Abstract
Methylphenidate (MPH) abuse damages brain cells. The neuroprotective effects of topiramate (TPM) have been reported previously, but its exact mechanism of action still remains unclear. This study investigated the in vivo role of various doses of TPM in the protection of rat amygdala cells against methylphenidate-induced oxidative stress and inflammation. Seventy adult male rats were divided into seven groups. Groups 1 and 2 received normal saline (0.7 ml/rat) and MPH (10 mg/kg), respectively, for 21 days. Groups 3, 4, 5, 6, and 7 were concurrently treated with MPH (10 mg/kg) and TPM (10, 30, 50, 70, and 100 mg/kg), respectively, for 21 days. elevated plus maze (EPM) was used to assess motor activity disturbances. In addition, oxidative, antioxidantand inflammatory factors and CREB, Ak1, CAMK4, MAPK3, PKA, BDNF, and c FOS gene levels were measured by RT-PCR, and also, CREB and BDNF protein levels were measured by WB in isolated amygdalae. MPH significantly disturbed motor activity and TPM (70 and 100 mg/kg) neutralized its effects. MPH significantly increased lipid peroxidation, mitochondrial GSSG levels and IL-1β and TNF-α level and CAMK4 gene expression in isolated amygdala cells. In contrast, superoxide dismutase, glutathione peroxidase, and glutathione reductase activities and CREB, BDNF Ak1, MAPK3, PKA, BDNF, and c FOS expression significantly decreased. The various doses of TPM attenuated these effects of MPH. It seems that TPM can be used as a neuroprotective agent and is a good candidate against MPH-induced neurodegeneration.
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Agarwal NB, Agarwal NK, Mediratta PK, Sharma KK (2011) Effect of lamotrigine, oxcarbazepine and topiramate on cognitive functions and oxidative stress in PTZ-kindled mice. Seizure 20(3):257–262
Aguiar AS, Castro AA, Moreira EL, Glaser V, Santos AR, Tasca CI, Latini A, Prediger RD (2011) Short bouts of mild-intensity physical exercise improve spatial learning and memory in aging rats: involvement of hippocampal plasticity via AKT, CREB and BDNF signaling. Mech Ageing Dev 132(11):560–567
Almeida R, Manadas B, Melo C, Gomes J, Mendes C, Graos M, Carvalho R, Carvalho A, Duarte C (2005) Neuroprotection by BDNF against glutamate-induced apoptotic cell death is mediated by ERK and PI3-kinase pathways. Cell Death Differ 12(10):1329–1343
Andreazza AC, Frey BN, Valvassori SS, Zanotto C, Gomes KM, Comim CM, Cassini C, Stertz L, Ribeiro LC, Quevedo J (2007) DNA damage in rats after treatment with methylphenidate. Prog Neuropsychopharmacol Biol Psychiatry 31(6):1282–1288
Armaǧan A, Kutluhan S, Yılmaz M, Yılmaz N, Bülbül M, Vural H, Soyupek S, Nazıroǧlu M (2008) Topiramate and vitamin E modulate antioxidant enzyme activities, nitric oxide and lipid peroxidation levels in pentylenetetrazol-induced nephrotoxicity in rats. Basic Clin Pharmacol Toxicol 103(2):166–170
Arnone D (2005) Review of the use of topiramate for treatment of psychiatric disorders. Ann Gen Psychiatry 4(1):5–15
Arundine M, Tymianski M (2003) Molecular mechanisms of calcium-dependent neurodegeneration in excitotoxicity. Cell Calcium 34(4):325–337
Babcock Q, Byrne T (2000) Student perceptions of methylphenidate abuse at a public liberal arts college. J Am Coll Health 49(3):143–145
Barrett SP, Pihl RO (2002) Oral methylphenidate-alcohol co-abuse. J Clin Psychopharmacol 22(6):633–634
Blendy JA (2006) The role of CREB in depression and antidepressant treatment. Biol Psychiatry 59(12):1144–1150
Cagetti E, Baicy KJ, Olsen RW (2004) Topiramate attenuates withdrawal signs after chronic intermittent ethanol in rats. NeuroReport 15(1):207–210
Cardenas-Rodriguez N, Coballase-Urrutia E, Huerta-Gertrudis B, García-Cruz M, Pedraza-Chaverri J, Coria-Jiménez R, Bandala C, Ruíz-García M (2013) Antioxidant activity of topiramate: an antiepileptic agent. Neurological Sciences 34(5):741–747
Carlezon WA, Duman RS, Nestler EJ (2005) The many faces of CREB. Trends Neurosci 28(8):436–445
