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Is there any place for macrolides in mood disorders?
Medical Hypotheses 78 (2012) 86–87
Contents lists available at SciVerse ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Is there any place for macrolides in mood disorders? Rami Bou Khalil ⇑ Psychiatric Hospital of the Cross, Jalledib, Lebanon Saint Joseph University, Beirut, Lebanon
a r t i c l e
i n f o
Article history: Received 2 August 2011 Accepted 28 September 2011
a b s t r a c t Macrolides are protein synthesis inhibitors exerting an action on the bacterial ribosome. The ribosomes coded for by the human mitochondrial deoxyribonucleic acid (DNA) are similar to those from bacteria in size and structure. In addition, mitochondria are thought to have originated from a symbiotic relationship between an anaerobic proto-eukaryotic cell that engulfed an aerobic bacterium. Morphological changes of mitochondria have been observed in bipolar disorder and schizophrenia. Manic episodes associated with the use of antimicrobial agents have been described since the discovery of isoniazid. The oxidative stress induced in the neuronal mitochondria is thought to underlie this effect. The inhibition of GSK-3b in the intra-mitochondrial Akt signaling pathway is thought to convey mood stabilizing properties. Rapamycin is a macrolide that, besides its antiepileptic effect, restores the Akt function and inhibits the mTOR pathway which may have an antidepressant effect. Accordingly, it is hypothesized that rapamycin may have mood stabilizing properties. Ó 2011 Elsevier Ltd. All rights reserved.
Introduction/background Many antimicrobial agents cross react with psychiatric disorders. In 1952, isoniazid’s antidepressant properties were discovered when researchers noted that the patients given this drug became ‘‘inappropriately happy’’. Subsequently N-isopropyl addition lead to development as an antidepressant and was approved for use in 1958. Mania associated with the use of isoniazid has been reported in several articles. Other manic episodes have been described during the administration of many antimicrobial drugs especially macrolides like clarithromycin and erythromycin. This complication of antimicrobial administration is also called antibiomania [1]. Hypothesis/theory Antibiomania is a disorder that can be induced by the antimicrobial agent’s effect on mitochondrial functioning. Accordingly, some macrolides may have mood stabilizing properties via their interference in the mitochondrial functioning of neurons. Evaluation of the hypothesis/idea Mitochondria abnormalities in severe mental disorders Gene and protein expression studies point to a decrease of factors and enzymes involved in adenosine triphosphate (ATP) generation ⇑ Psychiatric Hospital of the Cross, PO Box 60090, Jalledib, Lebanon. Tel.: +961 70946430/4710224. E-mail address: [email protected] 0306-9877/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2011.09.046
and storage, and linkage analysis showed an association of bipolar disorder and schizophrenia with genes involved in mitochondrial function. Mitochondrial structural abnormalities have been reported in patients suffering from bipolar disorder, and both diseases are associated with mitochondrial deoxyribonucleic acid DNA (mtDNA) mutations and polymorphisms [2]. Morphological changes of mitochondria have been observed in bipolar disorder and schizophrenia, in brain tissue as well as peripheral tissue. Mitochondria were significantly smaller in the prefrontal cortex (PFC) of bipolar patients compared to normal controls [3]. In the PFC of schizophrenia patients, oligodendrocytes show drastic reductions in mitochondrial number and volume [4]. Schizophrenia patients have also fewer mitochondria in the striatum than controls or individuals with other psychiatric diagnoses [5].
Mechanism of action of macrolides on bacteria and human cells Macrolides are protein synthesis inhibitors. The mechanism of action of macrolides is inhibition of bacterial protein synthesis. They are thought to do this by preventing peptidyltransferase from adding the peptidyl attached to transfer ribonucleic acid (tRNA) to the next amino acid as well as by inhibiting ribosomal translocation [6]. Mitochondria are thought to have originated from a symbiotic relationship between an anaerobic protoeukaryotic cell that engulfed an aerobic bacterium. As such, mitochondria retain bacterial characteristics [7]. The ribosomes coded for by the human mitochondrial DNA are similar to those from bacteria in size and structure. Human mitochondrial ribosomes lack several of the major RNA stem structures of bacterial ribosomes but they contain a correspondingly higher
R. Bou Khalil / Medical Hypotheses 78 (2012) 86–87
protein content (as many as 80 proteins), suggesting a model where proteins have replaced RNA structural elements during the evolution of these ribosomes [8].
