İbrahim ONARAN, Serpil DEMİRCİ, Halil AŞCI, Sanem AŞCI, Duygu Kumbul DOĞUÇ

Neuroprotective Effects of Pregabalin on Cerebral Ischemia and Reperfusion

Background: Stroke is one of the most common causes of death and the leading cause of disability in adults. Cerebral ischemia/reperfusion injury causes cerebral edema, hemorrhage, and neuronal death. Aims: In post-ischemic reperfusion, free radical production causes brain tissue damage by oxidative stress. Pregabalin, an antiepileptic agent was shown to have antioxidant effects. The aim of this study was to evaluate the neuroprotective and antioxidant effects of pregabalin on ischemia and reperfusion in rat brain injury. Study Design: Animal experimentation. Methods: Male Wistar rats weighing (250-300 g) were randomly divided into six groups, each consisting of 6 rats: control (C), pregabalin (P), ischemia (I), pregabalin + ischemia (PI), ischemia + reperfusion (IR) and ischemia + reperfusion + pregabalin (PIR). Rats were initially pre-treated with 50 mg/kg/d pregabalin orally for two days. Then, animals that applied ischemia in I, PI, IR and PIR groups were exposed to carotid clamping for 30 minutes and 20 minutes reperfusion was performed in the relevant reperfusion groups. Results: NR2B receptor levels were significantly lower in the PIR group in comparison to the IR group. In the PIR group, Thiobarbituric acid reactive substance (TBARS) level had statistically significant decrease compared with IR group. Glutathione peroxidase (GSH-PX) levels were also significantly increased in the PIR group compared with I, IR and control groups. In the PI and PIR groups, catalase (CAT) levels were also significantly increased compared with I and IR groups (p=0.03 and p=0.07, respectively). Conclusion: Pregabalin may protect the damage of oxidative stress after ischemia + reperfusion. This result would illuminate clinical studies in the future

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Siegler JE, Martin-Schild S. Early Neurological Deterioration (END) after stroke: the END depends on the definition. Int J Stroke 2011;6:211-2. [CrossRef]
Mohagheghi F, Khalaj L, Ahmadiani A, Rahmani B. Gemfibrozil pretreatment affecting antioxidant defense system and inflam- matory, but not Nrf-2 signaling pathways resulted in female neu- roprotection and male neurotoxicity in the rat models of global cerebral ischemia-reperfusion. Neurotox Res 2013;23:225-37. [CrossRef]
Volkova IuV, Sukhova LL, Davydov VV, Goloborod'ko AV. The activity of the first line enzymes of the antioxidant defence in the liver of pubertal rats during stress. Biomed Khim 2012;58:573-8. [CrossRef]
Wu JQ, Kosten TR, Zhang XY. Free radicals, antioxidant de- fense systems, and schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2013;46:200-6. [CrossRef]
Pérez-Asensio FJ, de la Rosa X, Jiménez-Altayó F, Gorina R, Martínez E, Messeguer A, et al. Antioxidant CR-6 protects against reperfusion injury after a transient episode of focal brain ischemia in rats. J Cereb Blood Flow Metab 2010;30:638-52. [CrossRef]
Lee G, MacLean DM, Ulrich H, Zhao X, Aronowski J, Jayara- man V. RNA based antagonist of NMDA receptors. ACS Chem Neurosci 2014;5:559-67. [CrossRef]
Guard DB, Swartz TD, Ritter RC, Burns GA, Covasa M. Block- ade of hindbrain NMDA receptors containing NR2 subunits in- creases sucrose intake. Am J Physiol Regul Integr Comp Physiol 2009;296:921-8. [CrossRef]
Brouns R, De Deyn PP. The complexity of neurobiological processes in acute ischemic stroke. Clin Neurol Neurosurg 2009;111:483-95. [CrossRef]
Lason W, Chlebicka M, Rejdak K. Research advances in basic mechanisms of seizures and antiepileptic drug action. Pharma- col Rep 2013;65:787-801. [CrossRef]
Maher A, El-Sayed NS, Breitinger HG, Gad MZ. Overexpres- sion of NMDAR2B in an inflammatory model of Alzheim- er's disease: Modulation by NOS inhibitors. Brain Res Bull 2014;109:109-16. [CrossRef]
Schwer CI, Lehane C, Guelzow T, Zenker S, Strosing KM, Spassov S, et al. Thiopental inhibits global protein synthesis by repression of eukaryotic elongation factor 2 and protects from hypoxic neuronal cell death. PLoS One 2013 22;8:e77258.
