial cells possibly inhibit p-glycoprotein expression, a known drugefflux pump (Al-Massarani et al., 2008; Wijdicks, 2001). The alternative route is for CsA to bind to low-density lipoprotein (LDL) particles. Hypocholesterolemia, which is expected in patients with significant liver failure, may upregulate LDL receptors in the brain, increasing the chance of entry into the brain (de Groen et al., 1987; Wijdicks, 2001). Palmer and Toto (1991) reported on three stable renal transplant patients with therapeutic levels of CsA who developed complex and severe neurotoxicity that was completely reversible on discontinuation of the drug. Diffuse cognitive changes such as depression and personality changes, which have been described in these patients, might also correlate with analogous paroxysmal EEG abnormalities (Famiglio et al., 1989). Nonetheless, both lower and higher doses of CsA decreased acetylcholinesterase activity in the hippocampus and frontal cortex to practically the same extent (Herink et al., 2003). Several human studies propose a direct seizure-inducing effect of CsA due to seizure attacks after i.v. administration of this drug (Adams et al., 1987; Trullemans et al., 2001). 2.1.2. Immunophilin binding drugs: effects on CNS and neuropsychological functions in experimental animals Data in experimental animals demonstrate neurotoxic and neuropsychological effects of acute and chronic treatment with calcineurin inhibitors. For example, 200 mg/kg CsA i.p. in mice significantly increased the intensity of convulsions induced by an intracerebroventricular injection of bicuculline 25 pmol (Fujisaki et al., 2002). In mice with kainate-induced mesial temporal lobe epilepsy, on the other hand, CsA could significantly reduce the number of spontaneous recurrent seizures (Jung et al., 2012). Furthermore, CsA and TAC showed antiepileptic influences when administered to rats with pilocarpin-induced status epilepticus (Setkowicz and Ciarach, 2007). Chronic, systemic administration of CsA in rats resulted in elevated levels of anxiety-like behavior (von Horsten et al., 1998), which has recently been shown to be attributed to decreased calcineurin activity in the amygdala (Mineur et al., 2014). Similarly, chronic microinjection of CsA or FK506 into the medial prefrontal cortex (mPFC) increased depressive-like behaviors in rats via decreased mTOR activity, reversible by NMDA or the antidepressant venlafaxine (Yu et al., 2013). Similarly, it was demonstrated in rats that acute systemic administration of CsA caused changes in neuronal activity in amygdala neurons by a direct effect of this CNI.

€ sche, K., et al., Neurobehavioral consequences of small molecule-drug immunosuppression, Please cite this article in press as: Bo Neuropharmacology (2014), http://dx.doi.org/10.1016/j.neuropharm.2014.12.008

€sche et al. / Neuropharmacology xxx (2014) 1e11 K. Bo

More specific, total EEG power and cFOS expression were significantly elevated in rats' central nucleus of the amygdala and insular cortex two hours after one single i.p. injection with CsA (20 mg/kg). Moreover, administration of CsA induced a significant increase in mRNA expression of inflammatory cytokines (IL1-b, TNFa, IFNg) in the amygdala as well as an increased release of noradrenaline 2e6 h after acute peripheral CsA administration (Pacheco-Lopez et al., 2013). In a different study, high dose treatment with CsA in mice was shown to decrease the release of the neurotransmitters serotonin and dopamine, increased anxiety-like behavior and disturbed social behavior (Sato et al., 2007). Duruibe et al. (1990) found a selective depletion of glutathione in the rats' brain that they suspected to contribute to some of the neurological side effects of CsA. Several lines of evidence indicate that altered calcineurin signaling could comprise an important contributing factor in schizophrenia pathogenesis. The spectrum of forebrain-specific abnormalities in CN mutant mice is strikingly similar to that observed in schizophrenia patients. Therefore, CN mutant mice may even provide a novel schizophrenia mouse model (Miyakawa et al., 2003). Moreover, CsA seems to induce neurotoxic effects, as it lowers seizure threshold in patients and probably increases susceptibility to seizures in rodents, even at relatively low doses (Racusen et al., 1988, 1990). 2.2. mTOR inhibitors: mechanisms of action and therapeutic use Sirolimus, also known as rapamycin, is an immunosuppressant and anti-proliferative drug widely used in organ transplantation (Murgia et al., 1996; Vezina et al., 1975), that, like its derivates temsirolimus (or CCI-779) and everolimus, acts as inhibitor of the mammalian target of rapamycin (mTOR). mTOR is a serine/threonine protein kinase and a member of the phosphatidyl inositol 30 kinase (PI3K) family, known to play an important role in cell growth and proliferation (Aoki et al., 2001; Chong et al., 2010; Schmelzle and Hall, 2000; Sekulic et al., 2000). The mechanism of action is not completely understood yet, but sirolimus for example is assumed to form a complex with the FK binding protein 12 (FKBP12) that in turn inhibits mTOR and interleukin-2-driven T-cell proliferation (Guertin and Sabatini, 2009). Dysregulation of mTOR signaling occurs in various human tumors, and has been associated with cancer pathogenesis, disease progression, and treatment resistance. mTOR inhibitors block antigen-induced proliferation of T and B cells, antibody production (Sehgal, 2003), and exert broad anti-tumor activity in experimental animals as well as in cancer patients (Dancey, 2010; Guertin and Sabatini, 2009; Lane and Breuleux, 2009; Martin et al., 2013). 2.2.1. mTOR inhibitors: effects on CNS and neuropsychological functions in humans Due to the fact that cerebellar involvement has been demonstrated in neuropsychiatric conditions such as learning and memory, executive functioning, attention-deficit/hyperactivity disorder, autism spectrum disorders, and schizophrenia (O'Halloran et al., 2012), altered mTOR functioning in the cerebellum might also be of importance regarding neuropsychological side effects. However, beneficial outcomes of sirolimus on behavioral disturbances accompanying neurological diseases such as epilepsy, tuberous sclerosis complex, or traumatic brain injury have been documented (Cambiaghi et al., 2013; Chong et al., 2010; Ehninger, 2013; Erlich et al., 2007; Russo et al., 2012). mTOR signaling regulates transcription and protein synthesis and is implicated in synaptic plasticity and memory formation in the central nervous system (Hoeffer and Klann, 2010). Sirolimus-induced mTOR inhibition was observed to attenuate traumatic fear memory reconsolidation and also inhibited contextual fear memory (Blundell et al., 2008;

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Parsons et al., 2006). These interesting findings suggest that inhibition of mTOR signaling by sirolimus may be used as a potential therapeutic strategy for treating affective symptoms or anxiety accompanying neurological diseases (Chong et al., 2010; Cleary et al., 2008). Moreover, a clinical study described favorable psychiatric outcomes in transplant recipients observed after switching from treatment with CNIs to the mTOR inhibitor everolimus (Lang et al., 2009). Despite these proven beneficial effects of mTOR inhibitors and its widespread application in clinical conditions such as transplantation medicine and oncology, the knowledge of neuropsychological side effects of acute and chronic treatment in patients is surprisingly sparse. Improvements of psychiatric symptoms were reported after switching from treatment with the calcineurin inhibitor CsA to the mTOR inhibitor everolimus or after replacing tacrolimus by sirolimus, respectively (Forgacs et al., 2005; Lang et al., 2009). Thus, it is unclear whether the observed changes were just compensatory to the induced neuropsychiatric side effects known to occur during CsA treatment (Musselman et al., 2001). Contrary, single use of the mTOR inhibitor temsirolimus in tumor therapy has been shown to induce striking euphoria followed by melancholy, mimicking bipolar disorder in a large amount of patients. Importantly, these effects occurred in patients without a previous medical history of a psychiatric disorder (Raymond et al., 2004). Postmortem studies of patients with major depressive disorder revealed deficits in the mTOR signaling pathway in the prefrontal cortex (Jernigan et al., 2011). mTOR signaling in the brain appears to be particularly important since it is involved in processes contributing to nervous system physiology and pathology, in detail control of protein translation, local protein synthesis in dendrites and axons of neurons, autophagy and microtubule dynamics (Russo et al., 2012). 2.2.2. mTOR inhibitors: effects on CNS and neuropsychological functions in experimental animals Penetration of sirolimus into the brain has not extensively been studied, but data revealed that systemic administration in rodents result in increased drug concentrations in the brain as well as neurological effects (Beresford et al., 2012; Cleary et al., 2008). Moreover, a monkey lung transplant study could show that single daily oral doses (1.5 mg/kg for 4 weeks) of everolimus led to extremely high tissue concentrations of this compound and its metabolites in the cerebellum rather than in other parts of the brain (Serkova et al., 2000). Cambiaghi et al. (2013) showed that chronic sirolimus treatment in wild-type mice, starting from post-natal day (PND) 8 to PND 40, did not lead to depressive- or anxiety-like behavior. In vitro, sirolimus possesses neurotoxic potential at concentrations above, but close to those found in blood of sirolimus-treated patients and has synergistic neurotoxic effects in combination with CsA (Serkova et al., 1999). Recent investigations in rats demonstrated a temporal relationship between sirolimus-induced increment in neuronal amygdaloid activity, the occurrence of anxiety-like behavior, and a concomitantly running amygdaloid over-expression of anxietyrelated proteins KLK8 and FKBP51. Since mTOR signaling itself regulates transcription and protein synthesis in CNS, these results suggest that the acute neuronal and behavioral responses seen after systemic sirolimus are not directly attributed to mTOR inhibition but rather resulted from the activation of protein kinase pathways which are modulated by mTOR (Hadamitzky et al., 2014). mTOR inhibitors alter glucose metabolism in the brain of rodents via mTOR. This may play a crucial role for neurons that are mostly dependent on glycolysis (Christians et al., 2004; Klawitter et al., 2010). Moreover, decreased mTOR activity in rats led to depressive-like behavior that could be normalized by activation of

