Inhibition of DPP-4 Activity and Neuronal Atrophy with Genistein Attenuates Neurological Deficits Induced by Transient Global Cerebral Ischemia and Reperfusion in Streptozotocin-Induced Diabetic Mice

ABSTRACT Genistein, an isoflavonoid phytoestrogen, has been known for its potential pharmacological properties especially for neuroprotection and treating diabetes. The present study aims to determine the neuroprotective efficacy of genistein against global cerebral ischemia-reperfusion-induced neuronal injury in streptozotocin-induced diabetic mice and explore the underlying mechanisms. Streptozotocin-induced diabetic mice were subjected to transient cerebral ischemia by occluding both common carotid arteries for 30 min followed by 24 h reperfusion to induce neuronal injury. Effect of genistein (2.5, 5.0, and 10.0 mg/kg, i.p., o.d.) treatment on ischemia-reperfusion-induced neuronal injury in diabetic mice was evaluated in terms of cerebral infarct size, oxidative damage, mitochondrial activity in terms of neuronal apoptosis and cellular viability, dipeptidyl peptidase-4 activity and active glucagon-like peptide-1 concentration, and neurological functions measured as short-term memory and motor performance. Genistein administration following transient cerebral ischemia significantly ( p ˂ 0.0001) counteracted cognitive impairment and re-established ( p ˂ 0.001) motor performance in diabetic mice. Ischemia-reperfusion increased the infarct size, genistein administration prevented the increase in cerebral infarct size ( p ˂ 0.0001) and significantly suppressed ( p ˂ 0.001) the increase in cerebral oxidative stress in transient cerebral ischemia-reperfusion subjected diabetic mice. Genistein treatment significantly ( p ˂ 0.001) reduced neuronal apoptosis and increased cellular viability ( p ˂ 0.0001), almost completely suppressed ( p ˂ 0.0001) the circulating dipeptidyl peptidase-4 activity, and enhanced ( p ˂ 0.0001) glucagon-like peptide-1 concentration in diabetic mice with cerebral ischemia-reperfusion. This study suggests that genistein has potent neuroprotective activity against global cerebral ischemia-reperfusion-induced neuronal injury and consequent neurological deficits in streptozotocin-induced diabetic mice.