Martinez JA, Kasamatsu M, Rosales-Hernandez A, Hanson LR, Frey WH, Toth CC. Comparison of central versus periph- eral delivery of pregabalin in neuropathic pain states. Mol Pain 2012;11:8:3.
Cunningham MO, Woodhall GL, Thompson SE, Dooley DJ, Jones RS. Dual effects of gabapentin and pregabalin on gluta- mate release at rat entorhinal synapses in vitro. Eur J Neurosci 2004;20:1566-76. [CrossRef]
Fink K, Dooley DJ, Meder WP, Suman-Chauhan N, Duffy S, Clusmann H, et al. Inhibition of neuronal Ca(2+) influx by ga- bapentin and pregabalin in the human neocortex. Neuropharma- cology 2002;42:229-36. [CrossRef]
Kammerer M1, Brawek B, Freiman TM, Jackisch R, Feuerstein TJ. Effects of antiepileptic drugs on glutamate release from rat and human neocortical synaptosomes. Naunyn Schmiedebergs Arch Pharmacol 2011;383:531-42. [CrossRef]
Ha KY, Carragee E, Cheng I, Kwon SE, Kim YH. Pregabalin as a neuroprotector after spinal cord injury in rats: biochemical analysis and effect on glial cells. J Korean Med Sci 2011;26:404- 11. [CrossRef]
André V, Rigoulot MA, Koning E, Ferrandon A, Nehlig A. Long- term pregabalin treatment protects basal cortices and delays the occurrence of spontaneous seizures in the lithium-pilocarpine model in the rat. Epilepsia 2003;44:893-903. [CrossRef]
Ha KY, Kim YH, Rhyu KW, Kwon SE. Pregabalin as a neuropro- tector after spinal cord injury in rats. Eur Spine J 2008;17:864- 72. [CrossRef]
Ben-Menachem E. Pregabalin pharmacology and its relevance to clinical practice. Epilepsia 2004;45:13-8. [CrossRef]
Safwen K, Selima S, Mohamed E, Ferid L, Pascal C, Mohamed A, et al. Protective effect of grape seed and skin extract on cere- bral ischemia in rat: implication of transition metals. Int J Stroke 2015;10:415-24. [CrossRef]
Rahman A, Ustundag B, Ozercan IH, Burma O, Cekirdekci A, Oz- veren MF, et al. The effect of flavonoids on reduction of reperfusion injury after global cerebral ischemia. TGKDCD 1999;7:430-4.
Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the folinphenol reagents. J Biol Chem 1951;193:265-75.
Liu Y, Belayev L, Zhao W, Busto R, Belayev A, Ginsberg MD. Neuroprotective effect of treatment with human albumin in per- manent focal cerebral ischemia: histopathology and cortical per- fusion studies. Eur J Pharmacol 2001;428:193-201. [CrossRef]
Woolliams JA, Wiener G, Anderson PH, McMurray CH. Varia- tion in the activities of glutathione peroxidase and superoxide dismutase and in the concentration of copper in the blood in various breed crosses of sheep. Res Vet Sci 1983;34:253-6.
Paglia DE, Valentine WN. Studies on the quantitative and quali- tative characterization of erythrocyte glutathione peroxidase. J Lab Clin Med 1967;70:158-69.