€ sche, K., et al., Neurobehavioral consequences of small molecule-drug immunosuppression, Please cite this article in press as: Bo Neuropharmacology (2014), http://dx.doi.org/10.1016/j.neuropharm.2014.12.008

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mTOR using the NMDA receptor antagonist ketamine, whereas in contrast, inhibition of mTOR by sirolimus reversed the antidepressant-like effect of ketamine (Tsai et al., 2013). Reduced phosphorylation of compounds of the mTOR pathway, for example after chronic unpredictable stress in rats, demonstrated an unfavorable effect on the amygdala signaling pathways and synaptic activity (Chandran et al., 2013). In mice, it has been shown that a single prenatally administered injection of sirolimus resulted in motor abnormalities and increased anxiety-related behaviors, both in early postnatal development and during adult stages (Tsai et al., 2013; Yu et al., 2013). 2.3. Inhibitors of nucleotide synthesis: mechanisms of action and therapeutic use Inhibitors of nucleotide synthesis that are used as immunosuppressants are mycophenolate mofetil (MMF) and leflunomide. MMF is the morpholinoethylester of mycophenolic acid (MPA). MPA inhibits the proliferation and clonal expansion of both B and T cells, thus disrupting antibody and cytotoxic T cell production (Mele and Halloran, 2000). MMF is usually administered in combination with cyclosporine or corticosteroids after kidney, heart or liver transplantation. Leflunomide is employed as a disease-modifying anti-rheumatic drug (DMARD). There are two hypothesized mechanisms of action: firstly, the reversible inhibition of the dihydroorotate dehydrogenase, a key enzyme in pyrimidine synthesis and secondly, the inhibition of tyrosine kinases (Ruckemann et al., 1998). The usage of leflunomide is indicated for the treatment in active rheumatoid arthritis. Leflunomide is used off-label as an immunosuppressant (Halloran, 2004). 2.3.1. Inhibitors of nucleotide synthesis: effects on CNS and neuropsychological functions in humans A phase I clinical trial showed that MMF was well tolerated in renal transplant patients at doses up to 3500 mg/day for up to two years. There was no correlation between the incidence of adverse effects and dose of MMF (Sollinger, 1995). The packages insert for MMF today reports depression as an adverse event. In this regard a case report of a 64-year-old woman describes the onset of a severe depressive disorder shortly after the start of therapy. The patient's depressive symptoms improved strikingly after only two days discontinuing therapy with MMF. The authors strongly suggest an assessment of psychological adverse events and further surveillance to characterize the relationship between depression and the use of MMF (Draper, 2008). Pinho de Oliveira Ribeiro et al. (2013) demonstrated in a study with 150 RA patients under different drug treatment that those treated with leflunomide showed less mental health impairment than otherwise treated groups of patients, indicating that leflunomide is a more efficient drug concerning the occurrence of psychiatric complications. 2.4. Antimetabolites: mechanisms of action and therapeutic use The DMARD azathioprine is a prodrug in rheumatoid arthritis that is converted to a purine analog and then incorporated into DNA. Thus, DNA synthesis and the subsequent proliferation of B or T cells are inhibited (Lindenfeld et al., 2004b). Azathioprine is also employed in renal homotransplantation to prevent graft rejection. Its anti-proliferative properties are less selective than those of MMF (Eugui et al., 1991; Platz et al., 1991; van Sandwijk et al., 2013). Another antimetabolite, methotrexate (MTX, formerly known as amethopterin), is a potent inhibitor of the enzyme dihydrofolate reductase and the production of thymidylate and purines. Due to this inhibition, MTX suppresses T-cell response and proliferation as well as expression of adhesion molecules (Nassar et al., 2014). It

was initially developed as a cytostatic agent for the treatment of oncological diseases and is now used for treatment of graft-versushost disease (GVHD). Moreover, low-dose MTX is an established and highly effective treatment in the management of arthritic and skin diseases, such as severe psoriasis and RA (Johnston et al., 2005; Kay and Westhovens, 2009; Kivity et al., 2014). 2.4.1. Antimetabolites: effects on CNS and neuropsychological functions in humans There are no reports on adverse side effects of azathioprine on CNS and behavior. In infants exposed to azathioprine in utero and via breastfeeding, age-appropriate mental development has been reported in a long-term follow-up study (Angelberger et al., 2011). However, RA patients treated with DMARDs have been shown to present with the highest rates of depression, anxiety and suicidal ideation compared to patients using methotrexate, leflunomide, hydroxychloroquine and biological drugs (Pinho de Oliveira Ribeiro et al., 2013). In the same study investigating the prevalence of anxiety, depression and suicidal ideation of different kinds of drugs used in RA, patients treated with MTX (together with those treated with leflunomide, see above) showed the lowest averages for the above mentioned categories, but had higher incidences of anxiety and depression compared to leflunomide-treated patients (Pinho de Oliveira Ribeiro et al., 2013). Even when given in low doses, MTX can have mild or severe side effects to the nervous system, such as mild symptoms of confusion, headache or difficulty in concentration as well as major central nervous system complications (Gonzalez-Suarez et al., 2014; Kivity et al., 2014; Wernick and Smith, 1989). In breast cancer patients, CMF chemotherapy (cyclophosphamide, MTX, and 5-Fluorouracil) has been shown to be associated with cognitive decline. This cognitive impairment ranges from very subtle to more severe and are observed in a wide range of brain functions, including memory, concentration, and speed of information processing (Kreukels et al., 2005), mostly discovered 2e6 years after treatment (Kreukels et al., 2005; Schagen et al., 1999), but can be noticed as early as 3 months after and up to 10 years after completion of cytotoxic treatment (Ahles et al., 2002). The nature of the cognitive impairment and the underlying mechanisms is fragmentary. However, a recent study revealed that patients following adjuvant chemotherapy displayed smaller gray and white matter volume in the prefrontal and parahippocampal gyrus 1 year after treatment, compared controls. Since this results correlated with impairments in attention, concentration and/or visual memory, it is suggested that treatment with certain antimetabolites have longterm neurodegenerating properties (Inagaki et al., 2007). 2.4.2. Antimetabolites: effects on CNS and neuropsychological functions in experimental animals Clinical studies have suggested that cognitive impairment in cancer patients which is attributed to chemotherapy also persists after treatment cessation. However, only a few animal studies examined possible side effects of treatment with antimetabolites or cytotoxic agents, mainly MTX. Even single high dose treatment with MTX (250 mg/kg i.p.) lead to long-lasting cognitive dysfunction in rats, such as impairments in short- and long term memory (Fardell et al., 2010). It is suggested that the behavioral outcome is attributed to retrograde amnesia, induced by a MTX-dependent decrease in hippocampal cell proliferation and white matter density (Seigers et al., 2009), since hippocampal cell proliferation is thought to be involved in learning and memory (Gould et al., 1999; Kempermann et al., 2004). In a different study (Gandal et al., 2008) male mice were given four, weekly injections of a combination of MTX (37.5 mg/kg) and 5FU (5-FU 75 mg/kg), components of the CMF regimen, frequently

€ sche, K., et al., Neurobehavioral consequences of small molecule-drug immunosuppression, Please cite this article in press as: Bo Neuropharmacology (2014), http://dx.doi.org/10.1016/j.neuropharm.2014.12.008

