Abstract
ABSTRACTPramipexole (PPX), a D2-like receptor agonist, is generally used in the treatment of Parkinson's disease and restless leg syndrome. Its neuroprotective effects have been shown against various neurological disorders. Recent research work has demonstrated that PPX exerts neuroprotection through mitochondria. However, the neuromodulator-related effects of PPX against traumatic brain injury (TBI) remain unexplored. The present study, therefore, investigated the mechanism of neuroprotection by PPX against oxidative stress, mitochondrial dysfunction and neuronal damage following TBI in rats. We hypothesized that the neuroprotection by PPX in TBI-subjected rats might involve activation of the Nrf2/HO-1 (also known as Nfe2l2/Hmox1) signaling pathway. PPX was injected intraperitoneally (0.25 mg/kg body weight and 1.0 mg/kg body weight) at different time intervals post-TBI. Several neurobehavioral parameters were assessed at 48 h post-TBI, and the brain was isolated for molecular and biochemical analysis. The results demonstrated that PPX treatment significantly improved the behavioral deficits, decreased the lipid peroxidation rate, increased glutathione levels and decreased 4-hydroxynonenal levels in TBI-subjected rats. PPX also increased the activities of glutathione peroxidase and superoxide dismutase enzymes. In addition, PPX treatment inhibited mitochondrial reactive oxygen species production, restored mitochondrial membrane potential and increased ATP levels after a TBI. Further, PPX treatment reduced the Bax/Bcl2 ratio and translocation of Bax to mitochondria and cytochrome-c to the cytosol. Finally, PPX treatment greatly accelerated the translocation of Nrf2 to the nucleus and upregulated HO-1 protein expression. We conclude that the neuroprotective effects of PPX are mediated by activation of the Nrf2/HO-1 signaling pathway following TBI.This article has an associated First Person interview with the first author of the paper.
Highlights
Traumatic brain injury (TBI) is a severe threat to human health among the several existing neurological disorders
We evaluated the grip test, and we found that TBI-subjected rats showed a significant decrease [F(3,28) = 11.9, p < 0.0001] in the mean value of grip score as compared to the Sham groups
We evaluated the performance of the rota-rod test, and we found that TBIsubjected rats showed a significantly reduced [F(3,28) = 11.0, p < 0.0001] time spent on rotating rod as compared to the sham rats
Summary
Traumatic brain injury (TBI) is a severe threat to human health among the several existing neurological disorders It is associated with difficulties in communications and behavioral impairments, which in turn contribute to a socioeconomic problem for people of all ages throughout the world (Bruns and Hauser, 2003). The brain trauma, in turn, can trigger compound molecular, neurochemical, and histopathological alterations to the injured tissue These changes can subsequently lead to deleterious side effects, and lead to neuronal cell death and dysfunction, permanent tissue damage and long-term neurological impairments (Mckee and Daneshvar, 2015). It is known as non-mechanical injury and can result in excitotoxicity, neuroinflammation, oxidative damage, calcium overload, pro-apoptotic gene activation, organelles dysfunction and neuronal apoptosis (Dobrachinski et al, 2017; Ng and Lee, 2019; Caglayan et al, 2019) Currently, there are no pharmacologically active chemicals that can attenuate TBI-induced oxidative damage, mitochondrial perturbation, and promote functional recovery following the TBI
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