SYNERGISTIC NEUROPROTECTION BY PHLOROGLUCINOL AND ORPHENADRINE COMBINATION VIA NRF2/HO-1/HIF-1Α/TFAM AXIS IN RAT MODEL OF CEREBRAL ISCHEMIA

Ischemic stroke (IS) reduces the blood flow to the brain regions that trigger oxidative stress-induced biochemical, behavioural, molecular, and cellular impairments. Current treatment strategies are limited due to their narrow therapeutic window. Thus, there is an urgent need for efforts to identify effective therapeutic strategies in clinical settings to promote beneficial outcomes in stroke patients. In this study, we focused on the neuro-protective potential of Phloroglucinol (PH) and Orphenadrine (OR) in ischemic brain injury via modulation in Nrf-2/HO-1/HIF-1α/TFAM pathway. MCAO surgery was performed for 90 min, followed by reperfusion on male Wistar rats, and the drugs were administered intra-peritoneal. Animals were then sacrificed to estimate infarct volume, brain edema, BBB permeability, inflammation, mitochondrial dysfunction, gene expression along with behavioural and morphological studies at different time intervals, i.e., 24 h and 21 days post-stroke, were assessed. Our results revealed that combination PH-OR treatment improved neurological functions by reducing infarct volume along with edema volume and by preserving BBB integrity and, and neuro-inflammation. The combination also improved the mitochondrial complexes (I-IV) functions by increasing the gene expression of HIF-1α and TFAM, reducing caspase-3 activation and iNOS gene expression, and enhancing antioxidants Nrf-2/HO-1 expression. Overall, our findings support the neuro-protective potential of PH-OR combination via modulation of Nrf-2/HO-1/HIF-1/TFAM pathways by improving mitochondrial functions, neurological functions, and increased neuronal survival. In conclusion, our findings declared that the treatment with combination is effective neuro-protective strategy and highlight their potential as a promising therapeutic target for the treatment of Ischemic stroke.