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used to treat human cancers. Here the treatment induced gating deficits, associated with a hyperactive response to fear conditioning and a reduced adaptation to novel objects, suggesting an additional component of emotional dysregulation. These findings suggest some degree of emotional dysregulation in chemotherapy-treated mice. However, a detailed review on chemotherapy-induced cognitive impairment in rodents is given by Seigers and Fardell (2011). 2.5. Sphingosin-1P-receptor-antagonist(s): mechanisms of action and therapeutic use Fingolimod (FTY720) is an oral therapeutic recently approved by the Food and Drug Administration (FDA) for use in relapsing MS. It has demonstrated efficacy in this disease superior to placebo as well as to interferon-beta, the most commonly used drug for MS treatment (Cohen et al., 2010; Kappos et al., 2010). Moreover, it is also used in phase III trials in renal transplantation (Halloran, 2004; Salvadori et al., 2006; Tedesco-Silva et al., 2006). FTY720 is phosphorylated by sphingosine kinases in vivo, whereas the active metabolite FTY720-P targets a new class of G-protein coupled receptors, termed S1P (Brinkmann et al., 2002). FTY720-P likely acts as a functional antagonist that down-modulates lymphocytic S1P1 receptors (Pham et al., 2008). This down-regulation is associated with the retention of central- but not effector memory T cells in lymphoid organs (Mehling et al., 2008). FTY720 crosses the bloodebrain barrier after oral and i.v. administration in rats and attains substantial concentrations in the CNS (Foster et al., 2007; Meno-Tetang et al., 2006). Since this drug readily penetrates the CNS in humans as well, (Brinkmann et al., 2010; Chun and Hartung, 2010; Cohen and Chun, 2011) it may also directly affect neuronal cells (Brinkmann et al., 2010; Miron et al., 2008). As it is highly effective in animal models of transplantation and synergistic in combination with other immunosuppressants, FTY720 is assigned to have significant potential as a new immunosuppressive treatment (Budde et al., 2002). 2.5.1. Sphingosin-1P-receptor-antagonist(s): effects on CNS and neuropsychological functions in humans In clinical studies, most reported side effects were as expected in a de novo transplant population with similar incidences of adverse events (Salvadori et al., 2006; Tedesco-Silva et al., 2006). The effects of FTY720 are also being investigated in patients with MS. However, the MS population differs considerably from the renal transplant population and the agent is used at lower doses than in the renal transplant setting (Budde et al., 2006). Although in a phase IIb study FTY720 combined with full dose CsA provided adequate protection from acute rejection, the safety profile was less favorable for adverse events than current standard immunosuppression in de novo renal transplant patients, since FTY720 was associated with higher incidences of bradycardia, respiratory disorders and lower creatinine clearances (Tedesco-Silva et al., 2007). While clinical trials have shown equivalent rates of depression in treatment and control groups (Scott, 2011), no report has been made of mania or psychosis directly associated with FTY720 treatment. Nevertheless, in July 2011 the German Arznei€ mittelkommission der deutschen Arzteschaft informed about depression and depressive symptoms occurring under MS therapy with Gilenya® (FTY720). Fitzpatrick et al. (2013) reported a case of a woman with relapsing-remitting MS and a short history of increasing manic and psychotic symptoms, whose treatment was switched from interferon-beta to FTY720 therapy. Subsequently, the commencement of FTY720 was associated with features, which are consistent with the emergence of a mixed affective psychosis. Recent evidence suggests that modification of T cell transmigration

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into the CNS may have an impact on neuroplastic processes, leading to psychiatric symptoms (Eyre and Baune, 2012). Regardless of the mechanism, these findings refer to the need for a careful monitoring of psychiatric symptoms when using FTY720, particularly in patients with previous mental health issues. 2.5.2. Sphingosin-1P-receptor-antagonist(s): effects on CNS and neuropsychological functions in experimental animals Currently, there are no reports on adverse side effects of FTY720 on CNS or behavior. Interestingly, a very recent study demonstrated, that phosphorylated FTY720 inhibits class I histone deacetylases (HDACs) in the hippocampus, resulting in enhanced LTP in hippocampal neurons and facilitated extinction of aversive memories without enhancing fear memory acquisition in mice. These findings suggest FTY720 as a more effective adjuvant therapy for eliminating aversive memories in, for example, posttraumatic stress disorder (PTSD), than other HDAC inhibitors (Hait et al., 2014). 2.6. Other small molecule-drugs: mechanisms of action and therapeutic use Cyclophosphamide is one of the most successful anti-cancer agents, approved by the FDA as the eighth cytotoxic anticancer agent in 1959. It is mostly used in combination therapies for the treatment of diverse cancers, in bone marrow transplantation, and for treatment of autoimmune disorders, such as MS (Emadi et al., 2009; Weiner and Cohen, 2002). Since cyclophosphamide is an inactive prodrug, its activation requires enzymatic and chemical activation to attain the wanted cytotoxic properties. After activation, the resultant nitrogen mustard produces inter- and intrastrand DNA crosslinks that account for its cytotoxic properties (Emadi et al., 2009). 2.6.1. Other small molecule-drugs: effects on CNS and neuropsychological functions in humans In general, chemotherapy in standard doses does not seem to cross the blood brain barrier even though it leads to cognitive function deficiencies, whose mechanisms are probably multifactorial (Jansen et al., 2005). In the summary of product characteristics (SPC) of cyclophosphamide, confusional states are reported as an adverse psychiatric event in very rare cases. Furthermore, various side effects on the nervous system are reported, such as occasionally occurring peripheral neuropathy, polyneuropathy or neuralgia, amongst others. As already stated (see Section 2.4.1.), CMF chemotherapy in breast cancer patients (cyclophosphamide, MTX, and 5Fluorouracil) has been shown to be associated with subtle or severe impairment of brain functioning, such as deficits in memory, concentration, or speed of information processing (Kreukels et al., 2005; Schagen et al., 1999). Standard dose systemic chemotherapy with FAC (5-fluorouracil, Adriamycin, and cyclophosphamide) is associated with a decline in cognitive function (including learning and memory, executive function, and processing speed) during and shortly after completion of chemotherapy in 65% of neuropsychologically evaluated breast cancer patients, together with a late cognitive decline in 61% of patients, with around a third of these patients showing new onset (Wefel et al., 2010). In a cyclophosphamide/doxorubicin (AC) combination therapy (alone or followed by a taxane), cognitive function in breast cancer patients was assessed prior to and after chemotherapy. Around half the women experienced a decline in a range of cognitive domains tested after the completion of chemotherapy, which returned to baseline level at 6 months in most of the cases suggesting that cognitive impairments might be a rather acute phenomenon

€ sche, K., et al., Neurobehavioral consequences of small molecule-drug immunosuppression, Please cite this article in press as: Bo Neuropharmacology (2014), http://dx.doi.org/10.1016/j.neuropharm.2014.12.008

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(Jansen et al., 2011). Overall, at four years post-chemotherapy, breast cancer patients that had received treatment with the different chemotherapeutic agents CTC (cyclophosphamide, thiotepa, and carboplatin), FEC (fluorouracil, epirubicin, and cyclophosphamide) and CMF were re-evaluated with neuropsychological tests, and an improvement in performance was found in all chemotherapy groups, suggesting that cognitive dysfunction following adjuvant chemotherapy in breast cancer patients might be transient (Schagen et al., 2002). Interestingly, an improvement of cognitive function was found in MS patients under cyclophosphamide/methylprednisolone treatment, probably as a result of cyclophosphamide, since studies on the treatment of MS also implicated a positive effect from this drug (Weiner and Cohen, 2002; Zephir et al., 2005). 2.6.2. Other small molecule-drugs: effects on CNS and neuropsychological functions in experimental animals In their review, Seigers and Fardell (2011) summarized the effects of chemotherapeutic treatment on cognition in experimental animals. The combination of cyclophosphamide and doxorubicin in female Sprague Dawley rats showed no effect on anxiety and passive avoidance behavior (Konat et al., 2008). Furthermore, no cognitive impairment could be demonstrated in a group of female fisher-344 rats under cyclophosphamide (or 5-fluorouracil, respectively) treatment (Lee et al., 2006). Macleod et al. (2007) found an impaired contextual fear memory in female ovariectomized Sprague Dawley rats, but no effect on cued-fear or acquisition of fear response. Furthermore, cyclophosphamide in male CF1 mice led to an impaired inhibitory avoidance, but still, there was no effect on anxiety behavior (Reiriz et al., 2006). Passive avoidance and novel memory ability were impaired in ICR mice after cyclophosphamide-treatment (Yang et al., 2010). Since then, several other studies have been published on the effects of cyclophosphamide on cognition in laboratory animals. Briones and Woods (2011) investigated the spatial learning, memory ability, and discrimination learning in female Wistar rats and found learning and memory impairment after CMF treatment, as well as a decreased hippocampal cell proliferation. Another study investigating the effects of cyclophosphamide on cognition and the survival and proliferation of newly generated hippocampal cells in male Lister-hooded rats reported that cyclophosphamide acutely reduced the survival of newly born hippocampal cells, but did not have a long-term effect on spatial working memory or hippocampal proliferation. The authors suggested that cyclophosphamide itself might be less neurotoxic than other chemotherapies with which cyclophosphamide is commonly used in combination therapy (Lyons et al., 2011). Clinically relevant doses of cyclophosphamide in athymic nude-rats were revealed to impair the cognitive ability of experimental animals performing the novel place recognition and the contextual fear conditioning tasks (Christie et al., 2012). In an investigation of cyclophosphamide/doxorubicin (AC) combination therapy in C57BL/6J mice, the authors could not find any evidence that AC treatment impaired performance on contextual fear conditioning or memory ability, one of the possible reasons being that mice are less vulnerable to chemotherapy, particularly AC combination treatment. The authors also critically stressed that the majority of studies were employing tumor-free subjects making a transfer to tumor patients even more difficult (Fremouw et al., 2012). 3. Future perspectives In the past five decades, immunosuppressive drugs have made transplantation and the treatment of cancer and autoimmune diseases indispensable life-saving therapies for many patients that

