Schizophrenia and Mitochondrial Dysfunction

Year 2014, Volume: 6 Issue: 4, 340 - 354, 06.11.2014

Süleyman Akarsu

https://doi.org/10.5455/cap.20140121114707

Abstract

Genetic factors play an important role in the development of schizophrenia that the etiology is clearly not known. However, specific inheritance mechanism of this disorder is still unclear. Inheritance of schizophrenia is thought to be polygenic or multifactorial. In the recent studies, mitochondrial function and cerebral energy metabolism abnormalities have been identified in patients with schizophrenia. Cognitive deficits and behavioral abnormalities evident as typically found in the clinical course of schizophrenia may develop due to the affection of neuronal plasticity and brain circuits by impaired function of mitochondria. Some changes were found in patients with schizophrenia compared with control subjects in the researches examining both brain and peripheral tissues. Also, it was seen that antipsychotics used in the treatment of schizophrenia might lead to a progressive reduction in oxidative phosphorylation capacity of mitochondria by inhibition of respiratory chain. Especially the findings of the peripheral tissues in patients with schizophrenia were considered to be used as a biological marker for schizophrenia in these studies. Changes in the mitochondria of platelets are considered as a peripheral model for the neurons because of the lack of the platelets' own DNA. These changes reflect the findings of the brain in a variety of neuropsychiatric disorders. At the present time, making the diagnosis of schizophrenia based on only clinical criteria reveal the necessity of finding peripheral biological marker for schizophrenia. Thus further systematic studies investigating the relationship between schizophrenia and changes in mitochondrial electron transport chain are required.

Keywords

Schizophrenia, mitochondrial dysfunction, biological marker

Şizofreni ve Mitokondrial Disfonksiyon

Abstract

Etyolojisi net olarak bilinmeyen şizofreninin oluşumunda genetik faktörler önemli rol oynamaktadır. Ancak, bu bozukluğun spesifik kalıtımsal mekanizması henüz açıklanamamıştır. Şizofreni kalıtımının poligenik veya multifaktöryel olabileceği düşünülmektedir. Son dönemde yapılan çalışmalarda, şizofreni olgularında mitokondrial fonksiyon ve serebral enerji metabolizmasında anormallikler tespit edilmiştir. Mitokondri fonksiyonlarındaki bozulma ile nöronal plastisite ve beyin devreleri etkilenerek, şizofreninin klinik tablosunda da belirgin olarak rastlanabilen davranış anormallikleri ve bilişsel defisitler gelişebilir. Şizofreni olgularının hem beyin hem de periferal dokularının incelendiği araştırmalarda, şizofreni olgularında sağlıklı olgulara göre bazı değişiklikler saptanmıştır. Ayrıca şizofreni tedavisinde kullanılan antipsikotiklerin solunum zinciri inhibisyonu yaparak mitokondrinin oksidatif fosforilasyon kapasitesinde progresif olarak azalmaya neden olabileceği görülmüştür. Bu çalışmalarda, özellikle periferal dokulardan elde edilen bulguların, şizofreni tanısında biyolojik bir belirteç olarak kullanılabileceği önerilmiştir. Plateletlerin kendi DNA'sı olmadığı için, platelet mitokondrisinde gerçekleşen değişiklikler nöronlar için periferal bir model olarak kabul edilmektedir. Bu değişiklikler çeşitli nöropsikiyatrik rahatsızlıklarda beyindeki bulguları yansıtmaktadır. Günümüzde şizofreni tanısının klinik ölçütlere dayalı olması, şizofreni için periferal biyolojik bir belirteç gerekliliğini ortaya koymaktadır. Bu nedenle mitokondrial elektron transport zincirindeki değişikliklerin şizofreni ile ilişkisini araştıran daha sistematik çalışmaların yapılması gereklidir.

Keywords

Şizofreni, mitokondrial disfonksiyon, biyolojik belirteç

References

• Sevi OM, Özyurt BE. Otomatik Düşünceler Ölçeği’nin şizofreni hastalarının olumsuz otomatik düşüncelerini değerlendirmede geçerlik ve güvenirliğine dair bir ön çalışma. Anatolian Journal of Clinical Investigation 2013; 7:1-9.
