EVALUATION OF SAFETY PROFILE AND CEREBROPROTECTIVE POTENTIAL OF DIMETHYL FUMARATE (DMF) AGAINST ISCHEMIA AND REPERFUSION INDUCED CEREBRAL INJURY IN WISTAR RATS
DOI:
https://doi.org/10.22159/ijpps.2017v9i2.16098Keywords:
Toxicity test, Cerebroprotective, DMF, LymphocytopeniaAbstract
Objective: Dimethyl fumarate (DMF) is the methyl ester of fumaric acid and used in the treatment of psoriasis, multiple sclerosis, etc. The present study was carried out to reveal safety as well as to find out the cerebro-protective potential of DMF against ischemia and reperfusion-induced cerebral injury in Wistar rats.
Methods: Acute and sub-acute toxicity tests were performed in mice at various increasing doses of DMF as per OECD guidelines 420 and 407 respectively. The cerebral ischemia-reperfusion injury was induced by bilateral common carotid artery (BCCA) occlusion for 1 h and reperfusion for 5 h in Wistar rats. The DMF was administered orally at doses 10 mg/kg and 20 mg/kg for the assessment of its cerebro-protective potential by evaluating % infarction and % protection of cerebral tissue using TTC staining method.
Results: The present study revealed that DMF is a safe drug as mortality was not observed in acute toxicity study up to 2000 mg/kg on oral administration, at the same time in sub-acute toxicity test DMF has showed no alteration in various parameters except a decrease in lymphocyte count. The DMF has shown a reduction in the % infarction. DMF at doses 10 mg/kg and 20 mg/kg has imparted 27.96±1.55% and 58.98±2.3% protection against ischemia and reperfusion-induced cerebral injury in Wistar rats.
Conclusion: The DMF is the relatively safe drug with significant cerebro-protective potential.
Downloads
References
Thomas J, Fitzpatrick L. Acute ischemic stroke review.J Neurosci Nursing 2008;40:69.
Jauch EC. Guidelines for the early management of patients with acute ischemic stroke a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2013;44:870-947.
Turner, White. Ischemic stroke: pathophysiology and principle of localisation. Neurol Board Rev Manual 2009;13:1-14.
Sundt TM.Correlation of cerebral blood flow and electro-encephalographic changes during carotid endarterectomy: with results of surgery and hemodynamics of cerebral ischemia. Mayo Clin Proc 1981;56:533-43.
Linker RA, Lee DH, Ryan S. Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway. Brain 2011;134:678-92.
Gilgun-Sherki Y, Melamed E, Offen D. The role of oxidative stress in the pathogenesis of multiple sclerosis: the need for effective antioxidant therapy. J Neurol 2004;251:261-8.
Kappos L. Efficacy and safety of oral fumarate in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study. Lancet 2008;372:1463-72.
Scannevin RH, Chollate S, Jung MY. Fumarates promote cytoprotection of central nervous system cells against oxidative stress via the Nrf2 pathway. J Pharmacol Exp Ther 2012;341:274-84.
Jingtao J, Sato S, Yamanaka N. Changes in cerebral blood flow and blood brain barrier in the gerbil hippocampal CA1 region following repeated brief cerebral ischemia. Med Electron Microsc 1999;32:175–83.
Chintamani Narasinh Joshi, Swatantra Kumar Jain, Puvvada Sri Ramachandra Murthy. An optimised triphenyl tetrazolium chloride method for identification of cerebral infarcts. J Brainresprot 2003;12:001.
Angela B, Krisztina M, ZsoltJ.Use of TTC staining for the evaluation of tissue injury in the early phases of reperfusion after focal cerebral ischemia in rats. Brain Res 2006;1116:159-65.
Jiang J, Wang W, Sun YJ. Neuroprotective effect of curcumin on focal cerebral ischemic rats by preventingblood-brain barrier damage. Eur J Pharmacol 2007;561:54-62.
Orsu P, Murthy BV, Akula A. Cerebroprotective potential of resveratrol through anti-oxidant and anti-inflammatory mechanisms in rats. JNeural Transmission 2013;120:1217-23.
Gaur V, Aggarwal A, Kumar A. Protective effect of naringin against ischemic reperfusion cerebral injury: possible neurobehavioral, biochemical and cellular alterations in rat brain. Eur J Pharmacol 2009;616:147-54.
Raghavendra M, Maiti R, Kumar S. Role of Centella asiatica on cerebral postischemic reperfusion and long term hypo perfusion in rats. Int J Green Pharm 2009;3:88-96.
Published
How to Cite
Issue
Section