Role of mitochondrial Akt of neurons mood stabilization In a mitochondrion, the combination of elevated Ca2+ levels and decreased ATP production will cause continuous cellular stress and reduce the ability to appropriately respond to temporary peaks in stressful stimuli such as increased glutamate release during emotional situations and drug use, or decreased glucose levels during times of famine or deliberate starvation [2]. The stimulation of a variety of cell types with insulin-like growth factor-1, insulin, or stress, induces the translocation of Akt – a protein involved in signaling pathways – to the mitochondria within only several minutes of stimulation, causing increases of nearly eight to twelvefold of the mitochondrial Akt in its phosphorylated active state. Two mitochondrial proteins are identified to be phosphorylated following stimulation of mitochondrial Akt, the b-subunit of ATP synthase and glycogen synthase kinase-3b (GSK-3b). In experiments, it has been shown that certain concentrations of lithium chloride (LiCl) inhibit GSK-3b in the Wnt signaling pathway. This inhibition of GSK-3b is currently believed to underlie the therapeutic usefulness of lithium salts for the treatment of mood disorders. Other GSK-3 inhibitors are being evaluated for the treatment of Alzheimer’s disease and bipolar disorder [9–11]. Mood stabilizing properties of rapamycin Rapamycin, also known as sirolimus, is a macrocyclic polyketide that belongs to the family of macrolides, isolated from Streptomyces hygroscopicus. It has been shown to exhibit antifungal, antitumor, and immunosuppressant properties. The mode of action of rapamycin is to bind the cytosolic protein FK-binding protein 12 (FKBP12). The sirolimus-FKBP12 complex inhibits the mammalian target of rapamycin (mTOR) pathway by directly binding the mTOR Complex1 (mTORC1) [12]. This pathway has been shown to be inhibited by the action of the antidepressant drug sertraline via protein synthesis inhibition [13]. It has been shown that the rapid antidepressant action of ketamine is due to the fact that it rapidly activates the mammalian target of rapamycin (mTOR) pathway, leading to increased synaptic signaling proteins and increased number and function of new spine synapses in the prefrontal cortex of rats [14]. Everolimus (RAD-001), the 40-O-(2-hydroxyethyl) derivative of sirolimus, has been proved to be efficient in maintenance heart transplant recipients in providing significant improvement in memory, concentration, and overall psychiatric symptoms [15]. In addition, there is restoration of phospho-Akt and phospho-glycogen synthase kinase-3 (phospho-GSK-3) levels in treated mice with both rapamycin and everolimus, consistent with restoration of Akt function [16]. Rapamycin has been shown to prevent epileptogenesis [17].
87
Consequences of the hypothesis and discussion In conclusion, rapamycin belongs to the macrolides superfamily where manic episodes have been described when administered to patients. Accordingly, rapamycin (and possibly everolimus) may theoretically manifest antidepressant and/or mood stabilizing effect because of their inhibition of epileptogenesis, their action on Akt, mTORC, GSK-3b and on mitochondrial protein synthesis. Clinical randomized and controlled trials are needed in order to prove this hypothesis. Conflict of interest There is no conflict of interest for both authors of this work. There is no funding source supporting this work. References [1] Abouesh A, Stone C, Hobbs WR. Antimicrobial-induced mania (antibiomania): a review of spontaneous reports. J Clin Psychopharmacol 2002;22:71–81. [2] Clay HB, Sillivan S, Konradi C. Mitochondrial dysfunction and pathology in bipolar disorder and schizophrenia. Int J Dev Neurosci 2011;29:311–24. [3] Cataldo AM, McPhie DL, Lange NT, Punzell S, Elmiligy S, Ye NZ, et al. Abnormalities in mitochondrial structure in cells