MONOMETHYL FUMARATE MITIGATES ISCHEMIA REPERFUSION INJURY BY ACTIVATING NRF2/HO1 PATHWAY IN EXPERIMENTAL MODEL OF ISCHEMIC STROKE IN RAT
Devendra Singh1, K.H. Reeta1, Uma Sharma2, N.R. Jagannathan2, A.K. Dinda3, Y.K. Gupta1
1Department of Pharmacology.
2Department of NMR & MRI Facility.
3Department of Pathology.
All India Institute of Medical Sciences, New Delhi, INDIA.
Background and Aims
Despite advances in understanding the pathophysiology of cerebral ischemia, tPA remains to be the only treatment option, leaving stroke a major cause of mortality and long term disability. Increasing number of evidences suggest that activating endogenous antioxidant pathway by stimulation of nuclear factor erythroid-2-related factor 2 (Nrf2) can play a key role in cellular defense against oxidative stress in ischemic penumbra. The study was planned to test the hypothesis that monomethy fumarate (MMF) exerts neuro-protective role via activation of Nrf2/HO1 pathway.
Methods
Middle cerebral artery occluded using a 3.0 monofilament in Male Sprague Dawley rats (270±20g) for 90 min was confirmed by Laser Doppler flow meter. MMF (10 mg/kg) was administered at two time points, 30 min post ischemia and 5 min post reperfusion. Twenty four hours later, neurobehavioral parameters were assessed followed by T2 imaging using 7.0T animals MRI to assess effect on infarct. After MRI, rats were euthanized, perfused with paraformaldehyde, cryosections were stained with Nrf2, HO1 and NeuN followed by counterstaining with DAPI.
Results
Post occlusion, cerebral blood flow reduced by 80.2 ± 2.9% of baseline and post reperfusion 70.4 ± 4.1% of blood flow was restored. MMF treatment significantly (p<0.05) improved neurobehavioral parameters and cerebral infarct when compared to MCAo group. Immunofluorescence study revealed increase in expression of Nrf2 in neurons, HO1 in neuron and non-neuronal cells in peri-infarct region of MMF group when compared with MCAo group. Conclusion
Our results indicate the neuro-protective effect of MMF in ischemia reperfusion injury by activating Nrf2/HO1 pathway