Challman TD, Lipsky JJ (2000) Methylphenidate: its pharmacology and uses. In: Mayo Clinic Proceedings, Elsevier, pp 711–721
Davids E, Zhang K, Tarazi FI, Baldessarini RJ (2002) Stereoselective effects of methylphenidate on motor hyperactivity in juvenile rats induced by neonatal 6-hydroxydopamine lesioning. Psychopharmacology 160(1):92–98
Demirci S, Kutluhan S, Nazıroğlu M, Uğuz AC, Yürekli VA, Demirci K (2013) Effects of selenium and topiramate on cytosolic Ca2 + influx and oxidative stress in neuronal PC12 cells. Neurochem Res 38(1):90–97
Dudley JT, Sirota M, Shenoy M, Pai RK, Roedder S, Chiang AP, Morgan AA, Sarwal MM, Pasricha PJ, Butte AJ (2011) Computational repositioning of the anticonvulsant topiramate for inflammatory bowel disease. Science translational medicine 3(96):96ra76
Dworkin S, Mantamadiotis T (2010) Targeting CREB signalling in neurogenesis. Expert Opin Ther Targets 14(8):869–879
Fagundes AO, Rezin GT, Zanette F, Grandi E, Assis LC, Dal-Pizzol F, Quevedo J, Streck EL (2007) Chronic administration of methylphenidate activates mitochondrial respiratory chain in brain of young rats. Int J Dev Neurosci 25(1):47–51
Frey BN, Martins MR, Petronilho FC, Dal-Pizzol F, Quevedo J, Kapczinski F (2006a) Increased oxidative stress after repeated amphetamine exposure: possible relevance as a model of mania. Bipolar Disord 8(3):275–280
Frey BN, Valvassori SS, Gomes KM, Martins MR, Dal-Pizzol F, Kapczinski F, Quevedo J (2006b) Increased oxidative stress in submitochondrial particles after chronic amphetamine exposure. Brain Res 1097(1):224–229
Garnett WR (2000) Clinical pharmacology of topiramate: a review. Epilepsia 41(s1):61–65
Gibbs JE, Walker MC, Cock HR (2006) Levetiracetam: antiepileptic properties and protective effects on mitochondrial dysfunction in experimental status epilepticus. Epilepsia 47(3):469–478
Gomes KM, Comim CM, Valvassori SS, Réus GZ, Inácio CG, Martins MR, Souza RP, Quevedo J (2010) Diurnal differences in memory and learning in young and adult rats treated with methylphenidate. J Neural Transm 117(4):457–462
Guo W, Crossey EL, Zhang L, Zucca S, George OL, Valenzuela CF, Zhao X (2011) Alcohol exposure decreases CREB binding protein expression and histone acetylation in the developing cerebellum. PLoS One 6(5):e19351
Huss M, Lehmkuhl U (2001) Methylphenidate and substance abuse: a review of pharmacology, animal, and clinical studies. J Atten Disord 6:S65–S71
Jones Z, Dafny N (2014) Acute and chronic dose–response effect of methylphenidate on ventral tegmental area neurons correlated with animal behavior. J Neural Transm 121(3):327–345
Khan S, Liberzon I (2004) Topiramate attenuates exaggerated acoustic startle in an animal model of PTSD. Psychopharmacology 172(2):225–229
Kitagawa K (2007) CREB and cAMP response element-mediated gene expression in the ischemic brain. FEBS J 274(13):3210–3217
Klein-Schwartz W (2002) Abuse and toxicity of methylphenidate. Curr Opin Pediatr 14(2):219–223
Koçer A, Memişoğullari R, Domaç FM, Ilhan A, Koçer E, Okuyucu Ş, Özdemir B, Yüksel H (2009) IL-6 levels in migraine patients receiving topiramate. Pain Pract 9(5):375–379
Kuczenski R, Segal DS (2001) Locomotor effects of acute and repeated threshold doses of amphetamine and methylphenidate: relative roles of dopamine and norepinephrine. J Pharmacol Exp Ther 296(3):876–883
Kudin AP, Debska-Vielhaber G, Vielhaber S, Elger CE, Kunz WS (2004) The mechanism of neuroprotection by topiramate in an animal model of epilepsy. Epilepsia 45(12):1478–1487
Kutluhan S, Nazıroğlu M, Çelik Ö, Yılmaz M (2009) Effects of selenium and topiramate on lipid peroxidation and antioxidant vitamin levels in blood of pentylentetrazol-induced epileptic rats. Biol Trace Elem Res 129(1–3):181–189
Lau JW, Senok S, Stadlin A (2000) Methamphetamine-induced oxidative stress in cultured mouse astrocytes. Ann N Y Acad Sci 914(1):146–156