from patients with bipolar disorder. Am J Pathol 2010;177:575–85. [4] Uranova N, Orlovskaya D, Vikhreva O, Zimina I, Kolomeets N, Vostrikov V, et al. Electron microscopy of oligodendroglia in severe mental illness. Brain Res Bull 2001;55:597–610. [5] Kung L, Roberts RC. Mitochondrial pathology in human schizophrenic striatum: a postmortem ultrastructural study. Synapse 1999;31:67–75. [6] Tenson T, Lovmar M, Ehrenberg M. The mechanism of action of macrolides, lincosamides and streptogramin B reveals the nascent peptide exit path in the ribosome. J Mol Biol 2003;330:1005–14. [7] Wallace DC. A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine. Annu Rev Genet 2005;39:359–407. [8] O’Brien TW. Properties of human mitochondrial ribosomes. IUBMB Life 2003;55:505–13. [9] Klein PS, Melton DA. A molecular mechanism for the effect of lithium on development. Proc Natl Acad Sci USA 1996;93:8455–9. [10] Kaladchibachi SA, Doble B, Anthopoulos N, Woodget JR, Manoukian AS. Glycogen synthase kinase 3, circadian rhythms, and bipolar disorder: a molecular link in the therapeutic action of lithium. J Circadian Rhythms 2007;5:3. [11] Meijer L, Flajolet M, Greengard P. Pharmacological inhibitors of glycogen synthase kinase 3. Trends Pharmacol Sci 2004;25:471–80. [12] Vézina C, Kudelski A, Sehgal SN. Rapamycin (AY-22, 989), a new antifungal antibiotic. J Antibiot 1975;28:721–6. [13] Lin CJ, Robert F, Sukarieh R, Michnick S, Pelletier J. The antidepressant sertraline inhibits translation initiation by curtailing mammalian target of rapamycin signaling. Cancer Res 2010;70:3199–208. [14] Hashimoto K. Role of the mTOR signaling pathway in the rapid antidepressant action of ketamine. Expert Rev Neurother 2011;11:33–6. [15] Lang UE, Heger J, Willbring M, Domula M, Matschke K, Tugtekin SM. Immunosuppression using the mammalian target of rapamycin (mTOR) inhibitor everolimus: pilot study shows significant cognitive and affective improvement. Transplant Proc 2009;41:4285–8. [16] Meikle L, Pollizzi K, Egnor A, Kramvis I, Lane H, Sahin M, et al. Response of a neuronal model of tuberous sclerosis to mammalian target of rapamycin (mTOR) inhibitors: effects on mTORC1 and Akt signaling lead to improved survival and function. J Neurosci 2008;28:5422–32. [17] McDaniel SS, Wong M. Therapeutic role of mammalian target of rapamycin (mTOR) inhibition in preventing epileptogenesis. Neurosci Lett 2011 Feb 24. [Epub ahead of print].
Contents lists available at SciVerse ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Is there any place for macrolides in mood disorders? Rami Bou Khalil ⇑ Psychiatric Hospital of the Cross, Jalledib, Lebanon Saint Joseph University, Beirut, Lebanon
a r t i c l e
i n f o
Article history: Received 2 August 2011 Accepted 28 September 2011
a b s t r a c t Macrolides are protein synthesis inhibitors exerting an action on the bacterial ribosome. The ribosomes coded for by the human mitochondrial deoxyribonucleic acid (DNA) are similar to those from bacteria in size and structure. In addition, mitochondria are thought to have originated from a symbiotic relationship between an anaerobic proto-eukaryotic cell that engulfed an aerobic bacterium. Morphological changes of mitochondria have been observed in bipolar disorder and schizophrenia. Manic episodes associated with the use of antimicrobial agents have been described since the discovery of isoniazid. The oxidative stress induced in the neuronal mitochondria is thought to underlie this effect. The inhibition of GSK-3b in the intra-mitochondrial Akt signaling pathway is thought to convey mood stabilizing properties. Rapamycin is a macrolide that, besides its antiepileptic effect, restores the Akt function and inhibits the mTOR pathway which may have an antidepressant effect. Accordingly, it is hypothesized that rapamycin may have mood stabilizing properties. Ó 2011 Elsevier Ltd. All rights reserved.