• Ohara K, Nagai M, Tani K, Nakamura Y, Ino A, Ohara K. Functional polymorphism of 141 ins/del in the dopamine D2 receptor gene promoter and schizophrenia. Psychiatry Res 1998; 81:117-123.
• Sobell JL, Mikesell MJ, Mcmurray CT. Genetics and etiopatho-physiology of schizophrenia. Mayo Clin Proc 2002; 7:106810
• Bren G, Brown J, Maude S, Fox H, Collier D, Li T et al. 141 C Del/Ins polymorphism of the dopamine receptor 2 gene is associated with schizophrenia in British population. Am J Med Genet 1997; 88:407-410.
• Virgos C, Martorell L, Valero J, Figuera L, Civeira F, Joven J et al. Association study of schizophrenia with polymorphisms at six candidate genes. Schizophr Res 2001; 49:65-71.
• Gelernter J, Kranzler H, Cubells JF, Ichinose H, Nagatsu T. DRD2 alele frequencies and linkage disequilibria, ıncluding the – 141 C Ins/Del promoter polymorphism, in European-American, African-American, and Japanese Subjects. Genomics 1998; 5:21Itokawa M, Arinami T, Futamura N, Hamaguchi H, Toru M. A structural polymorphism of human dopamine D2 receptor, D2 (Ser311Cys). Biochem Biophys Res Commun 1993; 196:1369-1375.
• Gelernter J, Kranzler H. D2 Dopamine receptor gene (DRD2) alele and haplotype frequencies in alcohol dependent and control subjects: no association with phenotype or severity of phenotype. Neuropsychopharmacology 1999; 20:640-649. Hori H, Ohmori O, Shinkai T, Kojima H, Nakamura J. Association analysis between two functional dopamine d2 receptor gene polymorphisms and schizophrenia. Am J Med Genet 2001; 105:176-178.
• Ben Shachar D. Mitochondrial dysfunction in schizophrenia: a pos-sible linkage to dopamine. J Neurochem 2002; 83:1241–1251.
• Ben Shachar D, Laifenfeld D. Mitochondria, synaptic plasticity, and schizophrenia. Int Rev Neurobiol 2004; 59:273–296. Buchsbaum MS. The frontal lobes, basal ganglia, and temporal lobes as sites for schizophrenia. Schizophr Bull 1990; 16:379–389.
• Buchsbaum MS, Nuechterlein KH, Haier RJ, Wu J, Sicotte N, Hazlett E et al. Glucose metabolic rate in normals and schizophrenics during the continuous performance test assessed by positron emission tomography. Br J Psychiatry 1990; 156:216–227.
• Buchsbaum MS, Buchsbaum BR, Hazlett EA, Haznedar MM, Newmark R, Tang CY et al. Relative glucose metabolic rate higher in white matter in patients with schizophrenia. Am J Psychiatry 2007; 164:1072–1081.
• Cohen RM, Semple WE, Gross M, Nordahl TE, King AC, Pickar D et al. Evidence for common alterations in cerebral glucose metabolism in major affective disorders and schizophrenia. Neuropsychopharmacology 1989; 2:241–254.
• Gur RE, Mozley PD, Resnick SM, Mozley LH, Shtasel DL, Gallacher F et al. Resting cerebral glucose metabolism in firstepisode and previously treated patients with schizophrenia relates to clinical features. Arch Gen Psychiatry 1995; 52:657– 6
• Hazlett EA, Buchsbaum MS, Haznedar MM, Singer MB, Germans MK, Schnur DB et al. Prefrontal cortex glucose metabolism and startle eyeblink modification abnormalities in unmedicated schizophrenia patients. Psychophysiology 1998; 35:186– 1
• Hazlett EA, Buchsbaum MS, Kemether E, Bloom R, Platholi J, Brickman AM et al. Abnormal glucose metabolism in the mediodorsal nucleus of the thalamus in schizophrenia. Am J Psychiatry 2004; 161:305–314.
