Role of pERK1/2-NFκB signaling in the neuroprotective effect of thalidomide against cerebral ischemia reperfusion injury in rats

In the present investigation, we tested the hypothesis that suppression of the phospho-extracellular signal regulated kinase (pERK1/2)-nuclear factor kappa (NFκ)-B signaling, subsequent to tumor necrosis factor-α (TNF-α) inhibition, underlies thalidomide (TLM) mediated neuroprotection. Male Wistar rats (250–280 g) were divided into five groups: (1) sham; (2) negative control receiving TLM (5μg/1μl/site) and 3 groups of ischemia-reperfusion (IR) injury rats pretreated with: (3) vehicle (DMSO 100%); (4) TLM (5μg/1μl/site) or (5) PD98059 (0.16μg/1μl/site). IR rats were subjected to occlusion of both common carotid arteries for 45 min followed by reperfusion for 24 h. Drugs and/or vehicles were administered by unilateral intrahippocampal injection after removal of the carotid occlusion and at the beginning of the reperfusion period. IR rats exhibited significant infarct size, histopathological damage, memory impairment, motor incoordination and hyperactivity. Unilateral intra-hippocampal TLM ameliorated these behavioral deficits along with the following ex vivo hippocampal effects: (i) abrogation of the IR-evoked elevations in hippocampal TNF-α, pERK1/2, NFκB, BDNF, iNOS contents and (ii) partial restoration of the reduced anti-inflammatory cytokine IL-10 and p-nNOS S852. These neurochemical effects, which were replicated by the pERK1/2 inhibitor PD98059, likely underlie the reductions in c-Fos and caspase-3 levels as well as the anti-apoptotic effect of TLM in the IR model. These results suggest a crucial anti-inflammatory role for pERK1/2 inhibition in the salutary neuronal and behavioral effects of TLM in a model of brain IR injury. [Display omitted] •Thalidomide has a neuroprotective role in cerebral ischemia reperfusion injury.•Thalidomide ameliorates cognition and motor co-ordination following the injury.•pERK1/2/NFκ-B/TNF-α pathway is a key player in Thalidomide neuroprotective effects.•pERK1/2 inhibition is pivotal for Thalidomide anti-inflammatory effects.