were facing death (Miller, 1996). Nonetheless, transplant patients have to cope with chronic health problems as a result of their medical history that were shown to lead to psychological stress, depression, anxiety and an overall reduced quality of life (Goetzmann et al., 2008a). However, the significance of the role of immunosuppressive compounds in this context is unknown. Understandably, physicians and researchers are more concerned about prolonging life in general than about quality of their patients' life. For recipient selection, it is recommended to do a neuropsychiatric evaluation with the transplant candidates (Toyoda et al., 2013), however psychological treatment is not an official adjunct therapy after transplantation. This matter is represented by the low number of publications regarding neurobehavioral consequences of patients, undergoing immunosuppressive therapy. Interestingly, heart and lung transplant patients getting intensive medical and psychosocial treatment, leading to significantly less worries about their transplanted organ, compared to liver or kidney recipients (Goetzmann et al., 2008b). This effect together with the growing knowledge about the mechanisms steering the nocebo effect (Bingel, 2014; Enck et al., 2013) implicates a positive outcome of psychological treatment for transplant patients, indicating that neuropsychological therapy should be considered an additional standard treatment. For the future, more animal studies need to be conducted, especially on those drugs with little or no known effects on the CNS and behavior (e.g. MMF or leflunomide). Moreover, the obtained findings from animal studies need to be investigated more intense in humans or other suitable in vitro models, as the translation from animals to humans is not an easy endeavor (Boraschi and PentonRol, 2013). Likewise, functional data (e.g. fMRI, neuropsychological testing) in healthy human subjects are required to clarify the genuine CNS effects of immunosuppressants and to be able to differentiate between these drug effects and the CNS effects of transplantation or the disease requesting transplantation or immunosuppressive therapy. With a better understanding of the human immune system, it should be possible to create suitable drugs that sustain immunotolerance in transplantation medicine and/or antiproliferative properties in cancer therapy without the known adverse effects reported here (van Sandwijk et al., 2013). Optimizing the pharmacodynamics of drugs might not only induce an even drug concentration over time, but will also improve the drug handling by the patients (e.g. one versus repeated drug intake), and might also reduce unwanted neurotoxic drug side effects. It could be favorable to personalize immunosuppression to the individual needs of the patient, implying genomic and transcriptomic profiling of distinct drug responses (Boraschi and Penton-Rol, 2013) as well as psychosocial therapy. Moreover, Pinho de Oliveira Ribeiro et al. (2013) pointed out that medical staff should be alerted of the fact that patients under immunosuppressive treatment will develop comorbid psychiatric conditions and that studies concerning the effects of the continuous use of prescription drugs on depression and anxiety are much-needed. Besides prolonging life, there should be a major focus on positive effects for the patients' quality of life. Acknowledgments This work was supported by a grant of the German Research Foundation (DFG) (Sche 341/19-1) and (Sche 341/19-2). References Adams, D.H., Ponsford, S., Gunson, B., Boon, A., Honigsberger, L., Williams, A., Buckels, J., Elias, E., McMaster, P., 1987. Neurological complications following liver transplantation. Lancet 1, 949e951.

€ sche, K., et al., Neurobehavioral consequences of small molecule-drug immunosuppression, Please cite this article in press as: Bo Neuropharmacology (2014), http://dx.doi.org/10.1016/j.neuropharm.2014.12.008

€sche et al. / Neuropharmacology xxx (2014) 1e11 K. Bo Ahles, T.A., Saykin, A.J., Furstenberg, C.T., Cole, B., Mott, L.A., Skalla, K., Whedon, M.B., Bivens, S., Mitchell, T., Greenberg, E.R., Silberfarb, P.M., 2002. Neuropsychologic impact of standard-dose systemic chemotherapy in longterm survivors of breast cancer and lymphoma. J. Clin. Oncol. 20, 485e493. Al-Massarani, G., Vacher-Coponat, H., Paul, P., Widemann, A., Arnaud, L., Loundou, A., Robert, S., Berland, Y., Dignat-George, F., Camoin-Jau, L., 2008. Impact of immunosuppressive treatment on endothelial biomarkers after kidney transplantation. Am. J. Transpl. 8, 2360e2367. Angelberger, S., Reinisch, W., Messerschmidt, A., Miehsler, W., Novacek, G., Vogelsang, H., Dejaco, C., 2011. Long-term follow-up of babies exposed to azathioprine in utero and via breastfeeding. J. Crohn's Colitis 5, 95e100. Aoki, M., Blazek, E., Vogt, P.K., 2001. A role of the kinase mTOR in cellular transformation induced by the oncoproteins P3k and Akt. Proc. Natl. Acad. Sci. U. S. A. 98, 136e141. Barnhart, K., Coutifaris, C., Esposito, M., 2001. The pharmacology of methotrexate. Expert Opin. Pharmacother 2, 409e417. Batiuk, T.D., Halloran, P.F., 1997. The downstream consequences of calcineurin inhibition. Transpl. Proc. 29, 1239e1240. Bechstein, W.O., 2000. Neurotoxicity of calcineurin inhibitors: impact and clinical management. Transpl. Int. 13, 313e326. Beresford, T., Fay, T., Serkova, N.J., Wu, P.H., 2012. Immunophyllin ligands show differential effects on alcohol self-administration in C57BL mice. J. Pharmacol. Exp. Ther. 341, 611e616. Bingel, U., 2014. Avoiding nocebo effects to optimize treatment outcome. JAMA 312, 693e694. Blundell, J., Kouser, M., Powell, C.M., 2008. Systemic inhibition of mammalian target of rapamycin inhibits fear memory reconsolidation. Neurobiol. Learn Mem. 90, 28e35. Boraschi, D., Penton-Rol, G., 2013. Perspectives in immunopharmacology: the future of immunosuppression. Immunol. Lett.. Borlongan, C.V., Emerich, D.F., Hoffer, B.J., Bartus, R.T., 2002. Bradykinin receptor agonist facilitates low-dose cyclosporine-A protection against 6hydroxydopamine neurotoxicity. Brain Res. 956, 211e220. Brinkmann, V., Billich, A., Baumruker, T., Heining, P., Schmouder, R., Francis, G., Aradhye, S., Burtin, P., 2010. Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis. Nat. Rev. Drug Discov. 9, 883e897. Brinkmann, V., Davis, M.D., Heise, C.E., Albert, R., Cottens, S., Hof, R., Bruns, C., Prieschl, E., Baumruker, T., Hiestand, P., Foster, C.A., Zollinger, M., Lynch, K.R., 2002. The immune modulator FTY720 targets sphingosine 1-phosphate receptors. J. Biol. Chem. 277, 21453e21457. Briones, T.L., Woods, J., 2011. Chemotherapy-induced cognitive impairment is associated with decreases in cell proliferation and histone modifications. BMC Neurosci. 12, 124. Bronster, D.J., Emre, S., Boccagni, P., Sheiner, P.A., Schwartz, M.E., Miller, C.M., 2000. Central nervous system complications in liver transplant recipientseincidence, timing, and long-term follow-up. Clin. Transpl. 14, 1e7. Bronster, D.J., Emre, S., Mor, E., Sheiner, P., Miller, C.M., Schwartz, M.E., 1994. Neurologic complications of orthotopic liver transplantation. Mt. Sinai J. Med. 61, 63e69. Budde, K., Schmouder, R.L., Brunkhorst, R., Nashan, B., Lucker, P.W., Mayer, T., Choudhury, S., Skerjanec, A., Kraus, G., Neumayer, H.H., 2002. First human trial of FTY720, a novel immunomodulator, in stable renal transplant patients. J. Am. Soc. Nephrol. 13, 1073e1083. Budde, K., Schutz, M., Glander, P., Peters, H., Waiser, J., Liefeldt, L., Neumayer, H.H., Bohler, T., 2006. FTY720 (fingolimod) in renal transplantation. Clin. Transpl. 20 (Suppl. 17), 17e24. Cambiaghi, M., Cursi, M., Magri, L., Castoldi, V., Comi, G., Minicucci, F., Galli, R., Leocani, L., 2013. Behavioural and EEG effects of chronic rapamycin treatment in a mouse model of tuberous sclerosis complex. Neuropharmacology 67, 1e7. Capuron, L., Ravaud, A., Gualde, N., Bosmans, E., Dantzer, R., Maes, M., Neveu, P.J., 2001. Association between immune activation and early depressive symptoms in cancer patients treated with interleukin-2-based therapy. Psychoneuroendocrinology 26, 797e808. Chandran, A., Iyo, A.H., Jernigan, C.S., Legutko, B., Austin, M.C., Karolewicz, B., 2013. Reduced phosphorylation of the mTOR signaling pathway components in the amygdala of rats exposed to chronic stress. Prog. Neuropsychopharmacol. Biol. Psychiatry 40, 240e245. Chang, S.H., Lim, C.S., Low, T.S., Chong, H.T., Tan, S.Y., 2001. Cyclosporine-associated encephalopathy: a case report and literature review. Transpl. Proc. 33, 3700e3701. Chong, Z.Z., Shang, Y.C., Zhang, L., Wang, S., Maiese, K., 2010. Mammalian target of rapamycin: hitting the bull's-eye for neurological disorders. Oxid. Med. Cell Longev. 3, 374e391. Christians, U., Gottschalk, S., Miljus, J., Hainz, C., Benet, L.Z., Leibfritz, D., Serkova, N., 2004. Alterations in glucose metabolism by cyclosporine in rat brain slices link to oxidative stress: interactions with mTOR inhibitors. Br. J. Pharmacol. 143, 388e396. Christie, L.A., Acharya, M.M., Parihar, V.K., Nguyen, A., Martirosian, V., Limoli, C.L., 2012. Impaired cognitive function and hippocampal neurogenesis following cancer chemotherapy. Clin. Cancer Res. 18, 1954e1965. Chun, J., Hartung, H.P., 2010. Mechanism of action of oral fingolimod (FTY720) in multiple sclerosis. Clin. Neuropharmacol. 33, 91e101. Cleary, C., Linde, J.A., Hiscock, K.M., Hadas, I., Belmaker, R.H., Agam, G., FlaisherGrinberg, S., Einat, H., 2008. Antidepressive-like effects of rapamycin in animal

