Effect of combination therapy with pramipexole and n-acetylcysteine on global cerebral ischemic reperfusion injury in rats

Document Type : Original Article

Authors

1 Department of Pharmacology, Acharya Nagarjuna University College of Pharmaceutical Sciences, Acharya Nagarjuna University, Guntur, India

2 Nirmala College of Pharmacy, Guntur, India

Abstract

Objective(s): The study was intended to investigate the combined influence of two neuroprotective agents pramipexole and n-acetylcysteine on global cerebral ischemic reperfusion injury (GCIRI) model in rats.
Materials and Methods: GCIRI was induced by bilateral common carotid artery ligation (BCCA) in rats. Animals were divided into six groups. Groups I, II, and III received saline intraperitoneally (IP) (5 ml/kg/day, 0.9 % saline). The remaining groups IV, V, and VI were treated with n-acetylcysteine (NAC-150 mg/kg/day, IP), pramipexole (PPX-0.23 mg/kg/day, IP) alone and in combination, respectively. BCCA was done in all groups except in groups I (control) and II (sham control) of animals. The treatment was given for one week before the surgery and continued for two days after surgery. Subsequently, behavioral performances, biochemical estimations, proinflammatory cytokines, and histopathological evaluations were done.
Results: NAC, PPX, and combination treatment groups showed significant ameliorative effects on behavioral, biochemical, proinflammatory cytokines, and histopathological studies as compared with the BCCA group. Whereas, the combination group showed a significant difference in ameliorating the pathological changes of biochemical parameters and histopathological changes in comparison with the PPX alone treated group but not with the NAC alone group.
Conclusion: The study concluded that in the combination treatment group the histopathological parameter improved and the oxidative stress parameters were mitigated significantly compared with the PPX alone treatment group but not with the NAC alone treatment group.