• Haznedar MM, Buchsbaum MS, Hazlett EA, Shihabuddin L, New A, Siever LJ. Cingulate gyrus volume and metabolism in the schizophrenia spectrum. Schizophr Res 2004; 71:249–262.
• Iwamoto K, Bundo M, Kato T. Altered expression of mitochondria-related genes in postmortem brains of patients with bipolar disorder or schizophrenia, as revealed by large-scale DNA microarray analysis. Hum Mol Genet 2005; 14:241–253. Middleton FA, Mirnics K, Pierri JN, Lewis DA, Levitt P. Gene expression profiling reveals alterations of specific metabolic pathways in schizophrenia. J Neurosci 2002; 22:2718–2729.
• Prabakaran S, Swatton JE, Ryan MM, Huffaker SJ, Huang JT, Griffin JL et al. Mitochondrial dysfunction in schizophrenia: evidence for compromised brain metabolism and oxidative stress. Mol Psychiatry 2004; 9:684–697.
• Shao L, Martin MV, Watson SJ, Schatzberg A, Akil H, Myers RM et al. Mitochondrial involvement in psychiatric disorders. Ann Med 2008; 40:281–295.
• Horton HR, Moran LA, Ochs RS, Rawn JD, Scrimgeour KG. Principles of Biochemistry. Englewood Cliffs, Neil Patterson Publishers, 1993.
• Schaitman C, Greenawalt JW. Enzymatic properties of the inner and outer membranes of rat liver mitochondria. J Cell Biol 1968;8:158–175.
• Smith D, Filipowicz C, McCauley R. Monoamine oxidase A and monoamine oxidase B activities are catalyzed by different proteins. Biochim Biophys Acta 1985;31:1–7.
• Clay HB, Sillivan S, Konradi C. Mitochondrial dysfunction and pathology in bipolar disorder and schizophrenia. Int J Dev Neurosci 2011; 29:311–324.
• 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.
• Brandon MC, Lott MT, Nguyen KC, Spolim S, Navathe SB, Baldi P et al. MITOMAP: a human mitochondrial genome database – 2004 update. Nucleic Acids Res 2005; 33:611–613.
• Wallace DC. Mitochondrial diseases in man and mouse. Science 1999; 283:1482–1488.
• Green DR, Kroemer G. The pathophysiology of mitochondrial cell death. Science 2004; 305:626-629.
• Lenaz G. The mitochondrial production of reactive oxygen species: mechanisms and implications in human pathology. IUBMB Life 2001; 52:159-164.
• Albin RL. Greenamyre JT. Alternative excitotoxic hypotheses. Neurology 1992; 42:733-738.
• Beal MF. Does impairment of energy metabolism result in cytotoxic neuronal death in neurodegenerative illnesses? Ann Neurol 1992; 31:119-130.
• Di Donato S. Disorders related to mitochondrial membranes: Phatology of the respiratory chain and neurodegeneration. J. Inherit Metab Dis 2000; 23:247–263.
• Manfredi G, Beal F. The role of mitochondria in the pathogenesis of neurodegenerative diseases. Brain Pathol 2000; 10:462–472.
• Van den Heuvel L, Smeitink J. The oxidative phophorylation (OXPHOS) system: nuclear genes and human genetic diseases. Bioessays 2001; 23:518–525.
• Mutisya EM, Bowling AC, Beal MF. Cortical cytochrome oxidase activity is reduced in Alzheimer's disease. J Neurochem 1994; 63:2179-2184.
• Parker WD, Filley CM, Parks JK. Cytochrome oxidase deficiency in Alzheimer's disease. Neurology 1990; 40:1302-1303.
• Schapira AHV, Cooper JM, Dexter D. Mitochondrial complex I deficiency in Parkinson's disease. J Neurochem 1990; 54:8238
• Beal MF. Aging, energy and oxidative stress in neurodegenerative diseases. Ann Neurol 1995; 38:357-366.
• Corral-Debrinski M, Horton T, Lott MT, Shoffner JM, Beal MF, Wallace DC. Mitochondrial DNA deletions in human brain: regional variability and increase with advancing age. Nature Genet 1992; 2:324-329.
