Thinking outside the brain for cognitive improvement: Is peripheral immunomodulation on the way?

Neuropharmacology xxx (2014) 1e11

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Invited review

Thinking outside the brain for cognitive improvement: Is peripheral immunomodulation on the way? Xiao Zheng a, b, *, Xueli Zhang c, An Kang d, Chongzhao Ran e, Guangji Wang b, Haiping Hao b, ** a

Nanjing University of Chinese Medicine Affiliated Hospital, Nanjing 210029, China State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China Zhong Da Hospital, Southeast University, Nanjing 210009, China d School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China e MGH/MIT/HMS Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital/Harvard Medical School, Boston 02129, United States b c

a b s t r a c t Keywords: Cognitive decline Neuroimmune interaction Brainegut axis Peripheral targets Gut microbiota CNS drug discovery

Cognitive impairment is a devastating condition commonly observed with normal aging and neurodegenerative disorders such as Alzheimer's Disease (AD). Although major efforts to prevent or slow down cognitive decline are largely focused within the central nervous system (CNS), it has become clear that signals from the systemic milieu are closely associated with the dysfunctional brain. In particular, the bidirectional crosstalk between the CNS and peripheral immune system plays a decisive role in shaping neuronal survival and function via neuroimmune, neuroendocrinal and bioenergetic mechanisms. Importantly, it is emerging that some neuroprotective and cognition-strengthening drugs may work by targeting the braineperiphery interactions, which could be intriguingly achieved without entering the CNS. We describe here how recent advances in dissecting cognitive deficits from a systems-perspective have contributed to a non-neurocentric understanding of its pathogenesis and treatment strategy. We also discuss the therapeutic and diagnostic implications of these exciting progresses and consider some key issues in the clinical translation. This article is part of a Special Issue entitled ‘Neuroimmunology and Synaptic Function’. © 2014 Elsevier Ltd. All rights reserved.

1. Introduction Cognitive decline is commonly observed with normal aging and neurological diseases. With an ever-expanding aging population, cognitive disability has now emerged as one of the greatest health threats worldwide (Bishop et al., 2010). Considered as exclusively a brain-centered disorder, cognitive disability is known to implicate global and regional disruptions in neurogenesis, synaptic coupling and neuronal circuits (Huang and Mucke, 2012; Kapogiannis and Mattson, 2011). Accordingly, major efforts in the past decades for the understanding of cognitive function as well as its decline have been directed toward the central nervous system (CNS), as has been extensively discussed (Benoit et al., 2011; Day and Sweatt, 2011;

* Corresponding author. Nanjing University of Chinese Medicine Affiliated Hospital, Nanjing 210029, China. Tel.: þ86 25 86529291; fax: þ86 25 86529290. ** Corresponding author. Tel./fax: þ86 25 83271060. E-mail addresses: [email protected], [email protected] (X. Zheng), [email protected] (H. Hao).

Lazarov et al., 2010). Not surprisingly, research efforts aimed at approaches to restore the cognitive ability or retard the devastating decline are largely centering within the brain (Bakker et al., 2012; Fischer et al., 2010; Sanchez et al., 2012; Verret et al., 2012). However, although important progresses have been made in understanding cognitive deficits under different contexts (Morrison and Baxter, 2012; van Praag, 2009; Whalley, 2008), the true etiology for this functional decline is largely elusive and currently there are no proven treatments. The brain is traditionally known to play an essential role in governing and coordinating systemic homeostasis. In recent years, it is also becoming clear that the health and disease of the brain are intimately associated with other physiological systems (Dantzer et al., 2008; Qureshi and Mehler, 2013). Remarkably, joint research efforts from the field of neuroscience, immunology and physiology have led to the realization that cognitive impairment has its pathological routes not restricted to the brain and the peripheral compartment is taking an active role in shaping the pathogenesis and progression of cognitive decline through multi-

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Please cite this article in press as: Zheng, X., et al., Thinking outside the brain for cognitive improvement: Is peripheral immunomodulation on the way?, Neuropharmacology (2014), http://dx.doi.org/10.1016/j.neuropharm.2014.06.020