Lee B, Butcher GQ, Hoyt KR, Impey S, Obrietan K (2005) Activity-dependent neuroprotection and cAMP response element-binding protein (CREB): kinase coupling, stimulus intensity, and temporal regulation of CREB phosphorylation at serine 133. J Neurosci 25(5):1137–1148
Mao X-Y, Cao Y-G, Ji Z, Zhou H-H, Liu Z-Q, Sun H-L (2015) Topiramate protects against glutamate excitotoxicity via activating BDNF/TrkB-dependent ERK pathway in rodent hippocampal neurons. Prog Neuropsychopharmacol Biol Psychiatry 60:11–17
Martins MR, Reinke A, Petronilho FC, Gomes KM, Dal-Pizzol F, Quevedo J (2006) Methylphenidate treatment induces oxidative stress in young rat brain. Brain Res 1078(1):189–197
Mattson MP (2007) Calcium and neurodegeneration. Aging Cell 6(3):337–350
McCool BA, Botting SK (2000) Characterization of strychnine-sensitive glycine receptors in acutely isolated adult rat basolateral amygdala neurons. Brain Res 859(2):341–351
Molina-Hernández M, Téllez-Alcántara NP, Olivera-Lopez JI, Jaramillo MT (2010) Antidepressant-like or anxiolytic-like actions of topiramate alone or co-administered with intra-lateral septal infusions of neuropeptide Y in male Wistar rats. Peptides 31(6):1184–1189
Motaghinejad M, Motevalian M (2016) Involvement of AMPA/kainate and GABA A receptors in topiramate neuroprotective effects against methylphenidate abuse sequels involving oxidative stress and inflammation in rat isolated hippocampus. Eur J Pharmacol 784:181–191
Motaghinejad M, Karimian M, Motaghinejad O, Shabab B, Yazdani I, Fatima S (2015a) Protective effects of various dosage of Curcumin against morphine induced apoptosis and oxidative stress in rat isolated hippocampus. Pharmacological Reports 67(2):230–235
Motaghinejad M, Karimian SM, Motaghinejad O, Shabab B, Asadighaleni M, Fatima S (2015b) The effect of various morphine weaning regimens on the sequelae of opioid tolerance involving physical dependency, anxiety and hippocampus cell neurodegeneration in rats. Fundam Clin Pharmacol 29(3):299–309
Motaghinejad M, Motevalian M, Ebrahimzadeh A (2015c) Reduction of methylphenidate induced anxiety, depression and cognition impairment by various doses of venlafaxine in rat. Int J Prev Med 4:52–58
Motaghinejad M, Motevalian M, Larijani SF, Khajehamedi Z (2015d) Protective effects of forced exercise against methylphenidate-induced anxiety, depression and cognition impairment in rat. Adv Biomed Res 21:134–137
Motaghinejad M, Motevalian M, Shabab B (2015e) Effects of chronic treatment with methylphenidate on oxidative stress and inflammation in hippocampus of adult rats. Neurosci Lett 619:106–113
Motaghinejad M, Motevalian M, Shabab B (2015f) Neuroprotective effects of various doses of topiramate against methylphenidate induced oxidative stress and inflammation in rat isolated hippocampus. Clin Exp Pharmacol Physiol 43:360–371
Mula M, Pini S, Cassano GB (2007) The role of anticonvulsant drugs in anxiety disorders: a critical review of the evidence. J Clin Psychopharmacol 27(3):263–272
Nazıroğlu M, Kutluhan S, Uğuz AC, Çelik Ö, Bal R, Butterworth PJ (2009) Topiramate and vitamin E modulate the electroencephalographic records, brain microsomal and blood antioxidant redox system in pentylentetrazol-induced seizure of rats. J Membr Biol 229(3):131–140
Pandey SC, Chartoff EH, Carlezon WA, Zou J, Zhang H, Kreibich AS, Blendy JA, Crews FT (2005) CREB gene transcription factors: role in molecular mechanisms of alcohol and drug addiction. Alcohol Clin Exp Res 29(2):176–184
Patrick KS, Markowitz JS (1997) Pharmacology of methylphenidate, amphetamine enantiomers and pemoline in attention-deficit hyperactivity disorder. Hum Psychopharmacol Clin Exp 12(6):527–546
Peng J, Sarkar S, Chang SL (2012) Opioid receptor expression in human brain and peripheral tissues using absolute quantitative real-time RT-PCR. Drug Alcohol Depend 124(3):223–228
Pinheiro RMC, de Lima MNM, Portal BCD, Busato SB, Falavigna L, Ferreira RDP, Paz AC, de Aguiar BW, Kapczinski F, Schröder N (2015) Long-lasting recognition memory impairment and alterations in brain levels of cytokines and BDNF induced by maternal deprivation: effects of valproic acid and topiramate. J Neural Transm 122(5):709–719