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models: implications for mTOR inhibition as a new target for treatment of affective disorders. Brain Res. Bull. 76, 469e473. Cohen, J.A., Barkhof, F., Comi, G., Hartung, H.P., Khatri, B.O., Montalban, X., Pelletier, J., Capra, R., Gallo, P., Izquierdo, G., Tiel-Wilck, K., de Vera, A., Jin, J., Stites, T., Wu, S., Aradhye, S., Kappos, L., 2010. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N. Engl. J. Med. 362, 402e415. Cohen, J.A., Chun, J., 2011. Mechanisms of fingolimod's efficacy and adverse effects in multiple sclerosis. Ann. Neurol. 69, 759e777. Dancey, J., 2010. mTOR signaling and drug development in cancer. Nat. Rev. Clin. Oncol. 7, 209e219. Dantzer, R., Meagher, M.W., Cleeland, C.S., 2012. Translational approaches to treatment-induced symptoms in cancer patients. Nat. Rev. Clin. Oncol. 9, 414e426. de Groen, P.C., Aksamit, A.J., Rakela, J., Forbes, G.S., Krom, R.A., 1987. Central nervous system toxicity after liver transplantation. The role of cyclosporine and cholesterol. N. Engl. J. Med. 317, 861e866. Draper, H.M., 2008. Depressive disorder associated with mycophenolate mofetil. Pharmacotherapy 28, 136e139. Duruibe, V.A., Okonmah, A., Panton, L., Blyden, G.T., 1990. Effect of cyclosporin A on rat kidney catecholamines. Life Sci. 47, 255e261. Ehninger, D., 2013. From genes to cognition in tuberous sclerosis: implications for mTOR inhibitor-based treatment approaches. Neuropharmacology 68, 97e105. Emadi, A., Jones, R.J., Brodsky, R.A., 2009. Cyclophosphamide and cancer: golden anniversary. Nat. Rev. Clin. Oncol. 6, 638e647. Enck, P., Bingel, U., Schedlowski, M., Rief, W., 2013. The placebo response in medicine: minimize, maximize or personalize? Nat. Rev. Drug Discov. 12, 191e204. Erlich, S., Alexandrovich, A., Shohami, E., Pinkas-Kramarski, R., 2007. Rapamycin is a neuroprotective treatment for traumatic brain injury. Neurobiol. Dis. 26, 86e93. Eugui, E.M., Almquist, S.J., Muller, C.D., Allison, A.C., 1991. Lymphocyte-selective cytostatic and immunosuppressive effects of mycophenolic acid in vitro: role of deoxyguanosine nucleotide depletion. Scand. J. Immunol. 33, 161e173. Eyre, H., Baune, B.T., 2012. Neuroplastic changes in depression: a role for the immune system. Psychoneuroendocrinology 37, 1397e1416. Famiglio, L., Racusen, L., Fivush, B., Solez, K., Fisher, R., 1989. Central nervous system toxicity of cyclosporine in a rat model. Transplantation 48, 316e321. Fardell, J.E., Vardy, J., Logge, W., Johnston, I., 2010. Single high dose treatment with methotrexate causes long-lasting cognitive dysfunction in laboratory rodents. Pharmacol. Biochem. Behav. 97, 333e339. Fitzpatrick, A., Clark, S.R., Newcombe, R., Davis, A., Baune, B.T., 2013. Fingolimod exacerbated affective psychosis? Aust. N. Z. J. Psychiatry 47, 399e400. Forgacs, B., Merhav, H.J., Lappin, J., Mieles, L., 2005. Successful conversion to rapamycin for calcineurin inhibitor-related neurotoxicity following liver transplantation. Transpl. Proc. 37, 1912e1914. Foster, C.A., Howard, L.M., Schweitzer, A., Persohn, E., Hiestand, P.C., Balatoni, B., Reuschel, R., Beerli, C., Schwartz, M., Billich, A., 2007. Brain penetration of the oral immunomodulatory drug FTY720 and its phosphorylation in the central nervous system during experimental autoimmune encephalomyelitis: consequences for mode of action in multiple sclerosis. J. Pharmacol. Exp. Ther. 323, 469e475. Fremouw, T., Fessler, C.L., Ferguson, R.J., Burguete, Y., 2012. Preserved learning and memory in mice following chemotherapy: 5-Fluorouracil and doxorubicin single agent treatment, doxorubicin-cyclophosphamide combination treatment. Behav. Brain Res. 226, 154e162. Fujisaki, Y., Yamauchi, A., Dohgu, S., Sunada, K., Yamaguchi, C., Oishi, R., Kataoka, Y., 2002. Cyclosporine A-increased nitric oxide production in the rat dorsal hippocampus mediates convulsions. Life Sci. 72, 549e556. Gandal, M.J., Ehrlichman, R.S., Rudnick, N.D., Siegel, S.J., 2008. A novel electrophysiological model of chemotherapy-induced cognitive impairments in mice. Neuroscience 157, 95e104. Gettings, L., 2010. Psychological well-being in rheumatoid arthritis: a review of the literature. Musculoskelet. Care 8, 99e106. Goetzmann, L., Ruegg, L., Stamm, M., Ambuhl, P., Boehler, A., Halter, J., Muellhaupt, B., Noll, G., Schanz, U., Wagner-Huber, R., Spindler, A., Buddeberg, C., Klaghofer, R., 2008a. Psychosocial profiles after transplantation: a 24-month follow-up of heart, lung, liver, kidney and allogeneic bone-marrow patients. Transplantation 86, 662e668. Goetzmann, L., Sarac, N., Ambuhl, P., Boehler, A., Irani, S., Muellhaupt, B., Noll, G., Schleuniger, M., Schwegler, K., Buddeberg, C., Klaghofer, R., 2008b. Psychological response and quality of life after transplantation: a comparison between heart, lung, liver and kidney recipients. Swiss Med. Wkly. 138, 477e483. Gonzalez-Suarez, I., Aguilar-Amat, M.J., Trigueros, M., Borobia, A.M., Cruz, A., Arpa, J., 2014. Leukoencephalopathy due to oral methotrexate. Cerebellum 13, 178e183. Gould, E., Beylin, A., Tanapat, P., Reeves, A., Shors, T.J., 1999. Learning enhances adult neurogenesis in the hippocampal formation. Nat. Neurosci. 2, 260e265. Guertin, D.A., Sabatini, D.M., 2009. The pharmacology of mTOR inhibition. Sci. Signal 2, pe24. Hadamitzky, M., Herring, A., Keyvani, K., Doenlen, R., Krugel, U., Bosche, K., Orlowski, K., Engler, H., Schedlowski, M., 2014. Acute systemic rapamycin induces neurobehavioral alterations in rats. Behav. Brain Res. 273C, 16e22. Hait, N.C., Wise, L.E., Allegood, J.C., O'Brien, M., Avni, D., Reeves, T.M., Knapp, P.E., Lu, J., Luo, C., Miles, M.F., Milstien, S., Lichtman, A.H., Spiegel, S., 2014. Active, phosphorylated fingolimod inhibits histone deacetylases and facilitates fear extinction memory. Nat. Neurosci. 17, 971e980.