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dimensional braineperiphery interconnections (Cryan and Dinan, 2012; Silver and Curley, 2013). Therefore, a much more complex picture has emerged concerning the exact pathological basis of cognitive deficits and many other neuropsychological disorders. These emerging findings have shed novel insights into cognitive dysfunctions and also raised a number of interesting questions on future preventive and therapeutic strategies. In this review, we firstly illustrate the emerging pathways that tightly couple the brain and cognitive function with the periphery. We then describe the excitingly new findings that prompt a systems-level view of cognitive deficits under neuropathological conditions and consider how aberrant braineperiphery interactions are involved. Subsequently, we present recent findings that support the therapeutic promise of targeting the peripheral system to cognitive deficits and several other brain disorders. Finally, we discuss potential opportunities for the treatment or amelioration of cognitive decline with a holistic approach, and also highlight several challenges for its clinical translation. We propose that a ‘systems-level’ view of cognitive decline may have a profound impact on how this medical challenge would be better understood and provide a framework for future therapeutic strategies. 2. Braineperiphery interaction pathways and cognitive regulation Investigations into the molecular mechanisms of brain diseases have been expanding over the past decades and an interesting picture has emerged that the interaction between the brain and periphery plays a decisive role in the pathogenesis, progression and outcome of various brain disorders (Cryan and Dinan, 2012; Liblau et al., 2013; Marchi et al., 2014; Qureshi and Mehler, 2013). To date, the underlying pathways whereby fine control of the interaction is exerted and how the highly regulated mechanisms get deranged remain incompletely answered. However, a great deal of data have provided important clues on how the brain and periphery communicate (Fig. 1), which also forms the conceptual framework for systems insights into cognitive impairment and other brain diseases. 2.1. Neuroimmune signaling and cognition The nervous system and immune system have co-evolved exquisite communication mechanisms and this bidirectional crosstalk tightly couples the brain homeostasis with the periphery. In recent years, there is increasing evidence that such an intricate interaction is critical for dictating a variety of nervous system functions, such as neurogenesis, synaptic formation and plasticity (Kipnis et al., 2012; Kohman and Rhodes, 2013). In relaying systemic immune signals to the brain, circulating cytokines and chemokines such as interleukin-6 (IL-6), tumor necrosis factor-a (TNFa) and CeC motif ligand 11 (CCL11) are known to play evolutionarily important roles (Dantzer et al., 2008; Villeda et al., 2011). In particular, several immune modulators and pathways have been identified to mediate the systemic effects on cognition (Kipnis et al., 2004; Tong et al., 2012; Youm et al., 2013). A recent study also contributed to the interesting finding that infusion of young blood to aged mice could effectively counteract and reverse pre-existing impairments in neurogenesis and cognition partially via activating the act cyclic AMP response element binding protein (Creb) in the aged hippocampus (Villeda et al., 2014). In regard to the downstream sensors and effectors, brain resident immune cells represent key players in shaping learning and cognitive functions (Barres, 2008; Silver and Curley, 2013). For example, microglia are highly dynamic surveillants of the immune cues from systemic infections (van Gool et al., 2010), peripheral organ injury (D'Mello et al., 2009) and chronic systemic inflammation (Drake et al.,

2011; Perry, 2004), which could translate to the secretion of a large plethora of molecules with neuroimmune activities (Rivest, 2009). To date, deregulation of microglia has been recognized as a key driver to the pathological events underlying learning and cognitive deficits such as neurodegeneration and impairment of hippocampal neurogenesis (Block et al., 2007; Ekdahl et al., 2003; Perry et al., 2010). The peripheral immune system is also under the feedback regulation of neural circuits that operate reflexively (Tracey, 2009). In this regard, the ‘cholinergic anti-inflammatory pathway’ (i.e., regulation of cytokine production at the periphery by the vagus nerve via acetylcholine) (Rosas-Ballina et al., 2008) and the innervations of sympathetic nerves to immune interfaces/organs (Straub et al., 2006) have received the most attention. Interestingly, studies in recent years have revealed that the brain exerts a fine control on peripheral pathologies such as diabetes (Shi et al., 2013), obesity (Lu et al., 2011) and tumor (Cao et al., 2010), thereby underscoring a previously unappreciated role of the brain on peripheral pathology. A more recent study also showed that nuclear factor-kappa B (NF-kB) activation in the hypothalamus mediated the development of systemic aging in mice (Zhang et al., 2013), which may form a vicious cycle with the central pathology to drive cognitive decline. Clearly, the neuroimmune interaction at the central and systemic level collectively plays a critical role in fine-tuning the microenvironment for neurogenesis and cognitive function. 2.2. Endocrinal signaling and cognition At the systems level, neuroendocrine plays an essential role in coordinating the whole-organism responses to external and internal factors. Via the neuroendocrinal connections, multiple organs are integrated together by sensing and secreting bioactive molecules like peptides and hormones (e.g., islet-derived insulin, adipocyte-secreted leptin, gut-derived ghrelin). As these circulating peptides and hormones are actively sensed and regulated by the central nervous networks, they are well-positioned to transmit the bidirectional signals between the brain and the systemic environment. In particular, the brain has evolved specific structures to sense the endocrinal signals, and neuroendocrinal homeostasis is essential in CNS development and functional integrity. Besides the regulation of food intake and energy metabolism, the endocrinal molecules are increasingly identified as messengers in immune and neuronal regulation, which are closely associated with behavior, emotion, learning and cognition (Fernandez and Torres-Aleman, 2012). Unsurprisingly, neuroendocrinal disturbances are closely implicated with diseases affecting the CNS and other systems. A typical example is glucocorticoid, the elevated level of which may evoke pathological signals in the brain especially the hippocampus (Frank et al., 2014). Of note, studies in both insulin deficient and resistant animals have linked diabetes to cognitive impairment resulting from glucocorticoid-mediated deficits in neurogenesis and synaptic plasticity. Meanwhile, glucocorticoid receptor blockade could normalize hippocampal alterations and cognitive impairment in streptozotocin-induced type 1 diabetes mice (Revsin et al., 2009). Although the clinical impact remains undetermined, these intriguing findings suggest that neuroendocrinal signals are essential for us to understand the homeostasis and disturbance of brain functions such as cognition at the systems level. 2.3. Metabolic signaling and cognition Cognitive decline is increasingly observed to coexist with metabolic syndromes such as hyperlipidemia, obesity and diabetes, in which bioenergetic and metabolic disturbances have been the common pathological denominator. It is becoming clear that many