Aebi H. Catalase in vitro. Methods Enzymol 1984;105:121-6. [CrossRef]
Wang Z, Liu T, Gan L, Wang T, Yuan X, Zhang B, et al. Shi- konin protects mouse brain against cerebral ischemia/reperfu- sion injury through its antioxidant activity. Eur J Pharmacol 2010;643:211-7. [CrossRef]
Reddy VD, Padmavathi P, Kavitha G, Saradamma B, Vara- dacharyulu N. Alcohol-induced oxidative/nitrosative stress alters brain mitochondrial membrane properties. Mol Cell Bio- chem 2013;375:39-47.
Ozerol E, Bilgic S, Iraz M, Cigli A, Ilhan A, Akyol O. The pro- tective effect of erdosteine on short-term global brain ischemia/ reperfusion injury in rats. Prog Neuropsychopharmacol Biol Psychiatry 2009;33:20-4. [CrossRef]
Ahmad A, Khan MM, Ishrat T, Khan MB, Khuwaja G, Raza SS, et al. Synergistic effect of selenium and melatonin on neu- roprotection in cerebral ischemia in rats. Biol Trace Elem Res 2011;139:81-96. [CrossRef]
Cengiz N, Colakoglu N, Kavakli A, Sahna E, Parlakpinar H, Acet A. Effects of caffeic acid phenethyl ester on cerebral cortex: struc- tural changes resulting from middle cerebral artery ischemia re- perfusion. Clin Neuropathol 2007;26:80-4. [CrossRef]
Sun L, Tian X, Gou L, Ling X, Wang L, Feng Y, et al. Ben- eficial synergistic effects of concurrent treatment with theanine and caffeine against cerebral ischemia-reperfusion injury in rats. Can J Physiol Pharmacol 2013;91:562-9. [CrossRef]
Blommel ML, Blommel AL. Pregabalin: An antiepileptic agent useful for neuropathic pain. Am J Health Syst Pharm 2007;64:1475-82. [CrossRef]
Kumar A, Goyal R. Possible involvement of GABAergic modu- lation in the protective effect of gabapentin against immobiliza- tion stress-induced behavior alterations and oxidative damage in mice. Fundam Clin Pharmacol 2007;21:575-81. [CrossRef]
Liu Z, Zhao W, Xu T, Pei D, Peng Y. Alterations of NMDA re- ceptor subunits NR1, NR2A and NR2B mRNA expression and their relationship to apoptosis following transient forebrain isch- emia. Brain Res 2010;18;1361:133-9. [CrossRef]
Ogunro PS, Bolarinde AA, Owa OO, Salawu AA, Oshodi AA. Antioxidant status and reproductive hormones in women during reproductive, perimenopausal and postmenopausal phase of life. Afr J Med Med Sci 2014;43:49-57.
Qian H, Liu L. Protective effect of hydrogen sulfide on mice with experimental viral myocarditis and its mechanism. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi 2014;30:708-12.
Gozzi GJ, Pires AD, Martinez GR, Rocha ME, Noleto GR, Eche- varria A, et al. The antioxidant effect of the mesoionic compound SYD-1 in mitochondria. Chem Biol Interact 2013;205:181-7. [CrossRef]
Babu CS, Ramanathan M. Post-ischemic administration of ni- modipine following focal cerebral ischemic-reperfusion injury in rats alleviated excitotoxicity, neurobehavioural alterations and partially the bioenergetics. Int J Dev Neurosci 2011;29:93-105. [CrossRef]
Maheshwari A, Badgujar L, Phukan B, Bodhankar SL, Thakurd- esai P. The protective effect of Etoricoxib against middle cere- bral artery occlusion induced transient focal cerebral ischemia in rats. Eur J Pharmacol 2011;667:230-7. [CrossRef]
Guo C, Tong L, Xi M, Yang H, Dong H, Wen A. Neuroprotective effect of calycosin on cerebral ischemia and reperfusion injury in rats. J Ethnopharmacol 2012;144:768-74.[CrossRef]