Abstract
ABSTRACT Chronic alcohol consumption leads to hippocampal neuronal impairment, which related to neuronal death, oxidative stress, and inflammatory response. Rho-associated protein kinase 2 (ROCK2) is a major regulator in the central nervous system injury. However, the effects of ROCK2 in ethanol-induced brain injury have not been explored. In this work, we investigated the neuroprotective effects and the mechanism of ROCK2 inhibition in vivo. Wistar rats were exposed to 37% ethanol for 8 weeks to establish brain injury models. Morris water maze test was performed to evaluate cognitive function, and we found that the down-regulation of ROCK2 reduced the escape latency and increased the passing times and percentage of time spent in the target quadrant of rats. The results of H&E staining and Nissl staining showed that ROCK2 inhibition alleviated the pathological injury induced by ethanol. PI staining and Western blot confirmed that inhibiting ROCK2 attenuated the neuronal death and apoptosis as reflected by the reduced PI-positive neurons and the decreased expression of cleaved-caspase-3 and cleaved-caspase-9. Furthermore, the down-regulation of ROCK2 ameliorated the oxidative stress and inflammatory response induced by ethanol in rats as reflected by the up-regulation of IL-10, SOD, and GSH and reduction of TNF-α, IL-6, and MDA respectively. Additionally, Western blot and EMSA analysis revealed that the down-regulation of ROCK2 suppressed the nuclear transfer of NF-κB p65. In conclusion, our data suggested that ROCK2 inhibition ameliorated ethanol-mediated hippocampal neuronal impairment by anti-apoptotic, anti-inflammatory, anti-oxidative effects at least partially through the suppression of the NF-κB pathway.
Highlights
In many societies, alcohol consumption is an inte gral part of daily life
We found that inhibiting Rho-associated protein kinase 2 (ROCK2) alleviated the cogni tive dysfunction and pathological injury induced by ethanol in rats, and ROCK2 inhibition reduced the neuronal apoptosis, inflammatory response, and oxidative stress in rats partially through regulating NF-κB signaling pathway
These results suggested that ROCK2 was involved in ethanol-induced cognitive dysfunction of rats, and this impairment was alleviated when ROCK2 was inhibited
Summary
The World Health Organization lists alcohol as one of the major causes of the global burden of disease in industria lized countries [1]. The patho genesis of alcohol has been studied extensively, little is known about the underlying protective mechanisms against its harmful effects [3]. Recent studies reported that alcohol consump tion is related to neuroinflammation which may be a crucial cause of neuronal dysfunction [4]. Longterm exposure to ethanol leads to the activation of inflammasome in the brain [5]. Meisel et al [6] found that ethanol triggers widespread apoptotic neurodegeneration in developing rat forebrain. Oxidative inflammation and neuronal apoptosis were shown to be involved in chronic alcohol-induced brain injury [8]
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