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Fig. 1. Schematic illustration of the braineperiphery crosstalk pathway in the regulation of cognitive function. One essential pathway is the neural route, which is achieved through the innervation of the distant organs (e.g., gut, spleen, liver) and the neuroimmune signals could transmit bidirectionally between the brain and periphery. Another important pathway is via the blood, where circulating immune signals (e.g., cytokines, chemokines and immune cells) and bioenergetic signals (e.g., endogenous metabolites, microbial products and hormone) exert a systemic impact on the brain microenvironment. Such immune/bioenergetic signals may interact with the bloodebrain barrier (BBB) that propagates signals to the brain, or, on the other hand, directly exert neuronal and immune activities after entering the brain. Among the braineperiphery crosstalk pathways, signals transmitted along the microbiotaegutebrain axis have received much attention. These intricate links play a profound role in the regulation of neurogenesis and synaptic plasticity, and therefore necessitate a holistic insight into the global pathological traits of cognitive impairment. Abbreviations: BBB, bloodebrain barrier; 5-HT, serotonin; SCFA, short chain fatty acid; GLP-1, glucogan-like peptide 1.

endogenous metabolites (e.g., butyrate, kynurenines, endocannabinoids) actually take active roles in fine-tuning immune and neuronal responses and serve as versatile messengers between different organs (De Vadder et al., 2014; Stone et al., 2013). For cognitive functions, endogenous metabolites from the systemic circulation are also found to exert a profound impact on the neurovascular microenvironment of cognition (Collins et al., 2012; Rangroo Thrane et al., 2013; Reger et al., 2004; Stone et al., 2013). A typical example in this regard is the kynurenine pathway of tryptophan metabolism, from which the circulating tryptophan, kynurenine and 3-hydroxykynurenine (3-HK) could readily cross the bloodebrain barrier via the large neutral amino acid transporter. Of note, the metabolic fate of kynurenine has been increasingly recognized to mediate the effects of neurological, psychological and systemic factors on cognition and behavior (Schwarcz et al., 2012). Abnormalities in the kynurenine pathway in the periphery or the CNS are associated with a large spectrum of neurodegenerative and neuropsychiatric disorders (Schwarcz et al., 2012). These observations underscore that the systemic bioenergetic factors are important parameters associated with cognitive state. 2.4. The bloodebrain barrier (BBB) as a signaling hub By virtue of its strategic location, the BBB serves as a dynamic hub orchestrating bidirectional signaling events between the brain

and periphery. As has been discussed, the transport of blood-borne molecules such as leptin and kynurenine across the BBB is critical for the braineperiphery communication. Moreover, it has been acknowledged that the BBB is actively participating in the regulation of neuroimmune responses (Minogue et al., 2014). By the intimate contact with CNS-derived and blood-borne cells, it is endowed with the capacity to respond to immune signals from both sides and coordinate the actions of neighboring cells (Grammas et al., 2011). Indeed, perturbation of normal BBB functions has been recognized as the hallmark of a wide range of brain conditions including cognitive impairment (Huber, 2008; Neuwelt et al., 2011; Palmer, 2010; Tomkins et al., 2007). The compromise of BBB integrity has received extensive attention in aging and various brain disorders. During central or peripheral immune disturbances, the CNS infiltration of peripheral immune cells has been found to induce BBB disruption, and vise versa. As a typical example, peripheral surgery in mice was found to induce BBB disruption via TNF-a signaling, which facilitated macrophage migration into the hippocampus and cognitive decline. In contrast, augmentation of the endogenous inflammation-resolving pathway could prevent TNF-a-induced NFkB activation, macrophage migration, and resolve postoperative neuroinflammation and cognitive decline (Terrando et al., 2011). In spite of these findings, converging evidence also suggests that activated BBB, not necessarily with apparent changes in integrity, is functionally adequate to relay the information flow (Banks and