Introduction/background Many antimicrobial agents cross react with psychiatric disorders. In 1952, isoniazid’s antidepressant properties were discovered when researchers noted that the patients given this drug became ‘‘inappropriately happy’’. Subsequently N-isopropyl addition lead to development as an antidepressant and was approved for use in 1958. Mania associated with the use of isoniazid has been reported in several articles. Other manic episodes have been described during the administration of many antimicrobial drugs especially macrolides like clarithromycin and erythromycin. This complication of antimicrobial administration is also called antibiomania [1]. Hypothesis/theory Antibiomania is a disorder that can be induced by the antimicrobial agent’s effect on mitochondrial functioning. Accordingly, some macrolides may have mood stabilizing properties via their interference in the mitochondrial functioning of neurons. Evaluation of the hypothesis/idea Mitochondria abnormalities in severe mental disorders Gene and protein expression studies point to a decrease of factors and enzymes involved in adenosine triphosphate (ATP) generation ⇑ Psychiatric Hospital of the Cross, PO Box 60090, Jalledib, Lebanon. Tel.: +961 70946430/4710224. E-mail address: [email protected] 0306-9877/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2011.09.046
and storage, and linkage analysis showed an association of bipolar disorder and schizophrenia with genes involved in mitochondrial function. Mitochondrial structural abnormalities have been reported in patients suffering from bipolar disorder, and both diseases are associated with mitochondrial deoxyribonucleic acid DNA (mtDNA) mutations and polymorphisms [2]. Morphological changes of mitochondria have been observed in bipolar disorder and schizophrenia, in brain tissue as well as peripheral tissue. Mitochondria were significantly smaller in the prefrontal cortex (PFC) of bipolar patients compared to normal controls [3]. In the PFC of schizophrenia patients, oligodendrocytes show drastic reductions in mitochondrial number and volume [4]. Schizophrenia patients have also fewer mitochondria in the striatum than controls or individuals with other psychiatric diagnoses [5].
Mechanism of action of macrolides on bacteria and human cells Macrolides are protein synthesis inhibitors. The mechanism of action of macrolides is inhibition of bacterial protein synthesis. They are thought to do this by preventing peptidyltransferase from adding the peptidyl attached to transfer ribonucleic acid (tRNA) to the next amino acid as well as by inhibiting ribosomal translocation [6]. Mitochondria are thought to have originated from a symbiotic relationship between an anaerobic protoeukaryotic cell that engulfed an aerobic bacterium. As such, mitochondria retain bacterial characteristics [7]. The ribosomes coded for by the human mitochondrial DNA are similar to those from bacteria in size and structure. Human mitochondrial ribosomes lack several of the major RNA stem structures of bacterial ribosomes but they contain a correspondingly higher
R. Bou Khalil / Medical Hypotheses 78 (2012) 86–87
protein content (as many as 80 proteins), suggesting a model where proteins have replaced RNA structural elements during the evolution of these ribosomes [8].
Role of mitochondrial Akt of neurons mood stabilization In a mitochondrion, the combination of elevated Ca2+ levels and decreased ATP production will cause continuous cellular stress and reduce the ability to appropriately respond to temporary peaks in stressful stimuli such as increased glutamate release during emotional situations and drug use, or decreased glucose levels during times of famine or deliberate starvation [2]. The stimulation of a variety of cell types with insulin-like growth factor-1, insulin, or stress, induces the translocation of Akt – a protein involved in signaling pathways – to the mitochondria within only several minutes of stimulation, causing increases of nearly eight to twelvefold of the mitochondrial Akt in its phosphorylated active state. Two mitochondrial proteins are identified to be phosphorylated following stimulation of mitochondrial Akt, the b-subunit of ATP synthase and glycogen synthase kinase-3b (GSK-3b). In experiments, it has been shown that certain concentrations of lithium chloride (LiCl) inhibit GSK-3b in the Wnt signaling pathway. This inhibition of GSK-3b is currently believed to underlie the therapeutic usefulness of lithium salts for the treatment of mood disorders. Other GSK-3 inhibitors are being evaluated for the treatment of Alzheimer’s disease and bipolar disorder [9–11]. Mood stabilizing properties of rapamycin Rapamycin, also known as sirolimus, is a macrocyclic polyketide that belongs to the family of macrolides, isolated from Streptomyces hygroscopicus. It has been shown to exhibit antifungal, antitumor, and immunosuppressant properties. The mode of action of rapamycin is to bind the cytosolic protein FK-binding protein 12 (FKBP12). The sirolimus-FKBP12 complex inhibits the mammalian target of rapamycin (mTOR) pathway by directly binding the mTOR Complex1 (mTORC1) [12]. This pathway has been shown to be inhibited by the action of the antidepressant drug sertraline via protein synthesis inhibition [13]. It has been shown that the rapid antidepressant action of ketamine is due to the fact that it rapidly activates the mammalian target of rapamycin (mTOR) pathway, leading to increased synaptic signaling proteins and increased number and function of new spine synapses in the prefrontal cortex of rats [14]. Everolimus (RAD-001), the 40-O-(2-hydroxyethyl) derivative of sirolimus, has been proved to be efficient in maintenance heart transplant recipients in providing significant improvement in memory, concentration, and overall psychiatric symptoms [15]. In addition, there is restoration of phospho-Akt and phospho-glycogen synthase kinase-3 (phospho-GSK-3) levels in treated mice with both rapamycin and everolimus, consistent with restoration of Akt function [16]. Rapamycin has been shown to prevent epileptogenesis [17].