• Tritschler HJ, Packer L, Medori R. Oxidative stress and mitochondrial dysfunction in neurodegeneration. Biochem Mol Biol Int 1994; 34:169-181.
• Kato T. The other, forgotten genome: mitochondrial DNA and mental disorders. Mol Psychiatry 2001; 6:625–633.
• Wallace DC. Diseases of the mitochondrial DNA. Annu Rev Biochem 1992; 61:1175–1212.
• Hao H, Bonilla E, Manfredi G, DiMauro S, Moraes CT. Segregation patterns of a novel mutation in the mitochondrial tRNA glutamic acid gene associated with myopathy and diabetes mellitus. Am J Hum Genet 1995; 56:1017–1025.
• Simon DK, Johns DR. Mitochondrial disorders: clinical and genetic features. Annu Rev Med 1999; 50:111–127.
• Fattal O, Budur K, Vaughan AJ, Franco K. Review of the literature on major mental disorders in adult patients with mitochondrial diseases. Psychosomatics 2006; 47:1–7.
• Di Mauro S, Moraes CT. Mitochondrial encephalomyopathies. Arch Neurol 1993; 50:1197–1208.
• Oexle K, Zwirner A. Advanced telomere shortening in respiratory chain disorders. Hum Mol Genet 1997; 6:905–908.
• Prayson RA, Wang N. Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke like episodes (MELAS) syndrome: an autopsy. Arch Pathol Lab Med 1998; 122:978–981.
• Siciliano G, Tessa A, Petrini S, Mancuso M, Bruno C, Grieco GS et al. Autosomal dominant external ophthalmoplegia and bipolar affective disorder associated with a mutation in the ANT1 gene. Neuromuscul Disord 2003; 13:162–165.
• Grover S, Padhy SK, Das CP, Vasishta RK, Sharan P, Chakrabarti S. Mania as a first presentation in mitochondrial myopathy. Psychiatry Clin Neurosci 2006; 60:774–775.
• Kasahara T, Kubota M, Miyauchi T, Noda Y, Mouri A, Nabeshima T et al. Mice with neuronspecific accumulation of mitochondrial DNA mutations show mood disorder-like phenotypes. Mol Psychiatry 2006; 11:577–593.
• Takahashi Y. An enzymological study on brain tissue of schizophrenic patients: carbohydrate metabolism. Folia Psychiatrica Neurologica Japonica 1954; 7:214-237.
• Uranova NA, Aganova EA. Ultrastructure of synapses of the anterior limbic cortex in schizophrenia. Zhurnal Nevropatologii i Psikhiatrii im S.S. Korsakova 1989; 89:56-59.
• Kung L, Roberts RC. Mitochondrial pathology in human schizophrenic striatum: a postmortem ultrastructural study. Synapse 1999; 31:67–75.
• 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.
• Wong-Riley M. Cytochrome oxidase: an endogenous metabolic marker for neuronal activity. Trends Neurosci 1989; 12:94–
• Cavelier L, Jazin E, Eriksson I, Prince J, Bave B, Oreland L et al. Decreased cytochrome c oxidase activity and lack of age related accumulation of mtDNA in brain of schizophrenics. Genomics 1995; 29:217–228.
• Prince JA, Blennow K, Gottfries CG, Karlsson I, Oreland L. Mitochondrial function in differentially altered in the basal ganglia of chronic schizophrenics. Neuropsychopharmacology 1997; 21:372–379.
• Maurer I, Moller HJ. Inhibition of complex I by neuroleptics in normal human brain cortex paralles the extrapyramidal toxicity of neuroleptics. Mol Cell Biochem 1997; 174:255–259.
• Prince JA, Harro J, Blennow K, Gottfries CG, Karlsson I, Oreland L. Putamen mitochondrial energy metabolism is highly correlated to emotional and intellectual impairment in schizophrenics. Neuropsychopharmacology 2000; 22:284–292.
• Whatley SA, Curi D, Marchbanks RM. Mitochondrial involvement in schizophrenia and other functional psychoses. Neurochem Res 1996; 21:995–1004.