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Erickson, 2010; Shechter et al., 2013; Verma et al., 2006). A recent review also summarized that the BBB is a regulatory interface for mast cells, residing on the brain side of the BBB, to act as sensors and effectors in neuronevasculareimmune crosstalk, and such interactions are closely correlated with cognition and emotion (Silver and Curley, 2013). 2.5. The brainegutemicrobiota axis and cognition The brain and the gastrointestinal system are traditionally known to be coupled in the regulation of food intake and digestive functions. In recent years, there has been an increasing appreciation of the brainegut axis in governing the gastrointestinal, cerebral and systemic physiology (Foster and McVey Neufeld, 2013). It also becomes clear that dysfunctional brain-gut interactions are implicated in the comorbidity of neurobehavioral symptoms and gastrointestinal disorders (Rhee et al., 2009). The routes behind the brainegut interaction have been revealed to include the neural, endocrinal and immune pathways, in which the gut microbiota have emerged as a predominant player (Collins et al., 2012). The microbiota possess the ability to shape the systemic metabolic and immune status thereby exerting a remote effect on anxiety, mood, and cognition (Heijtz et al., 2011; Ochoa-Reparaz et al., 2011). Remarkably, structural and functional changes in the microbiota could exert pathophysiological influences on a large spectrum of brain diseases ranging from autism to cognitive impairment (Cryan and Dinan, 2012). 3. Braineperiphery crosstalk in brain disorders associated with cognitive impairment 3.1. Stroke Stroke is the second leading cause of death worldwide and there is a compelling need to improve the mechanistic understanding and expand the narrow repertoire of therapeutic strategies (Moskowitz et al., 2010). Cognitive impairment and vascular dementia are common sequelae after stroke. Unsolved inflammation plays a decisive role in stroke etiology and may contribute to cognitive impairment after stroke (Kliper et al., 2013). It is notable that, in addition to local neuroinflammatory events, a great deal of attention has centered upon systemic immune disturbances, which have been recognized as aggravators to cerebral injury and neurovascular deficit (Denes et al., 2010a; Emsley and Hopkins, 2008; McColl et al., 2008). For example, systemic immunosuppression and associated infections after stroke have received much attention as a major clinical concern that may exacerbate brain injury and cognitive impairment and increase the risk of mortality. By disrupting the parenchymal microenvironment that is critical for neuronal rehabilitation, repair and remodeling after stroke, systemic inflammation and infection, before or after stroke attack, could exacerbate neurological deficit and adversely impact on the outcome (Denes et al., 2010b; Emsley and Hopkins, 2008). Another burgeoning interest in recent years is the endogenous mechanisms for repair and rehabilitation from the brain and periphery after stroke, which signifies another potential avenue to improve the stroke outcome (Liesz et al., 2009; Murphy and Corbett, 2009). It is anticipated that progresses from this evolving frontier may yield novel insights for improving post-stroke cognitive abilities. 3.2. Alzheimer's disease Alzheimer's disease (AD) is the leading cause of dementia in the elderly. There is strong epidemiological and clinical evidence that abnormality in inflammatory signals in the brain contributes to the

slow degeneration of neurons, deposition of amyloid protein and early dysfunction in the brains of AD patients (Huang and Mucke, 2012). Meanwhile, accumulating evidence has lead to the realization that the mediators of neurodegeneration behind cognitive decline and memory loss could also derive from the periphery (Perry and Holmes, 2014). Interestingly, induction of AD in mice could increase inflammatory responses both in the brain and blood, suggesting that inflammatory events in the peripheral system are closely associated with AD pathogenesis (Jiang et al., 2009). In this regard, suppression of peripheral inflammatory factors proved a working preventive approach against chronic neurodegeneration and cognitive decline (Cunningham et al., 2005; Terrando et al., 2010). A recent study also showed that inhibition of peripheral kynurenine 3-monooxygenase (KMO) could effectively prevents spatial memory deficits, anxiety-related behavior, and synaptic loss in the transgenic mouse model of AD (Zwilling et al., 2011). Of interest, with more data suggesting the dysfunction of systemic immune cells to effectively clear amyloid deposits in AD pathology, strategies have also been proposed to take advantage of the systemic immune cells to fight off the amyloid plaques (Hawkes and McLaurin, 2009), which is believed to inspire new therapeutic avenues to neurodegeneration (Schwartz and Shechter, 2010; Yong and Rivest, 2009). 3.3. Huntington's disease Huntington's disease (HD) is an inherited neurodegenerative disorder that involves progressive psychiatric, cognitive and motor symptoms, and there are currently no remedies nor diseasemodifying treatments. Though incompletely understood, inflammation and immune activation are established features in HD and may account for the disrupted hippocampal neurogenesis and cellular plasticity implicated in the cognitive and affective symptoms in HD (Bjorkqvist et al., 2008). Besides the genetic abnormality and neuronal dysfunctions in the brain, pathological marks have also been documented in the periphery. For example, plasma concentrations of cytokines and chemokines were significantly increased in clinical HD patients (Wild et al., 2011) and the pattern of several molecules (e.g., CCL2, CCL11) showed good correlation with disease stage and clinical score (Dalrymple et al., 2007). The nature of immune activation in the periphery remains incompletely understood but is likely to involve inflammatory changes at the gastrointestinal site and the passage of inflammatory molecules across the BBB in a bidirectional manner (Bjorkqvist et al., 2009; van der Burg et al., 2011). In the context of these pathological hallmarks, inflammation-targeted interventions for HD are gaining momentum (Reinhart et al., 2011). Future studies are therefore warranted to explore the therapeutic promise of targeting the systemic factors for combating HD. 3.4. Traumatic brain injury Traumatic brain injury (TBI) has become an important publichealth issue and, besides the acute brain insults, much attention has been paid to the enormous need to treat the long-lasting neurobehavioral sequelae of TBI. There is evidence that a history of TBI, in combination with brain changes associated with normal aging, might lead to exacerbated cognitive decline in older adults (Moretti et al., 2012). Cognitive rehabilitation therapy in TBI patients is therefore highly needed but surrounded by many complexities at present. An important observation in experimental and clinical study is that peripheral immune disturbance has also emerged in the context of severe brain damage. Besides local effects, the inflammatory challenge and immunological alternations elicited by brain

