Targeting the sigma-1 receptor with pridopidine induces functional neurorestoration in spinal cord ischemia-reperfusion injury.

Abstract

Spinal cord ischemia reperfusion injury (IRI) occurs with an incidence of 1-32%, often leading to paraplegia with limited prevention options. Pridopidine (Prdpn), a highly selective sigma-1 receptor (Sig-1R) agonist, serves as a protein chaperone that is engaged in neuroplasticity and cellular defense. This research aimed to assess the neuroprotective properties of Prdpn in spinal cord IRI in rats and investigate the underlying mechanisms. Forty male Wistar albino rats were randomly allocated into 4 groups: control, sham, IRI, and IRI + Prdpn. Tarlov's test was used to examine behavioral performance, as well as withdrawal from agonizing stimuli and the placing/stepping reflex (SPR). Biochemical markers, including spinal malondialdehyde (MDA), AOPP, antioxidant GPX, TNF-α and IL-1β, and apoptotic caspase-3, were measured, along with BDNF, GDNF, and Sig-1R gene expression. Histopathological changes in spinal cord tissue were also evaluated. Spinal cord IRI significantly caused neurological deficits, evidenced by lower scores in Tarlov's test, withdrawal from agonizing stimuli, and SPR. Biochemically, spinal cord IRI led to decreased GPX and increased MDA, AOPP, TNF-α, IL-1β, caspase-3, and GDNF levels, along with downregulated BDNF and Sig-1R gene expression. Histopathologically, spinal cord IRI resulted in greater spinal neuronal degeneration, apoptosis, and demyelination. However, treatment with Prdpn significantly improved behavioral outcomes and partially reversed the biochemical and histopathological alterations. Prdpn improved spinal cord IRI-induced behavioral deficits through its antioxidant, anti-inflammatory, anti-apoptotic, and neurotrophic properties. It suggests promise as a potential treatment option to stop spinal cord IRI.