• Dror N, Klein E, Karry R, Sheinkman A, Kirsh Z, Mazor M. State dependent alterations in mitochondrial complex I activity in platelets: a potential peripheral marker for schizophrenia. Mol Psychiatry 2002; 7:995–1001.
• Albensi BC, Sullivan PG, Thompson MB, Scheff SW, Mattson MP. Cyclosporin ameliorates traumatic brain-injury-induced alterations of hippocampal synaptic plasticity. Exp Neurol 2000; 162:385–389.
• Calabresi P, Gubellini P, Picconi B, Centonze D, Pisani A, Bonsi P et al. Inhibition of mitochondrial complex II induces a long-term potentiation of NMDA-mediated synaptic excitation in the striatum requiring endogenous dopamine. J Neurosci 2001; 21:5110 –5120.
• Mattson MP, La Ferla FM, Chan SL, Leissring MA, Shepel PN, Geiger JD. Calcium signaling in the ER: Its role in neuronal plasticity and neurodegenerative disorders. Trends Neurosci 2000; 23:222–229.
• Weeber EJ, Levy M, Sampson MJ, Anflous K, Armstrong DL, Brown SE et al. The role of mitochondrial porins and the permeability transition pore in learning and synaptic plasticity. J Biol Chem 2002; 277:18891– 18897.
• Karry R, Klein E, Ben Shachar D. Mitochondrial complex I subunits expression ıs altered in schizophrenia: a postmortem study. Biol Psychiatry 2004; 55:676–684.
• Fukuzako H, Fukuzako T, Hashiguchi T, Kodama S, Takigawa M, Fujimoto T. Changes in levels of phosphorus metabolites in temporal lobes of drug-naive schizophrenic patients. Am J Psychiatry 1999; 156:1205–1208.
• Volz HR, Riehemann S, Maurer I, Smesny S, Sommer M, Rzanny R et al. Reduced phosphodiesters and high-energy phosphates in the frontal lobe of schizophrenic patients: A 31P chemical shift spectroscopic-imaging study. Biol Psychiatry 2000; 47:954 –961.
• Barnes J, Howard RJ, Senior C, Brammer M, Bullmore ET, Simmons A et al. Cortical activity during rotational and linear transformations. Neuropsychologia 2000; 38:1148 –1156.
• Aleman A, Bocker KBE, Hijman R, Kahn RS et al. Hallucinations in schizophrenia: Imbalance between imagery and perception. Schizophr Res 2002; 57:315–316.
• Frith C, Dolan RJ. Brain mechanisms associated with top-down processes in perception. Phils Trans R Soc Lond B Biol Sci 1997; 352:1221–1230.
• Whittaker JF, Deakin JF, Tomenson B. Face processing in schizophrenia: Defining the deficit. Psychol Med 2001; 31:499 – 50
• Harrison PJ, Weinberger DR. Schizophrenia genes, gene exp-ression, and neuropathology: on the matter of their convergence. Mol Psychiatry 2005; 10:40–68.
• Chouinard G, Miller R. A rating scale for psychotic symptoms (RSPS) part I: theoretical principles and subscale 1: perception symptoms (illusions and hallucinations). Schizophr Res 1999; 38:101–122.
• Ben Shachar D, Bonne O, Chisin R, Klein E, Lester H, Aharon-Peretz J et al. Cerebral glucose utilization and platelet mitochondrial complex I activity in schizophrenia: A FDG-PET study. Prog Neuropsychopharmacol Biol Psychiatry 2007; 31:807–813.
• Ben Shachar D, Karry R. Neuroanatomical pattern of mitochondrial Complex I pathology varies between schizophrenia, bipolar disorder and major depression. PLoS ONE 2008; 3:e3676.
• Weinberger DR. Implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry 1987; 44:660–669.
• Boksa P. Animal models of obstetric complications in relation to schizophrenia. Brain Research. Brain Res Rev 2004; 45:1–
• Golan H, Huleihel M. The effect of prenatal hypoxia on brain development: Short and long-term consequences demonstrated in rodent models. Dev Sci 2006; 9:338–349.