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injury could profoundly affect the immune system and organs at the periphery. Findings in animal models demonstrated that acute inflammatory challenge to the brain could induce acute-phase responses in the periphery (Campbell et al., 2003), which were accompanied by hepatic release of acute-phase proteins, cytokines and chemokines (Campbell et al., 2005). The gastrointestinal tract is another peripheral site that is susceptible to the effect of CNS injury. Seminal investigations have reported alterations of intestinal mucosal structure and barrier function (Hang et al., 2003; Wang et al., 2011). Microorganisms translocation and microbial products secretion into the circulation could further aggravate the systemic immune disturbance (Catania et al., 2009), eliciting a second wave of inflammatory insult to the brain. Taken together, the systemic responses to TBI deserves further understandings to find novel routes to improve neurological outcome and ameliorate cognitive impairment. 4. Novel preventive/treatment strategies The limited choice of therapeutics in the clinic and the modest overall effects for cognitive decline underscore the knowledge gap concerning disease etiology and drug discovery strategy (Husain and Mehta, 2011). In light of the braineperiphery interplay in cognitive deficits, targeting the mediators connecting the brain and periphery might open up new vistas. 4.1. Peripheral cytokines/chemokines Deregulation of proinflammatory cytokines and chemokines in the periphery has been strongly implicated in neurological and neuropsychiatric disorders (Westin et al., 2012). The findings that central and peripheral pathology are intricately connected in the regulation of cognitive functions therefore suggest a potential novel approach by targeting inflammatory mediators at the periphery. In a mouse model of surgery-induced cognitive decline, peripheral antibody blockade of TNF-a or IL-1b, could prevent neuroinflammation, synaptic dysfunction and cognitive decline (Cibelli et al., 2010; Terrando et al., 2010), although only intracisternal injection of IL-1 receptor antagonist (IL-1RA) could prevent postoperative cognitive decline in aged rats (Barrientos et al., 2012). Interestingly, a previous study also showed that antagonism of blood IL-1b action with IL-1RA could prevent pilocarpine-induced seizures and BBB disruption (Marchi et al., 2009). These findings therefore signify the potential of targeting blood-borne inflammatory mediators for the amelioration of cognitive impairment and cerebral inflammatory disturbances. 4.2. Peripheral immune cells Therapeutic intervention of leukocyte recruitment to the CNS has proven effective for autoimmune brain diseases such as multiple sclerosis. For cognitive functions such as learning and memory, circulating immune cells have also been validated to be critical modulators (Ziv et al., 2006). An important basis of such effects is the regulation of blood-borne immune factors by immune cells. In addition to the cytokines and chemokines, many novel metabolites from immune cells are increasingly found to act on the brain. For example, sustained inhibition of KMO in peripheral monocytes could effectively elevate the neuroprotective kynurenic acid levels in the brain and reverse a number of cognitive and motor deficits measured in AD and HD models (Campesan et al., 2011; Zwilling et al., 2011), and this pathway was revealed to be a novel anti-AD mechanism for JM6, a prodrug KMO inhibitor that failed to cross the BBB. A recent study also demonstrated that the mechanism of Glatiramer acetate, a marketed drug for the treatment of multiple

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sclerosis, derived primarily from its immunomodulating effects on peripheral T cells as no direct neuronal protective effects were found (Herrmann et al., 2010). These findings support that peripheral immune cell-based therapies might become effective therapeutics for cognitive disorders. Interaction of peripheral immune cell with the CNS at the BBB is also a key step in tuning the brain immune environment and shaping its function. A typical example is related to CNS antigen reactive T cells, which accumulate to the borders of the CNS such as the choroid plexus (CP) when sensing cognitive task signals (Ziv et al., 2006). A recent study showed that, with aging in mice, the CD4þ effector memory cells switched to a T helper type 2 (Th2) phenotype leading to elevated levels of Th2-derived IL-4. Such a local cytokine shift was shown to trigger the CP epithelium to produce CCL11 that mediated cognitive dysfunction. Notably, restoration of the T cell balance by lymphopenia could partially restore cognitive ability in aged mice (Baruch et al., 2013). This novel finding suggests that the immune mediators at the BBB interface, which are amenable to immunomodulation, may serve as unique targets for arresting age-related cognitive decline. Future studies are therefore necessary to define key mediators that link the signaling events at the BBB to cognitive functions and explore the therapeutic values. 4.3. The microbiota Long-standing clinical observations have shown that a subset of patients with brain disorders commonly experience dysfunctions in the gastrointestinal site (Koloski et al., 2012; Pfeiffer, 2003). Research insights in recent years have contributed to the further understanding that the gastrointestinal dysfunctions are characterized with barrier compromise and structural changes of the microbiota, which are closely correlated with systemic immune disturbances in brain disorders. Of note, the pathological roles of structurally-altered microbiota have been validated in a remarkably large spectrum of diseases ranging from colitis to brain disorders (Cryan and Dinan, 2012). In particular, the effect of microbiota on mood and behavior has prompted extensive interests to investigate possible therapeutic effects of targeting the abnormal microbiota composition. Indeed, treatment of probiotics, live microorganisms that have claimed health benefits (e.g., Lactobacillus rhamnosus, Bacteroides fragilis), has shown beneficial effects on cognitive impairment associated with diabetes (Davari et al., 2013), behavioral abnormalities in autism spectrum disorder (Hsiao et al., 2013) and stress-induced depression and anxiety in animal studies (Bravo et al., 2011). These effects are largely attributed to the regulation of inflammatory signals along the microbiomeegutebrain axis and the host metabolome. Although the exact mechanism is elusive and translation of these results into human trials has not been confirmed, these findings have identified a potential probiotic therapy to behavioral symptoms. 4.4. Non-pharmacological approach Non-pharmacological approaches have also been attempted for their potential benefits on cognition. Environmental enrichment (EE), in particular, has long been confirmed to exert robust morphological and functional effects on the brain with cognitive benefits. In addition to the therapeutic effects on aging associated cognitive decline, exposure to an enriched environment was recently found to relieve anxiety-associated behaviors from acute restraint stress and attenuate cognitive impairment after severe status epilepticus (Fares et al., 2013), TBI (Piao et al., 2013) and peripheral influenza infection (Jurgens and Johnson, 2012). Notably, physical exercise was shown to be the major contributing factor to