€ sche, K., et al., Neurobehavioral consequences of small molecule-drug immunosuppression, Please cite this article in press as: Bo Neuropharmacology (2014), http://dx.doi.org/10.1016/j.neuropharm.2014.12.008

10

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Haley, P.J., 2012. Small molecule immunomodulatory drugs: challenges and approaches for balancing efficacy with toxicity. Toxicol. Pathol. 40, 261e266. Halloran, P.F., 2004. Immunosuppressive drugs for kidney transplantation. N. Engl. J. Med. 351, 2715e2729. Herink, J., Krejcova, G., Bajgar, J., Svoboda, Z., Kvetina, J., Zivnu, P., Palicka, V., 2003. Cyclosporine A inhibits acetylcholinesterase activity in selected parts of the rat brain. Neurosci. Lett. 339, 251e253. Hoeffer, C.A., Klann, E., 2010. mTOR signaling: at the crossroads of plasticity, memory and disease. Trends Neurosci. 33, 67e75. Hotson, J.R., Pedley, T.A., 1976. The neurological complications of cardiac transplantation. Brain 99, 673e694. Inagaki, M., Yoshikawa, E., Matsuoka, Y., Sugawara, Y., Nakano, T., Akechi, T., Wada, N., Imoto, S., Murakami, K., Uchitomi, Y., 2007. Smaller regional volumes of brain gray and white matter demonstrated in breast cancer survivors exposed to adjuvant chemotherapy. Cancer 109, 146e156. Jansen, C., Miaskowski, C., Dodd, M., Dowling, G., Kramer, J., 2005. Potential mechanisms for chemotherapy-induced impairments in cognitive function. Oncol. Nurs. Forum 32, 1151e1163. Jansen, C.E., Cooper, B.A., Dodd, M.J., Miaskowski, C.A., 2011. A prospective longitudinal study of chemotherapy-induced cognitive changes in breast cancer patients. Support Care Cancer 19, 1647e1656. Jernigan, C.S., Goswami, D.B., Austin, M.C., Iyo, A.H., Chandran, A., Stockmeier, C.A., Karolewicz, B., 2011. The mTOR signaling pathway in the prefrontal cortex is compromised in major depressive disorder. Prog. Neuropsychopharmacol. Biol. Psychiatry 35, 1774e1779. Johnston, A., Gudjonsson, J.E., Sigmundsdottir, H., Ludviksson, B.R., Valdimarsson, H., 2005. The anti-inflammatory action of methotrexate is not mediated by lymphocyte apoptosis, but by the suppression of activation and adhesion molecules. Clin. Immunol. 114, 154e163. Jung, S., Yang, H., Kim, B.S., Chu, K., Lee, S.K., Jeon, D., 2012. The immunosuppressant cyclosporin A inhibits recurrent seizures in an experimental model of temporal lobe epilepsy. Neurosci. Lett. 529, 133e138. Kahan, B.D., 1994. Role of cyclosporine: present and future. Transpl. Proc. 26, 3082e3087. Kahan, B.D., Flechner, S.M., Lorber, M.I., Golden, D., Conley, S., Van Buren, C.T., 1987. Complications of cyclosporine-prednisone immunosuppression in 402 renal allograft recipients exclusively followed at a single center for from one to five years. Transplantation 43, 197e204. Kappos, L., Radue, E.W., O'Connor, P., Polman, C., Hohlfeld, R., Calabresi, P., Selmaj, K., Agoropoulou, C., Leyk, M., Zhang-Auberson, L., Burtin, P., 2010. A placebocontrolled trial of oral fingolimod in relapsing multiple sclerosis. N. Engl. J. Med. 362, 387e401. Kay, J., Westhovens, R., 2009. Methotrexate: the gold standard without standardisation. Ann. Rheum. Dis. 68, 1081e1082. Kempermann, G., Wiskott, L., Gage, F.H., 2004. Functional significance of adult neurogenesis. Curr. Opin. Neurobiol. 14, 186e191. Kim, H.J., Barsevick, A.M., Fang, C.Y., Miaskowski, C., 2012. Common biological pathways underlying the psychoneurological symptom cluster in cancer patients. Cancer Nurs. 35, E1eE20. Kivity, S., Zafrir, Y., Loebstein, R., Pauzner, R., Mouallem, M., Mayan, H., 2014. Clinical characteristics and risk factors for low dose methotrexate toxicity: a cohort of 28 patients. Autoimmun. Rev.. Klawitter, J., Gottschalk, S., Hainz, C., Leibfritz, D., Christians, U., Serkova, N.J., 2010. Immunosuppressant neurotoxicity in rat brain models: oxidative stress and cellular metabolism. Chem. Res. Toxicol. 23, 608e619. Konat, G.W., Kraszpulski, M., James, I., Zhang, H.T., Abraham, J., 2008. Cognitive dysfunction induced by chronic administration of common cancer chemotherapeutics in rats. Metab. Brain Dis. 23, 325e333. Kreukels, B.P., Schagen, S.B., Ridderinkhof, K.R., Boogerd, W., Hamburger, H.L., van Dam, F.S., 2005. Electrophysiological correlates of information processing in breast-cancer patients treated with adjuvant chemotherapy. Breast Cancer Res. Treat. 94, 53e61. Lane, H.A., Breuleux, M., 2009. Optimal targeting of the mTORC1 kinase in human cancer. Curr. Opin. Cell Biol. 21, 219e229. Lang, U.E., Heger, J., Willbring, M., Domula, M., Matschke, K., Tugtekin, S.M., 2009. Immunosuppression using the mammalian target of rapamycin (mTOR) inhibitor everolimus: pilot study shows significant cognitive and affective improvement. Transpl. Proc. 41, 4285e4288. Lee, G.D., Longo, D.L., Wang, Y., Rifkind, J.M., Abdul-Raman, L., Mamczarz, J.A., Duffy, K.B., Spangler, E.L., Taub, D.D., Mattson, M.P., Ingram, D.K., 2006. Transient improvement in cognitive function and synaptic plasticity in rats following cancer chemotherapy. Clin. Cancer Res. 12, 198e205. Lindenfeld, J., Miller, G.G., Shakar, S.F., Zolty, R., Lowes, B.D., Wolfel, E.E., Mestroni, L., Page 2nd, R.L., Kobashigawa, J., 2004a. Drug therapy in the heart transplant recipient: part I: cardiac rejection and immunosuppressive drugs. Circulation 110, 3734e3740. Lindenfeld, J., Miller, G.G., Shakar, S.F., Zolty, R., Lowes, B.D., Wolfel, E.E., Mestroni, L., Page 2nd, R.L., Kobashigawa, J., 2004b. Drug therapy in the heart transplant recipient: part II: immunosuppressive drugs. Circulation 110, 3858e3865. Lyons, L., Elbeltagy, M., Bennett, G., Wigmore, P., 2011. The effects of cyclophosphamide on hippocampal cell proliferation and spatial working memory in rat. PLoS One 6, e21445.