• Clarke MC, Harley M, Cannon M. The role of obstetric events in schizophrenia. Schizophr Bull 2006; 32:3–8.
• Becker A, Grecksch G, Bernstein HG, Hollt V, Bogerts B. Social behaviour in rats lesioned with ibotenic acid in the hippocampus: quantitative and qualitative analysis. Psychopharmacology 1999; 144:333–338.
• Goto Y, O’Donnell P. Delayed mesolimbic system alteration in a developmental animal model of schizophrenia. J Neurosci 2002; 22:9070–9077.
• Le Pen G, Grottick AJ, Higgins GA, Martin JR, Jenck F, Moreau JL. Spatial and associative learning deficits induced by neonatal excitotoxic hippocampal damage in rats: further evaluation of an animal model of schizophrenia. Behav Pharmacol 2000; 11:257–268.
• Le Pen G, Moreau JL. Disruption of prepulse inhibition of startle reflex in a neurodevelopmental model of schizophrenia: reversal by clozapine, olanzapine and risperidone but not by haloperidol. Neuropsychopharmacology 2002; 27:1–11.
• Lipska BK, Jaskiw GE, Weinberger DR. Postpubertal emergence of hyperresponsiveness to stress and to amphetamine after neonatal excitotoxic hippocampal damage: a potential animal model of schizophrenia. Neuropsychopharmacology 1993; 9:67–75.
• Lipska BK, Weinberger DR. To model a psychiatric disorder in animals: schizophrenia as a reality test. Neuropsychopharmacology 2000; 23:223–239.
• Schroeder H, Grecksch G, Becker A, Bogerts B, Hoellt V. Alterations of the dopaminergic and glutamatergic neurotransmission in adult rats with postnatal ibotenic acid hippocampal lesion. Psychopharmacology 1999; 145:61–66. Bertolino A, Frye M, Callicott JH, Mattay VS, Rakow R, Shelton-Repella J et al. Neuronal pathology in the hippocampal area of patients with bipolar disorder: a study with proton magnetic resonance spectroscopic imaging. Biol Psychiatry 2003; 53:906–913.
• Lipska BK, Lerman DN, Khaing ZZ, Weickert CS, Weinberger DR. Gene expression in dopamine and GABA systems in an animal model of schizophrenia: effects of antipsychotic drugs. Eur J Neurosci 2003; 18:391–402.
• Tseng KY, Lewis BL, Lipska BK, O’Donnell P. Post-pubertal disruption of medial prefrontal cortical dopamine– glutamate interactions in a developmental animal model of schizophrenia. Biol Psychiatry 2007; 62:730–738.
• Ben Shachar D, Nadri C, Karry R, Agam G. Mitochondrial complex I subunits are altered in rats with neonatal ventral hippocampal damage but not in rats exposed to oxygen restriction at neonatal age. J Mol Neurosci 2009; 38:143–151.
• Buchsbaum MS, Hazlett EA. Positron emission tomography studies of abnormal glucose metabolism in schizophrenia. Schizophr Bull 1998; 24:343–346.
• Patel TB, Clark JB. Synthesis of N-acetyl-L-aspartate by rat brain mitochondria and its involvement in mitochondrial/cytosolic carbon transport. Biochem J 1979; 184:539–546.
• Clark JB. N-acetyl aspartate: a marker for neuronal loss or mitochondrial dysfunction. Dev Neurosci 1998; 20:271–276.
• Steen RG, Hamer RM, Lieberman JA. Measurement of brain metabolites by 1H magnetic resonance spectroscopy in patients with schizophrenia: a systematic review and meta-analysis. Neuropsychopharmacology 2005; 30:1949–1962. Yildiz-Yesiloglu A, Ankerst DP. Neurochemical alterations of the brain in bipolar disorder and their implications for pathophysicology: a systematic review of the in vivo proton magnetic resonance spectroscopy findings. Prog Neuropsychopharmacol Biol Psychiatry 2006; 30:969–995.