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enhanced hippocampal neurogenesis (Kohman et al., 2012), and synaptic plasticity (Barrientos et al., 2011) by EE. In addition to the neurobiological mechanisms (Voss et al., 2013), induction of peripheral growth factors and regulation of systemic immune responses by physical exercise have been proposed as key reasons (Cotman et al., 2007). Collectively, these findings suggest that nonpharmacological lifestyle strategies such as EE and physical exercise could become promising approaches to attenuate cognitive decline. 5. Therapeutic implications Once thought to only restricted in the brain, it is now apparent that the sensors and modulators of cerebral microenvironment also reside in the periphery (Perry et al., 2007; van Gool et al., 2010), which prompts us to re-evaluate the current dogma about CNS disease pathology and explore how this trait could be harnessed for therapeutic purposes. As has been discussed, better interpretation of the peripheral changes and their biological connections to neurological and neurobehavioral outcomes may revolutionize the way we look at brain health and disease, and how we explore novel treatment, prevention and diagnosis for cognitive decline and many other brain disorders. 5.1. Drug discovery for cognitive impairment Attempts to improve cognitive function in patients with brain disorders have been pursued for a long time. However, to date, experimental and clinical studies have demonstrated relatively modest overall effects of the so-called ‘cognitive enhancers’ (Husain and Mehta, 2011). As evidenced by the examples discussed here, the participation of the peripheral system in brain dysfunction argues for the need to encompass the integral role of the periphery in deciphering the pathogenesis and formulating prevention/treatment strategies. In the drug discovery efforts, targeting the cerebral microenvironment has been attempted for decades to treat cognitive impairment and other brain disorders (Bishop et al., 2010; Frankola et al., 2011; Hirsch and Hunot, 2009; Huang and Mucke, 2012; Tansey and Goldberg, 2010). In addition, for drugs with brain benefits, the conventional wisdom generally ascribe the action sites directly to the brain (Clapper et al., 2010; Zheng et al., 2013). Challenging this paradigm, however, converging evidence has suggested that the primary target behind the beneficial effects might exist in the periphery. Table 1 lists neuroprotective agents whose efficacies are very likely to derive from pharmacological actions at the periphery. A good argument is the fact that many of these agents fail to penetrate into the brain, while their effects on the peripheral targets might provide an indirect route to the central effects (Kang et al., 2011; Reinhart and Kelly, 2011; Steinman, 2010). Moreover, for those drugs with good BBB permeability, the primary sites of action are not necessarily reside in the brain. For example, in the delineation of the sites of action for adenosine receptor modulators, the neuroprotection afforded by A2A receptor agonist was found to primarily rely on peripheral effects as its direct injection into the brain failed to protect the neurons (Paterniti et al., 2011). Based on such a novel action modality, future efforts are necessary to fill the knowledge gap with regard to the exact mechanism of action and systematically evaluate the therapeutic promise for CNS drugs. Although the concept that systemic factors contribute to brain pathology has been established, manipulation of peripheral targets to provide neuropharmaceuticals is only beginning to be appreciated (Reinhart and Kelly, 2011; Steinman, 2010). From the perspective of drug development, modulation of peripheral targets