Keywords

Main Subjects


1. Helen MB, Dalton DW. Pathophysiology of cerebral ischemia and brain trauma: Similarities and differences. J Cerebr Blood Flow Metab 2003; 24:133-150.
2. Dirnagl U, Ladecola C, Moskowitz MA. Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci 1999; 22:391-397.
3. Neetu S, Gaurav S, Nilendra S and Kashif H. Acomparative study of neuroprotective effect of single and combined blockade of AT1 receptor and PARP-1 in focal cerebral ischemia in rat. Int J Stroke 2012; 9:560-568.
4. Suresh LM, Namratta M, Ram R. Molecular targets in cerebral ischemia for developing novel therapeutics. Brain Res Rev 2007; 54:34-66.
5. Huck JH, Freyer D, Bottcher C, Mladinov M, Muselmann-Genschow C, Thielke M, et al. De novo expression of dopamine D2 receptors on microglia after stroke. J Cerebr Blood Flow Metab 2015; 35:1804-1811.
6. Ling ZD, Robie HC, Tong CW, Carvey PM. Both the antioxidant and D3 agonist actions of pramipexole mediate its neuroprotective actions in mesencephalic cultures. J Pharmacol Exp Ther 1999; 289:202-210
7. Ma J, Wang Z, Liu C, Shen H, Chen Z, Yin J, et al. Pramipexole-induced Hypothermia Reduces Early Brain Injury Via PI3K/AKT/GSK3β pathway in Subarachnoid Hemorrhage rats. Sci Rep 2016; 6:1-11.
8. Goossens J, Hachimi-Idrissi S. Combination of therapeutic hypothermia and other neuroprotective strategies after an ischemic cerebral insult. Curr Neuropharmacol 2014; 12:399-412.
9. Erkut B, Ozyazicioglu A, Karapolat BS, Kocogullari CU, Keles S, Ates A, et al. Effect of ascorbic acid, alpha-tocopherol and allopurinol on ischemic-reperfusion injury in rabbit skeletal muscle: an experimental study. Drug Target Insights 2007; 2:249-258.
10. Eakin K, Baratz-Goldstein R, Pick CG, Zindel O, Balaban CD, Hoffer ME, et al. Effect of N-acetyl cysteine in traumatic brain injury. PLoS One 2014; 9:e90617.
11. Ozdemir HH, Ilhan S, Demir CF, Akgun B, Kapan O, Atas E, et al. Effects of memantine and clopidogrel alone and in combination in cerebral ischemia-reperfusion model. Neurol Psychiat BR 2015; 21:73-77.
12. Kulkarni SK. Handbook of Experimental Pharmacology. New delhi: VallabhPrakashan; 1999.
13. Hunter AJ, Hatcher J, Virley D, Nelson P, Irving E, Hadingham SJ, et al. Functional assessments in mice and rats after focal stroke. Neuropharmacol 2000; 39:806-816.
14. Hong SH, Belayev L, Khoutorova L, Obenaus A, Bazan NG. Docosahexaenoic acid confers enduring neuroprotection in experimental stroke. J Neurol Sci 2014;338:135-141.
15. Wolf A, Bauer B, Abner EL, Ashkenazy-Frolinger T, Hartz AM. A comprehensive behavioral test battery to assess learning and memory in 129s6/tg2576 mice. PLoS One 2016; 11:e0147733.
16. Bora KS, Sharma A. Neuroprotective effect of Artemisia absinthium L. on focal ischemia and reperfusion-induced cerebral injury. J Ethnopharmacol 2010; 129:403-409.
17. Akhtar M, Pillai KK, Vohora D. Effect of thioperamide on oxidative stress markers in middle cerebral artery occlusion model of focal cerebral ischemia in rats. Hum Exp toxicol 2008;27:761-767.
18. Sedlak J, Lindsay RH. Estimation of total, protein bound, and nonprotein sulfhydryl groups in tissue with Ellman’s reagent. Anal biochem 1968; 25:192-205.
19. Ellman GL. Tissue sulfhydryl groups. Arch Biochem Biophys 1959; 82:70-77.
20. Marklund S, Marklund G. Involvement of the superoxide anion radical in the autoxidation of pyrogallol and a convenient assay for superoxide dismutase. Eur J Biochem 1974; 47:469-474.
21. Srikumar BN, Ramkumar K, Raju TR and Shankaranarayana Rao BS. Assay of Acetyl cholinesterase activity in the brain. Neuro Sci 2004; 142-144.
22. Seo JH, Park HP, Jeon YT, Lim YJ, Nam K, Hwang JW. Combined treatment with celecoxib and sevoflurane after global cerebral ischaemia has no additive neuroprotective effects in rats. Brit J Anaesth 2013:aet009.
23. Fisher M, Hanley DF, Howard G, Jauch EC, Warach S. Recommendations from the STAIRV meeting on acute stroke trials, technology and outcomes. Stroke 2007; 38: 2391-2398.
