Resveratrol evokes neuroprotective effects and improves foot stance following kainate-induced excitotoxic damage to the mouse spinal cord

Excitotoxicity, characterized by over-activation of glutamate receptors, is a major contributor to spinal cord injury (SCI) pathophysiology, resulting in neuronal death and loss of locomotor function. In our previous in vitro studies, we showed that excitotoxicity induced by the glutamate analogue kainate (KA) leads to a significant reduction in the number of neurons, providing a model for SCI. Our current objective was to assess the neuroprotective role of resveratrol (RESV), a natural polyphenol, following KA-induced SCI. In vivo excitotoxicity was induced by intraspinal injection of KA immediately followed by RESV administration to Balb/C adult male mice. In neonatal mouse spinal cord preparations, excitotoxicity was transiently induced by bath-applied KA, either with or without RESV. KA administration resulted in a significant deterioration in hindlimb motor coordination and balance during locomotion, which was partially reverted by RESV. Additionally, RESV preserved neurons in both dorsal and ventral regions. Sirtuin 2 (SIRT2) immunoreactive signal was increased by RESV, while the selective SIRT1 inhibitor 6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide (EX-527) attenuated RESV neuroprotective effects. These findings suggest that RESV attenuation of excitotoxic-induced neuronal loss and locomotor deficits is mediated, at least in part, through the activation of SIRT1, potentially involving SIRT2 as well. Indeed, our results highlight the potential use of RESV to enhance neuroprotective strategies for SCI.