features feasibility and safety advantages and may serve as good complement to current paradigm. Firstly, good BBB permeability, which has been a long-held requirement by conventional CNStargeting drugs (Gabathuler, 2010; Palmer, 2010), is not necessarily a prerequisite for those peripherally active drugs. Conventional therapeutic approaches to neurological diseases generally prefer those chemical entities with favorable brain entrance, which actually stood as a major obstacle to the success of current CNS drug discovery (Neuwelt et al., 2008). As such, neuroprotective agents functioning with peripheral pharmacological mechanisms could be feasible alternatives and/or desirable combination partners to current therapeutic repertoires. In fact, Etanercept, an antibody specifically blocking the effect of TNF-a at the periphery, has demonstrated desirable therapeutic effects to cerebral injuries under several lines of experimental conditions (Aden et al., 2010; Campbell et al., 2007; Steinman, 2010). Secondly, targeting the periphery could safely reverse or slow the course of disease and avoid unwanted or harmful CNS side effects. This is best exemplified by the experimental finding that agonist of the peripheral cannabinoid receptors could attenuate inflammatory pain perception while obviating the psychotropic effects of conventional drugs targeting central cannabinoid signaling (Clapper et al., 2010). Additional evidence favoring the safety advantage was provided in a report that specifically blocking peripheral AMPA receptors by peripherally applied AMPAR antagonists could afford alleviation of chronic inflammatory pain without eliciting central side effects (Gangadharan et al., 2011). Such merits, if fully validated, might add tremendous advantage to future CNS drug development. 5.2. Peripheral immune mediators as cognitive biomarkers It should be noted that one therapeutic hurdle in the clinic is the fact that the neuropathological processes responsible for cognitive symptoms in chronic neurodegenerative diseases such AD may begin well before overt disease onset or diagnosis by current biochemical and imaging criteria (Braskie and Thompson, 2013). The failure to fill the gap between disease onset and diagnosis could severely hamper intervention opportunities and therapeutic benefits. Given the systemic manifestations of several neurological diseases and their close correlation with disease-specific progression (Bermejo et al., 2008; Kapczinski et al., 2011; Reale et al., 2009; Weng et al., 2011), peripheral markers related to systemic disturbances are ideally placed to bridge this gap and serve as accessible benchmarks for identifying patients at risk and monitoring the treatment response. Actually, a battery of potential biomarkers in this regard is on the horizon. For example, a peripheral molecular biomarker has been reported of clinical utility for the prospective evaluation of AD with a high accuracy and increased certainty in the early phase of disease progression (Khan and Alkon, 2006). Similarly, eighteen plasma signaling proteins reflective of dysregulated hematopoiesis and immune responses in the systemic circulation were validated to give an early prediction of progression to AD (Ray et al., 2007). With the advent of state-of-the-art techniques such as transcriptomic, proteomic and metabolic platforms, the exploration of peripheral non-invasive biomarkers is poised to provide unprecedented insights for achieving a better prediction and treatment of cognitive deficits and other brain disorders. 5.3. Translational considerations Despite the many billions of dollars that have been spent on neuroscience research, the biology of brain diseases remains poorly defined and few blockbuster drugs have emerged (Enna and Williams, 2009). Similarly, translating promising preclinical therapies to clinical treatments is an imperative need for cognitive

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Table 1 Summary of experimental evidence supporting peripheral pharmacological effects as mechanism for the brain beneficial effects. Model

Agents (route)

Pharmacological function

Peripheral effects

Brain access

CNS effects

Focal brain injury

Anti-CINC-1 antibody (i.v.) Dexamethasone 21-phosphate (i.p.) CGS21680 (i.p.)

CINC-1 neutralization

Neutrophil mobilization

No

Anti-inflammation Immunosuppression A2A receptor agonist Anti-inflammation TNF-a receptor antagonist Neutralization of TNF-a TNF-a receptor antagonist Neutralization of TNF-a Anti-inflammation

Hepatic CCL2 expression

Poor

Bone-marrow derived cells

Yes

Attenuation of neutrophil recruitment Attenuation of immune cell recruitment Neuroprotective (only via i.p.)

Peripheral TNF-a

No

Peripheral TNF-a

No

Intestinal immunity and systemic inflammation Immune cells : migration and inflammatory response Peripheral TNF-a

Poor

Circulating T cells

Poor

Peripheral IL-1b

Yes

Spinal cord injury

Neuroinflammation

Etanercept (s.c.) Etanercept (s.c.) Ginsenosides (p.o.) Minocycline

Excitotoxicity

Etanercept (i.p.) Dexamethasone (i.p.) IL-1Ra (i.v.)

Anti-inflammation Anti-apoptosis Anti-oxidation TNF-a receptor antagonist Neutralization of TNF-a Anti-inflammation Immunomodulation Inhibitor of IL-1

Yes No

Orthopedic surgery induced cognitive decline

Etanercept

TNF-a receptor antagonist Neutralization of TNF-a

Peripheral TNF-a

No

Transgenic mouse model of HD

JM6 (p.o.)

Inhibitor of kynurenine 3-monooxygenase

Kynurenine 3-monooxygenase on monocytes

No

Tg2576 mouse model of AD

JM6 (p.o.)

Inhibitor of kynurenine 3-monooxygenase

Kynurenine 3-monooxygenase on monocytes

No

SB-505124, SB-431542

Blockade of TGF-b downstream signaling

Peripheral macrophages

e

R838

Kinin receptor B1 agonist

Encephalitogenic Th17 cells migration

e

MiR-124 (i.v.)

Deactivation of macrophages

Peripheral macrophages

e

Berberine (i.g.)

Anti-inflammation

Th1 and Th17 cells

Poor

Glatiramer acetate (s.c.)

Immunomodulation

Regulatory Th 2/3 cells

Yes

6-Hydroxydopamine (i.p.)

Noradrenalin nerves

Depletion of noradrenalin nerve terminals

No

Clone R1-2 (i.p.)