• MacDonald ML, Naydenov A, Chu M, Matzilevich D, Konradi C. Decrease in creatine kinase messenger RNA expression in the hippocampus and dorsolateral prefrontal cortex in bipolar disorder. Bipolar Disord 2006; 8:255–264.
• Richter C, Gogvadze V, Laffranchi R, Schlapbach R, Schweizer M, Suter M et al. Oxidants in mitochondria: from physiology to disease. Biochim Biophys Acta 1995; 1271:67–74.
• Wei YH, Lu CY, Lee HC, Pang CY, Ma YS. Oxidative damage and mutation to mitochondrial DNA and agedependent decline of mitochondrial respiratory function. Ann NY Acad Sci 1998; 854:155–170.
• Mizuno Y, Suzuki K, Ohta S. Postmortem changes in mitochondrial respiratory enzymes in brain and a preliminary observation in Parkinson’s disease. J. Neurol Sci 1990; 96:49–57.
• Prince JA, Yassin M, Oreland L. A histochemical demonstration of altered cytochrome c oxidase activity in the rat brain by neuroleptics. Eur Neuropsychopharmacol 1998; 8:1–6.
• Li JZ, Vawter MP, Walsh DM, Tomita H, Evans SJ, Choudary PV et al. Systematic hanges in gene expression in postmortem human brains associated with tissue pH and terminal medical conditions. Hum Mol Genet 2004; 13:609–616.
• Bahn S, Augood SJ, Ryan M, Standaert DG, Starkey M, Emson PC. Gene expression profiling in the post-mortem human brain–no cause for dismay. J Chem Neuroanat 2001; 22:79–94.
• Ben Shachar D, Zuk R, Gazawi H, Reshef A, Sheinkman A, Klein E. Increased mitochondrial complex I activity in platelets of schizophrenic patients. Int J Neuropsychopharmacol 1999; 2:245–253.
• Mehler-Wex C, Duvigneau JC, Hartl RT, Ben-Shachar D, Warnke A, Gerlach M. Increased mRNA levels of the mitochondrial complex I 75-kDa subunit. a potential peripheral marker of early onset schizophrenia? Eur Child Adolesc Psychiatry 2006; 15:504–507.
• Whatley SA, Curi D, Das Gupta F. Superoxide, neuroleptics and the ubiquinone and cytochrome b5 reductases in brain and lymphocytes from normals and schizophrenic patients. Mol Psychiatry 1998; 3:227–237.
• Da Prada M, Cesura AM, Launany JM, Richards JC. Platelets as a model for neurons? Experientia 1998; 44:115–126.
• Camacho A, Dimsdale JE. Platelets and psychiatry, lessons learned from old and new studies. Psychosom Med 2000; 62:326–336.
• Brenner Lavie H, Klein E, Zuk R, Gazawi H, Ljubuncic P, Ben Shachar D. Dopamine modulates mitochondrial function in viable SH-SY5Y cells possibly via its interaction with complex I: relevance to dopamine pathology in schizophrenia. Biochimica et Biophysica Acta 2008; 1777:173–185.
• Schmauss C, Haroutunian V, Davis KL, Davidson M. Selective loss of dopamine D3-type receptor mRNA expression in parietal and motor cortices of patients with chronic schizophrenia. Proc Natl Acad Sci USA 1993; 90:8942-8946.
• Ilani T, Ben Shachar D, Strous RD, Mazor M, Sheinkman A, Kotler M et al. A peripheral marker for schizophrenia: Increased levels of D3 dopamine receptor mRNA in blood lymphocytes. Proc Natl Acad Sci USA 2001; 98:625–628.
• Kwak YT, Koo MS, Choi CH, Sunwoo I. Change of dopamine receptor mRNA expression in lymphocyte of schizophrenic patients. BMC Med Genet 2001; 2:3.
• Burkhardt C, Kelly JP, Lim YH, Filley CM, Parker WD. Neuro-leptic medications inhibit complex I of the electron transport chain. Ann Neurol 1993; 33:512–517.
• Balijepalli S, Boyd MR, Ravindranath V. Inhibition of mitochondrial complex I by haloperidol: the role of thiol oxidation. Neuropsychopharmacology 1999; 38:567–577.