Macleod, J.E., DeLeo, J.A., Hickey, W.F., Ahles, T.A., Saykin, A.J., Bucci, D.J., 2007. Cancer chemotherapy impairs contextual but not cue-specific fear memory. Behav. Brain Res. 181, 168e172. Martin, L.A., Andre, F., Campone, M., Bachelot, T., Jerusalem, G., 2013. mTOR inhibitors in advanced breast cancer: ready for prime time? Cancer Treat. Rev. 39, 742e752. Mateen, F.J., Dierkhising, R.A., Rabinstein, A.A., van de Beek, D., Wijdicks, E.F., 2010. Neurological complications following adult lung transplantation. Am. J. Transpl. 10, 908e914. Mehling, M., Brinkmann, V., Antel, J., Bar-Or, A., Goebels, N., Vedrine, C., Kristofic, C., Kuhle, J., Lindberg, R.L., Kappos, L., 2008. FTY720 therapy exerts differential effects on T cell subsets in multiple sclerosis. Neurology 71, 1261e1267. Mele, T.S., Halloran, P.F., 2000. The use of mycophenolate mofetil in transplant recipients. Immunopharmacology 47, 215e245. Meno-Tetang, G.M., Li, H., Mis, S., Pyszczynski, N., Heining, P., Lowe, P., Jusko, W.J., 2006. Physiologically based pharmacokinetic modeling of FTY720 (2-amino-2 [2-(-4-octylphenyl)ethyl]propane-1,3-diol hydrochloride) in rats after oral and intravenous doses. Drug Metab. Dispos. 34, 1480e1487. Merill, P.W., 1956. Walter S. Adams, Observer of Sun and Stars. Science 124, 67. Miller, A.H., Ancoli-Israel, S., Bower, J.E., Capuron, L., Irwin, M.R., 2008. Neuroendocrine-immune mechanisms of behavioral comorbidities in patients with cancer. J. Clin. Oncol. 26, 971e982. Miller, L.W., 1996. Cyclosporine-associated neurotoxicity. The need for a better guide for immunosuppressive therapy. Circulation 94, 1209e1211. Mineur, Y.S., Taylor, S.R., Picciotto, M.R., 2014. Calcineurin downregulation in the amygdala is sufficient to induce anxiety-like and depression-like behaviors in C57BL/6J male mice. Biol. Psychiatry 75, 991e998. Miron, V.E., Hall, J.A., Kennedy, T.E., Soliven, B., Antel, J.P., 2008. Cyclical and dosedependent responses of adult human mature oligodendrocytes to fingolimod. Am. J. Pathol. 173, 1143e1152. Miyakawa, T., Leiter, L.M., Gerber, D.J., Gainetdinov, R.R., Sotnikova, T.D., Zeng, H., Caron, M.G., Tonegawa, S., 2003. Conditional calcineurin knockout mice exhibit multiple abnormal behaviors related to schizophrenia. Proc. Natl. Acad. Sci. U. S. A. 100, 8987e8992. Murgia, M.G., Jordan, S., Kahan, B.D., 1996. The side effect profile of sirolimus: a phase I study in quiescent cyclosporine-prednisone-treated renal transplant patients. Kidney Int. 49, 209e216. Musselman, D.L., Lawson, D.H., Gumnick, J.F., Manatunga, A.K., Penna, S., Goodkin, R.S., Greiner, K., Nemeroff, C.B., Miller, A.H., 2001. Paroxetine for the prevention of depression induced by high-dose interferon alfa. N. Engl. J. Med. 344, 961e966. Nassar, A., Elgohary, G., Elhassan, T., Nurgat, Z., Mohamed, S.Y., Aljurf, M., 2014. Methotrexate for the treatment of graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. J. Transpl. 2014, 980301. O'Halloran, C.J., Kinsella, G.J., Storey, E., 2012. The cerebellum and neuropsychological functioning: a critical review. J. Clin. Exp. Neuropsychol. 34, 35e56. Pacheco-Lopez, G., Doenlen, R., Krugel, U., Arnold, M., Wirth, T., Riether, C., Engler, A., Niemi, M.B., Christians, U., Engler, H., Schedlowski, M., 2013. Neurobehavioural activation during peripheral immunosuppression. Int. J. Neuropsychopharmacol. 16, 137e149. Palmer, B.F., Toto, R.D., 1991. Severe neurologic toxicity induced by cyclosporine A in three renal transplant patients. Am. J. Kidney Dis. 18, 116e121. Parsons, R.G., Gafford, G.M., Helmstetter, F.J., 2006. Translational control via the mammalian target of rapamycin pathway is critical for the formation and stability of long-term fear memory in amygdala neurons. J. Neurosci. 26, 12977e12983. Pham, T.H., Okada, T., Matloubian, M., Lo, C.G., Cyster, J.G., 2008. S1P1 receptor signaling overrides retention mediated by G alpha i-coupled receptors to promote T cell egress. Immunity 28, 122e133. Pinho de Oliveira Ribeiro, N., Rafael de Mello Schier, A., Ornelas, A.C., Pinho de Oliveira, C.M., Nardi, A.E., Silva, A.C., 2013. Anxiety, depression and suicidal ideation in patients with rheumatoid arthritis in use of methotrexate, hydroxychloroquine, leflunomide and biological drugs. Compr. Psychiatry 54, 1185e1189. Platz, K.P., Sollinger, H.W., Hullett, D.A., Eckhoff, D.E., Eugui, E.M., Allison, A.C., 1991. RS-61443ea new, potent immunosuppressive agent. Transplantation 51, 27e31. Racusen, L.C., Famiglio, L.M., Fivush, B.A., Olton, D.S., Solez, K., 1988. Neurologic abnormalities and mortality in rats treated with cyclosporine A. Transpl. Proc. 20, 934e936. Racusen, L.C., McCrindle, B.W., Christenson, M., Fivush, B., Fisher, R.S., 1990. Cyclosporine lowers seizure threshold in an experimental model of electroshockinduced seizures in Munich-Wistar rats. Life Sci. 46, 1021e1026. Raymond, E., Alexandre, J., Faivre, S., Vera, K., Materman, E., Boni, J., Leister, C., Korth-Bradley, J., Hanauske, A., Armand, J.P., 2004. Safety and pharmacokinetics of escalated doses of weekly intravenous infusion of CCI-779, a novel mTOR inhibitor, in patients with cancer. J. Clin. Oncol. 22, 2336e2347. Reiriz, A.B., Reolon, G.K., Preissler, T., Rosado, J.O., Henriques, J.A., Roesler, R., Schwartsmann, G., 2006. Cancer chemotherapy and cognitive function in rodent models: memory impairment induced by cyclophosphamide in mice. Clin. Cancer Res. 12, 5000 author reply 5000e5001. Ruckemann, K., Fairbanks, L.D., Carrey, E.A., Hawrylowicz, C.M., Richards, D.F., Kirschbaum, B., Simmonds, H.A., 1998. Leflunomide inhibits pyrimidine de novo synthesis in mitogen-stimulated T-lymphocytes from healthy humans. J. Biol. Chem. 273, 21682e21691.