Lymphocyte infiltration

No

L. rhamnosus

Antibody to integrin alpha4beta1 Probiotic

No

B. longum

Probiotic

Modulation of intestinal microbiota Intestinal dysbiosis

Mouse EAE model of multiple sclerosis

Ischemic brain injury

Stress induced depression-like behavior Infection induced anxiety

research. Although current data implicating the contribution of peripheral system to cognitive functions are strong, there remain several key issues to be clarified. A major unanswered question is the prospective benefits of clinical regimen that target the neuroimmune interplay at the periphery. The etiology of brain disorders is rather complex, and the temporal nature of the dialogue between CNS and peripheral immune derangement remains unclear (Bjorkqvist et al., 2009). This knowledge gap might create uncertainty concerning the clinical results for a specific treatment regimen (Norflus et al., 2004). Indeed, clinical trials investigating the effects of NSAIDs on AD progression have yielded mixed or inconclusive results (Hoozemans et al., 2011) and it was proposed that the clinical benefits are closely correlated with the stage of disease pathology when drug intervention is initiated. In light of this caveat, it is imperative to define the therapeutic window and

No

Reduction in neutrophil recruitment Inhibition of sickness behavior Attenuation of peripheral inflammation Neuroprotection, Inhibition of leukocyte recruitment Attenuation of microglia activation and brain lesion Protection of BBB integrity Antagonism of the effect of IL-1b, BBB protection Attenuation of neuroinflammation and cognitive impaiement Extension of life span, attenuation of synaptic loss and microglial activation Prevention of memory deficits, synaptic loss and anxious behavior Increased endogenous Ab clearance, Improved behavior Attenuation of demyelination and axonal damage Amelioration of EAE sysmptoms and CNS inflammation Inhibition of Th17 and Th1 cell differentiation Anti-inflammation, neuroprotection (no direct protection on neuron) Protection against infection-related mortality Attenuation of secondary brain damage Modulation of central GABA receptor expression Normalized behavior and BDNF level

clinical efficacy. Also, given the inherent complexity in cognitive pathology, initiating interventions that target several pathological nodes in parallel might confer better clinical outcomes (Frautschy and Cole, 2010). Future investigations are therefore warranted to explore the intriguing possibility of combining certain peripherally active drugs with conventional CNS drugs to fully address the multifactoriality of cognitive deficits. In light of the side effects of current therapeutics to CNS disorders, another key issue is whether the peripheral mediators that contribute to brain pathology could be safely manipulated. The reason for such a concern derives from the dual nature and complexities of immune regulation, which, as is the case in many other diseases, could be protective and destructive largely depending on the state of immune activation and the microenvironment. Currently, anti-inflammatory therapies in the treatment of

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neurological disorders have yielded mixed results (Karampetsou et al., 2010; Schwartz and Shechter, 2010). In fact, not only do different types of inflammatory mediators contribute differentially to the pathogenesis of disease (Dalakas, 2008; Liesz et al., 2009; Ren et al., 2011), but also the same mediator may play different roles at different sites and stages of disease (Tesseur et al., 2006; Town et al., 2008). Actually, it was found that drug-induced suppression of the CD4þ cell recruitment to the CNS might explain the failure of systemic anti-inflammatory therapies to halt neurodegeneration (Schwartz and Shechter, 2010). Moreover, given the potential benefit of boosting systemic inflammation at certain stages of brain disease, attempts have been made to harness the systemic immune system to cure certain neurodegenerative diseases like AD and amyotrophic lateral sclerosis (Yong and Rivest, 2009). Further, the clinical benefit-risk ratio could vary in a disease-specific fashion, and the final outcomes should be carefully evaluated in clinical trials as suggested by the adverse neurological outcomes associated with monoclonal antibody based therapy (Bosch et al., 2011). Given the aforementioned challenges, a major step towards clinical translation will be to define the exact role of key mediators in braineperiphery crosstalk and design optimal intervention regimens. 6. Conclusions Despite much conceptual progress made so far, disappointment exists for the CNS drug discovery mode that solely focuses on the brain. This fact substantiates an urgent need to enhance the productivity in CNS drug discovery by conceptual innovation and paradigm shift. It is becoming clear that the brain and the peripheral system are closely coupled in systems health and disease. As can be concluded from the evidence reviewed here, incorporating a holistic perspective which takes into account the pathophysiological significance of central-peripheral interplay may be instrumental to the understanding and prevention/treatment of cognitive impairment and many other brain disorders. Importantly, exploring peripheral targets that are amenable to therapeutic intervention might be a promising complement to current therapeutic repertoires in the clinic. By understanding the peripheral mediators underlying cognitive function and its decline with brain disorders, it may be possible to design novel preventive or therapeutic strategies. To this goal, it will be imperative to look beyond the brain and integrate an interdisciplinary approach to the research pipeline. In the translation of these conceptual advances into clinical applications, a plethora of factors should be taken into account, such as the diverse nature of inflammation at various stage of brain disease, the distinctive temporal and spatial contributions of specific mediators, and the therapeutic regimen design. Researches aimed to disentangle these critical issues with a deeper appreciation of centralperipheral interplay might herald new directions and yield fruitful findings in the intervention approaches to cognitive impairment. Acknowledgments This work is supported in part by funds from the National Natural Science Foundation of China (No. 81325025 and 81202983) and Natural Science Foundation of Jiangsu province (No. BK20141035). References Aden, U., Favrais, G., Plaisant, F., Winerdal, M., Felderhoff-Mueser, U., Lampa, J., Lelievre, V., Gressens, P., 2010. Systemic inflammation sensitizes the neonatal

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