Price TO, Eranki V, Banks WA, Ercal N, Shah GN (2011) Topiramate treatment protects blood-brain barrier pericytes from hyperglycemia-induced oxidative damage in diabetic mice. Endocrinology 153(1):362–372
Réus GZ, Stringari RB, Ribeiro KF, Ferraro AK, Vitto MF, Cesconetto P, Souza CT, Quevedo J (2011) Ketamine plus imipramine treatment induces antidepressant-like behavior and increases CREB and BDNF protein levels and PKA and PKC phosphorylation in rat brain. Behav Brain Res 221(1):166–171
Sadasivan S, Pond BB, Pani AK, Qu C, Jiao Y, Smeyne RJ (2012) Methylphenidate exposure induces dopamine neuron loss and activation of microglia in the basal ganglia of mice. PLoS One 7(3):e33693
Schwartz K, Weizman A, Rehavi M (2006) The effect of psychostimulants on [3H] dopamine uptake and release in rat brain synaptic vesicles. J Neural Transm 113(9):1347–1352
Shaldubina A, Einat H, Szechtman H, Shimon H, Belmaker R (2002) Preliminary evaluation of oral anticonvulsant treatment in the quinpirole model of bipolar disorder. J Neural Transm 109(3):433–440
Shamoto-Nagai M, Maruyama W, Hashizume Y, Yoshida M, Osawa T, Riederer P, Naoi M (2007) In parkinsonian substantia nigra, α-synuclein is modified by acrolein, a lipid-peroxidation product, and accumulates in the dopamine neurons with inhibition of proteasome activity. J Neural Transm 114(12):1559–1567
Shi X-Y, Wang J-W, Cui H, Li B-M, Lei G-F, Sun R-P (2010) Effects of antiepileptic drugs on mRNA levels of BDNF and NT-3 and cell neogenesis in the developing rat brain. Brain Dev 32(3):229–235
Tagaya H (2010) Methylphenidate: pharmacology, indication and potential of abuse. Nihon rinsho Jpn J Clin Med 68(8):1550–1555
Trinh T, Kohllepel S, Yang P, Burau K, Dafny N (2013) Adult female rats’ altered diurnal locomotor activity pattern following chronic methylphenidate treatment. J Neural Transm 120(12):1717–1731
Vendruscolo LF, Izídio GS, Takahashi RN, Ramos A (2008) Chronic methylphenidate treatment during adolescence increases anxiety-related behaviors and ethanol drinking in adult spontaneously hypertensive rats. Behav Pharmacol 19(1):21–27
Williams RJ, Goodale LA, Shay-Fiddler MA, Gloster SP, Chang SY (2004) Methylphenidate and dextroamphetamine abuse in substance-abusing adolescents. Am J Addict 13(4):381–389
Woo NH, Teng HK, Siao C-J, Chiaruttini C, Pang PT, Milner TA, Hempstead BL, Lu B (2005) Activation of p75NTR by proBDNF facilitates hippocampal long-term depression. Nat Neurosci 8(8):1069–1077
Yamamoto BK, Raudensky J (2008) The role of oxidative stress, metabolic compromise, and inflammation in neuronal injury produced by amphetamine-related drugs of abuse. J Neuroimmune Pharmacol 3(4):203–217
Yang J, Shen J (2009) Elevated endogenous GABA concentration attenuates glutamate–glutamine cycling between neurons and astroglia. J Neural Transm 116(3):291–300
Yano M, Steiner H (2007) Methylphenidate and cocaine: the same effects on gene regulation? Trends Pharmacol Sci 28(11):588–596
Yürekli VA, Nazıroğlu M (2013) Selenium and topiramate attenuates blood oxidative toxicity in patients with Epilepsy: a clinical pilot study. Biol Trace Elem Res 152(2):180–186
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We thank head of Razi drug research center in Iran University of medical sciences for providing helpful facilities for this work.
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Motaghinejad, M., Motevalian, M., Falak, R. et al. Neuroprotective effects of various doses of topiramate against methylphenidate-induced oxidative stress and inflammation in isolated rat amygdala: the possible role of CREB/BDNF signaling pathway. J Neural Transm 123, 1463–1477 (2016). https://doi.org/10.1007/s00702-016-1619-1
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DOI: https://doi.org/10.1007/s00702-016-1619-1