Neuroprotective potential of orphenadrine in focal cerebral ischemia: A neurobehavioral and mechanistic study.

Ischemic stroke is a leading cause of mortality and disability globally, with limited therapeutic options. This study hypothesized that orphenadrine, an NMDA antagonist with neuroprotective, anti-inflammatory and analgesic properties would attenuate reperfusion brain injury in a rat middle cerebral artery occlusion (MCAO) model of focal cerebral ischemia. Male rats underwent 90-min MCAO followed by reperfusion, then received orphenadrine intraperitoneally (10 and 30 mg/kg) immediately 1 h post-reperfusion and daily for 21 days. Primary outcomes included neurological deficit scores, beam walk latency, locomotor activity, infarct volume, oxidative stress (MDA, glutathione, catalase), cytokines (IL-6, TNF-α), blood-brain barrier (BBB) integrity, and expression of HIF-1α, TFAM (mitochondrial functions), caspase-3, iNOS, and Nrf-2/HO-1. Orphenadrine administration significantly improved neurological functions, muscle strength, and locomotor activity (days 1, 7, 14 and 21), reduced infarct volume, lowered MDA and nitrite, while increased antioxidants (glutathione and catalase), and decreased neuroinflammation by lowering IL-6 and TNF-α levels. It preserved BBB integrity, enhanced mitochondrial genes, hypoxia-inducing factor 1 alpha (HIF-1α) and Transcription factor A, mitochondrial (TFAM), suppressed caspase-3 and enhanced nitric oxide synthase gene expression, and nuclear factor erythroid 2-related factor 2/ Heme oxygenase-1 (Nrf-2/HO-1) expression. These findings highlight Orphenadrine as a promising multi-target neuroprotective agent via antioxidative, anti-inflammatory, and mitochondrial preservation mechanisms in ischemic stroke, warranting further investigation for clinical translation.