€ sche, K., et al., Neurobehavioral consequences of small molecule-drug immunosuppression, Please cite this article in press as: Bo Neuropharmacology (2014), http://dx.doi.org/10.1016/j.neuropharm.2014.12.008

€sche et al. / Neuropharmacology xxx (2014) 1e11 K. Bo Russo, E., Citraro, R., Constanti, A., De Sarro, G., 2012. The mTOR signaling pathway in the brain: focus on epilepsy and epileptogenesis. Mol. Neurobiol. 46, 662e681. Salvadori, M., Budde, K., Charpentier, B., Klempnauer, J., Nashan, B., Pallardo, L.M., Eris, J., Schena, F.P., Eisenberger, U., Rostaing, L., Hmissi, A., Aradhye, S., 2006. FTY720 versus MMF with cyclosporine in de novo renal transplantation: a 1year, randomized controlled trial in Europe and Australasia. Am. J. Transpl. 6, 2912e2921. Saner, F.H., Sotiropoulos, G.C., Gu, Y., Paul, A., Radtke, A., Gensicke, J., Kavuk, I., Malago, M., Broelsch, C.E., 2007. Severe neurological events following liver transplantation. Arch. Med. Res. 38, 75e79. Sato, Y., Takayanagi, Y., Onaka, T., Kobayashi, E., 2007. Impact of cyclosporine upon emotional and social behavior in mice. Transplantation 83, 1365e1370. Schagen, S.B., Muller, M.J., Boogerd, W., Rosenbrand, R.M., van Rhijn, D., Rodenhuis, S., van Dam, F.S., 2002. Late effects of adjuvant chemotherapy on cognitive function: a follow-up study in breast cancer patients. Ann. Oncol. 13, 1387e1397. Schagen, S.B., van Dam, F.S., Muller, M.J., Boogerd, W., Lindeboom, J., Bruning, P.F., 1999. Cognitive deficits after postoperative adjuvant chemotherapy for breast carcinoma. Cancer 85, 640e650. Schmelzle, T., Hall, M.N., 2000. TOR, a central controller of cell growth. Cell 103, 253e262. Scott, L.J., 2011. Fingolimod: a review of its use in the management of relapsingremitting multiple sclerosis. CNS Drugs 25, 673e698. Sehgal, S.N., 2003. Sirolimus: its discovery, biological properties, and mechanism of action. Transpl. Proc. 35, 7Se14S. Seigers, R., Timmermans, J., van der Horn, H.J., de Vries, E.F., Dierckx, R.A., Visser, L., Schagen, S.B., van Dam, F.S., Koolhaas, J.M., Buwalda, B., 2010. Methotrexate reduces hippocampal blood vessel density and activates microglia in rats but does not elevate central cytokine release. Behav. Brain Res. 207, 265e272. Seigers, R., Fardell, J.E., 2011. Neurobiological basis of chemotherapy-induced cognitive impairment: a review of rodent research. Neurosci. Biobehav. Rev. 35, 729e741. Seigers, R., Schagen, S.B., Beerling, W., Boogerd, W., van Tellingen, O., van Dam, F.S., Koolhaas, J.M., Buwalda, B., 2008. Long-lasting suppression of hippocampal cell proliferation and impaired cognitive performance by methotrexate in the rat. Behav. Brain Res. 186, 168e175. Seigers, R., Schagen, S.B., Coppens, C.M., van der Most, P.J., van Dam, F.S., Koolhaas, J.M., Buwalda, B., 2009. Methotrexate decreases hippocampal cell proliferation and induces memory deficits in rats. Behav. Brain Res. 201, 279e284. Sekulic, A., Hudson, C.C., Homme, J.L., Yin, P., Otterness, D.M., Karnitz, L.M., Abraham, R.T., 2000. A direct linkage between the phosphoinositide 3-kinaseAKT signaling pathway and the mammalian target of rapamycin in mitogenstimulated and transformed cells. Cancer Res. 60, 3504e3513. Serkova, N., Hausen, B., Berry, G.J., Jacobsen, W., Benet, L.Z., Morris, R.E., Christians, U., 2000. Tissue distribution and clinical monitoring of the novel macrolide immunosuppressant SDZ-RAD and its metabolites in monkey lung transplant recipients: interaction with cyclosporine. J. Pharmacol. Exp. Ther. 294, 323e332. Serkova, N., Litt, L., James, T.L., Sadee, W., Leibfritz, D., Benet, L.Z., Christians, U., 1999. Evaluation of individual and combined neurotoxicity of the immunosuppressants cyclosporine and sirolimus by in vitro multinuclear NMR spectroscopy. J. Pharmacol. Exp. Ther. 289, 800e806. Setkowicz, Z., Ciarach, M., 2007. Neuroprotectants FK-506 and cyclosporin A ameliorate the course of pilocarpine-induced seizures. Epilepsy Res. 73, 151e155.

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Sollinger, H.W., 1995. Mycophenolate mofetil. Kidney Int. Suppl. 52, S14eS17. Stein, D.P., Lederman, R.J., Vogt, D.P., Carey, W.D., Broughan, T.A., 1992. Neurological complications following liver transplantation. Ann. Neurol. 31, 644e649. Taylor, D.O., Barr, M.L., Meiser, B.M., Pham, S.M., Mentzer, R.M., Gass, A.L., 2001. Suggested guidelines for the use of tacrolimus in cardiac transplant recipients. J. Heart Lung Transpl. 20, 734e738. Tedesco-Silva, H., Pescovitz, M.D., Cibrik, D., Rees, M.A., Mulgaonkar, S., Kahan, B.D., Gugliuzza, K.K., Rajagopalan, P.R., Esmeraldo Rde, M., Lord, H., Salvadori, M., Slade, J.M., 2006. Randomized controlled trial of FTY720 versus MMF in de novo renal transplantation. Transplantation 82, 1689e1697. Tedesco-Silva, H., Szakaly, P., Shoker, A., Sommerer, C., Yoshimura, N., Schena, F.P., Cremer, M., Hmissi, A., Mayer, H., Lang, P., 2007. FTY720 versus mycophenolate mofetil in de novo renal transplantation: six-month results of a double-blind study. Transplantation 84, 885e892. Tedesco, D., Haragsim, L., 2012. Cyclosporine: a review. J. Transpl. 2012, 230386. Tombazzi, C.R., Waters, B., Shokouh-Amiri, M.H., Vera, S.R., Riely, C.A., 2006. Neuropsychiatric complications after liver transplantation: role of immunosuppression and hepatitis C. Dig. Dis. Sci. 51, 1079e1081. Toyoda, Y., Guy, T.S., Kashem, A., 2013. Present status and future perspectives of heart transplantation. Circ. J. 77, 1097e1110. Trullemans, F., Grignard, F., Van Camp, B., Schots, R., 2001. Clinical findings and magnetic resonance imaging in severe cyclosporine-related neurotoxicity after allogeneic bone marrow transplantation. Eur. J. Haematol. 67, 94e99. Tsai, P.T., Greene-Colozzi, E., Goto, J., Anderl, S., Kwiatkowski, D.J., Sahin, M., 2013. Prenatal rapamycin results in early and late behavioral abnormalities in wildtype C57BL/6 mice. Behav. Genet. 43, 51e59. van Sandwijk, M.S., Bemelman, F.J., Ten Berge, I.J., 2013. Immunosuppressive drugs after solid organ transplantation. Neth. J. Med. 71, 281e289. Vezina, C., Kudelski, A., Sehgal, S.N., 1975. Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle. J. Antibiot. (Tokyo) 28, 721e726. von Horsten, S., Exton, M.S., Voge, J., Schult, M., Nagel, E., Schmidt, R.E., Westermann, J., Schedlowski, M., 1998. Cyclosporine A affects open field behavior in DA rats. Pharmacol. Biochem. Behav. 60, 71e76. Wefel, J.S., Saleeba, A.K., Buzdar, A.U., Meyers, C.A., 2010. Acute and late onset cognitive dysfunction associated with chemotherapy in women with breast cancer. Cancer 116, 3348e3356. Weiner, H.L., Cohen, J.A., 2002. Treatment of multiple sclerosis with cyclophosphamide: critical review of clinical and immunologic effects. Mult. Scler. 8, 142e154. Wernick, R., Smith, D.L., 1989. Central nervous system toxicity associated with weekly low-dose methotrexate treatment. Arthritis Rheum. 32, 770e775. Wijdicks, E.F., 2001. Neurotoxicity of immunosuppressive drugs. Liver Transpl. 7, 937e942. Yang, M., Kim, J.S., Song, M.S., Kim, S.H., Kang, S.S., Bae, C.S., Kim, J.C., Wang, H., Shin, T., Moon, C., 2010. Cyclophosphamide impairs hippocampus-dependent learning and memory in adult mice: possible involvement of hippocampal neurogenesis in chemotherapy-induced memory deficits. Neurobiol. Learn Mem. 93, 487e494. Yu, J.J., Zhang, Y., Wang, Y., Wen, Z.Y., Liu, X.H., Qin, J., Yang, J.L., 2013. Inhibition of calcineurin in the prefrontal cortex induced depressive-like behavior through mTOR signaling pathway. Psychopharmacology (Berl.) 225, 361e372. Zephir, H., de Seze, J., Dujardin, K., Dubois, G., Cabaret, M., Bouillaguet, S., Ferriby, D., Stojkovic, T., Vermersch, P., 2005. One-year cyclophosphamide treatment combined with methylprednisolone improves cognitive dysfunction in progressive forms of multiple sclerosis. Mult. Scler. 11, 360e363.

€ sche, K., et al., Neurobehavioral consequences of small molecule-drug immunosuppression, Please cite this article in press as: Bo Neuropharmacology (2014), http://dx.doi.org/10.1016/j.neuropharm.2014.12.008