24. Wu C, Zhang J, Chen Y. Study on the behavioral changes of a poststroke depression rat model. Exp Ther Med 2015; 10:159-163.
25. Jiang M, Li J, Peng Q, Liu Y, Liu W, Luo C, et al. Neuroprotective effects of bilobalide on cerebral ischemia and reperfusion injury are associated with inhibition of pro-inflammatory mediator production and down-regulation of JNK1/2 and p38 MAPK activation. J Neuroinflammation 2014; 11:167.
26. Dawson VL, Dawson TM. Free radicals and neuronal cell death. Cell Death Differ 1996; 3:71-78.
27. Erkut B, Onk OA. Effect of N-acetylcysteine and allopurinol combination to protect spinal cord ischemia/reperfusion injury induced by aortic cross-clamping in rat model. J Cardiothorac Surg 2015; 10:95.
28. Kilic U, Yilmaz B, Reiter RJ, Yüksel A, Kilic E. Effects of memantine and melatonin on signal transduction pathways vascular leakage and brain injury after focal cerebral ischemia in mice. Neuroscience 2013; 237:268-276.
29. Meldrum B. Protection against ischaemic neuronal damage by drugs acting on excitatory neurotransmission. Cerebrovas Brain Metab Rev 1989; 2:27-57.
30. Maddahi A, Kruse LS, Chen QW, Edvinsson L. The role of tumor necrosis factor-α and TNF-α receptors in cerebral arteries following cerebral ischemia in rat. J Neuroinflammation 2011; 8:107.
31. Allan SM, Tyrrell PJ, Rothwell NJ. Interleukin-1 and neuronal injury. Nat Rev Immunol 2005; 5:629-640.
32. Bavarsad Shahripour R, Harrigan MR, Alexandrov AV. N‐acetylcysteine (NAC) in neurological disorders: mechanisms of action and therapeutic opportunities. Brain Behav 2014; 4:108-122.
33. Zhang Z, Yan J, Taheri S, Liu KJ, Shi H. Hypoxia-inducible factor 1 contributes to N-acetylcysteine’s protection in stroke. Free Radic Biol Med 2014; 68:8-21.
34. Le WD, Jankovic J, Xie W, Appel SH. Antioxidant property of pramipexole independent of dopamine receptor activation in neuroprotection. J Neural Transm 2000; 107:1165-1173.
35. Li C, Guo Y, Xie W, Li X, Janokovic J, Le W. Neuroprotection of pramipexole in UPS impairment induced animal model of Parkinson’s disease. Neurochem Res 2010; 35:1546-1556.
36. Kim JY, Yenari MA. Hypothermia for treatment of stroke. Brain Circ 2015; 1:14.
37. Allahtavakoli M, Kahnouei MH, Rezazadeh H, Roohbakhsh A, Mahmoodi MH, Moghadam-Ahmadi A, Zarisfi M. Delayed combination therapy of local brain hypothermia and decompressive craniectomy on acute stroke outcome in rat. Iranian journal of basic medical sciences. 2014;17:476.
38. Ma J, Wang Z, Liu C, Shen H, Chen Z, Yin J, et al. Pramipexole-induced hypothermia reduces early brain injury via PI3K/AKT/GSK3β pathway in subarachnoid hemorrhage rats. Sci Rep 2016; 6.
39. Cuzzocrea S, Mazzon E, Costantino G, Serraino I, Dugo L, Calabrò G, et al. Beneficial effects of n‐acetylcysteine on ischaemic brain injury. Br J pharmacol 2000; 130:1219-1226.
40. Prakash A, Kumar A. Effect of N‐acetyl cysteine against aluminium‐induced cognitive dysfunction and oxidative damage in rats. Basic Clin Pharmacol Toxicol 2009; 105:98-104.
41. Khan M, Sekhon B, Jatana M, Giri S, Gilg AG, Sekhon C, et al. Administration of N‐acetylcysteine after focal cerebral ischemia protects brain and reduces inflammation in a rat model of experimental stroke. J Neurosci Res 2004; 76:519-527.
42. Khairova RA, Machado-Vieira R, Du J, Manji HK. A potential role for pro-inflammatory cytokines in regulating synaptic plasticity in major depressive disorder. Int J Neuropsychopharmacol 2009; 12:561-578.
43. Lieberknecht V, Cunha MP, Junqueira SC, dos Santos Coelho I, de Souza LF, dos Santos AR, et al. Antidepressant-like effect of pramipexole in an inflammatory model of depression. Behav Brain Res 2017; 320:365-373.
44. Dabaghian FH, Hashemi M, Entezari M, Movassaghi S, Goushegir SA, Kalantari S, et al. Effect of Cyperusrotundus on ischemia-induced brain damage and memory dysfunction in rats. Iran J Basic Med Sci 2015; 18:199.
45. Cuzzocrea S, Mazzon E, Costantino G, Serraino I, Dugo L, Calabrò G, et al. Beneficial effects of n‐acetylcysteine on ischaemic brain injury. Br J Pharmacol 2000; 130:1219-1226.