• Taurines R, Thome J, Duvigneau JC, Forbes-Robertson S, Yang L, Klampfl K et al. Expression analyses of the mitochondrial complex I 75-kDa subunit in early onset schizophrenia and autism spectrum disorder: increased levels as a potential biomarker for early onset schizophrenia. Eur Child Adolesc Psychiatry 2010; 19:441–448.
• Barrientos A, Marín C, Miro O, Casademont J, Gomez M, Nunes V et al. Biochemical and molecular effects of chronic haloperidol administration on brain and muscle mitochondria of rats. J Neurosci Res 1998; 53:475–481. 1 Balijepalli S, Kenchappa RS, Boyd MR, Ravindfanath V. Protein thiol oxidation by haloperidol results in inhibition of mitochondrial complex I in brain regions: comparison with atypical antipsychotics. Neurochem Int 2001; 38:425–435. 1 Gaspar P, Berger B, Febvret A, Vigny A, Henry J. Catecholamine innervation of the human cerebral cortex as revealed by comparative immunohistochemistry of tyrosine hydroxylase and dopamine-beta-hydroxylase. J Comp Neurol 1989; 279:249 –271. 1 Lewis DA, Melchitzky DS, Sesack SR, Whitehead RE, Auh S, Sampson A. Dopamine transporter immunoreactivity in monkey cerebral cortex: Regional, laminar, and ultrastructural localization. J Comp Neurol 2001; 432:119– 136. 1 Subramanyam B, Rollema H, Woolf T, Castagnoli N. Identification of a potentially neurotoxic pyridinium metabolite of haloperidol in rats. Biochem Biophys Res Commun 1990; 166:238–244. 1 Subramanyam B, Woolf T, Castagnoli N. Studies on the in vitro conversion of haloperidol to a potentially neurotoxic pyridinium metabolite. Chem Res Toxicol 1991; 4:123–128. 1 Rollema H, Skolnik M, D’engelbronner J, Igarashi K, Usukı E, Castagnoli N. MPP1-like neurotoxicity of a pyridium metabolite derived from haloperidol: In vivo microdialysis and in vitro mitochondrial studies. J Pharmacol Exp Ther 1994; 268:380–387. 1 Przedborski S, Jackson-Lewis V, Muthane U, Jiang H, Ferreria M, Naini AB et al. Chronic levodopa administration alters cerebral mitochondrial respiratory chain activity. Ann Neurol 1993; 34:715-723. 1 Chan P, Di Monte DA, Luo JJ, DeLanney LE, Irwin I, Langston JW. Rapid ATP loss caused by methamphetamine in the mouse striatum: relationship between energy impairment and dopaminergic neurotoxicity. J Neurochem 1994; 62:2484– 24 1 Berman SB, Hastings TG. Dopamine oxidation alters mitochondrial respiration and induces transition in brain mitochondria: implications for Parkinson’s disease. J Neurochem 1999; 73:1127–1137. 1 Cohen G, Farooqui R, Kesler N. Parkinson’s disease: a new link between monoamine oxidase and mitochondrial electron flow. Proc Natl Acad Sci USA 1997; 94:4890–4894. 1 Ben Shachar D, Zuk R, Glinka Y. Dopamine neurotoxicity: inhibition of mitochondrial respiration. J Neurochem 1995; 64:718–723. 1 Schapira AHV. Evidence for mitochondrial dysfunction in Parkinson’s disease – a critical appraisal. Mov Disord 1994; 9:125–138.
• Süleyman Akarsu, Uzm.Dr., Aksaz Asker Hastanesi, Marmaris Yazışma Adresi/Correspondence: Süleyman Akarsu, Aksaz Asker Hastanesi, Marmaris, Turkey. E-mail: [e-mail] Yazarlar bu makale ile ilgili herhangi bir çıkar çatışması bildirmemiştir. The authors reported no conflict of interest related to this article. Çevrimiçi adresi / Available online at: www.cappsy.org/archives/vol6/no4/ Çevrimiçi yayım / Published online 21 Ocak/January 21, 2014; doi: 10.5455/cap.20140121114707