87
Consequences of the hypothesis and discussion In conclusion, rapamycin belongs to the macrolides superfamily where manic episodes have been described when administered to patients. Accordingly, rapamycin (and possibly everolimus) may theoretically manifest antidepressant and/or mood stabilizing effect because of their inhibition of epileptogenesis, their action on Akt, mTORC, GSK-3b and on mitochondrial protein synthesis. Clinical randomized and controlled trials are needed in order to prove this hypothesis. Conflict of interest There is no conflict of interest for both authors of this work. There is no funding source supporting this work. References [1] Abouesh A, Stone C, Hobbs WR. Antimicrobial-induced mania (antibiomania): a review of spontaneous reports. J Clin Psychopharmacol 2002;22:71–81. [2] Clay HB, Sillivan S, Konradi C. Mitochondrial dysfunction and pathology in bipolar disorder and schizophrenia. Int J Dev Neurosci 2011;29:311–24. [3] Cataldo AM, McPhie DL, Lange NT, Punzell S, Elmiligy S, Ye NZ, et al. Abnormalities in mitochondrial structure in cells from patients with bipolar disorder. Am J Pathol 2010;177:575–85. [4] Uranova N, Orlovskaya D, Vikhreva O, Zimina I, Kolomeets N, Vostrikov V, et al. Electron microscopy of oligodendroglia in severe mental illness. Brain Res Bull 2001;55:597–610. [5] Kung L, Roberts RC. Mitochondrial pathology in human schizophrenic striatum: a postmortem ultrastructural study. Synapse 1999;31:67–75. [6] Tenson T, Lovmar M, Ehrenberg M. The mechanism of action of macrolides, lincosamides and streptogramin B reveals the nascent peptide exit path in the ribosome. J Mol Biol 2003;330:1005–14. [7] Wallace DC. A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine. Annu Rev Genet 2005;39:359–407. [8] O’Brien TW. Properties of human mitochondrial ribosomes. IUBMB Life 2003;55:505–13. [9] Klein PS, Melton DA. A molecular mechanism for the effect of lithium on development. Proc Natl Acad Sci USA 1996;93:8455–9. [10] Kaladchibachi SA, Doble B, Anthopoulos N, Woodget JR, Manoukian AS. Glycogen synthase kinase 3, circadian rhythms, and bipolar disorder: a molecular link in the therapeutic action of lithium. J Circadian Rhythms 2007;5:3. [11] Meijer L, Flajolet M, Greengard P. Pharmacological inhibitors of glycogen synthase kinase 3. Trends Pharmacol Sci 2004;25:471–80. [12] Vézina C, Kudelski A, Sehgal SN. Rapamycin (AY-22, 989), a new antifungal antibiotic. J Antibiot 1975;28:721–6. [13] Lin CJ, Robert F, Sukarieh R, Michnick S, Pelletier J. The antidepressant sertraline inhibits translation initiation by curtailing mammalian target of rapamycin signaling. Cancer Res 2010;70:3199–208. [14] Hashimoto K. Role of the mTOR signaling pathway in the rapid antidepressant action of ketamine. Expert Rev Neurother 2011;11:33–6. [15] Lang UE, Heger J, Willbring M, Domula M, Matschke K, Tugtekin SM. Immunosuppression using the mammalian target of rapamycin (mTOR) inhibitor everolimus: pilot study shows significant cognitive and affective improvement. Transplant Proc 2009;41:4285–8. [16] Meikle L, Pollizzi K, Egnor A, Kramvis I, Lane H, Sahin M, et al. Response of a neuronal model of tuberous sclerosis to mammalian target of rapamycin (mTOR) inhibitors: effects on mTORC1 and Akt signaling lead to improved survival and function. J Neurosci 2008;28:5422–32. [17] McDaniel SS, Wong M. Therapeutic role of mammalian target of rapamycin (mTOR) inhibition in preventing epileptogenesis. Neurosci Lett 2011 Feb 24. [Epub ahead of print].