Deficient PKR in RAX/PKR Association Ameliorates Ethanol-Induced Neurotoxicity in the Developing Cerebellum

Abstract

Ethanol-induced neuronal loss is closely related to the pathogenesis of fetal alcohol spectrum disorders. The cerebellum is one of the brain areas that are most sensitive to ethanol. The mechanism underlying ethanol neurotoxicity remains unclear. Our previous in vitro studies have shown that the double-stranded RNA (dsRNA)-activated protein kinase (PKR) regulates neuronal apoptosis upon ethanol exposure and ethanol activates PKR through association with its intracellular activator RAX. However, the role of PKR and its interaction with RAX in vivo have not been investigated. In the current study, by utilizing N-PKR−/− mice, C57BL/6J mice with a deficient RAX-binding domain in PKR, we determined the critical role of RAX/PKR association in PKR-regulated ethanol neurotoxicity in the developing cerebellum. Our data indicate that while N-PKR−/− mice have a similar BAC profile as wild-type mice, ethanol induces less brain/body mass reduction as well as cerebellar neuronal loss. In addition, ethanol promotes interleukin-1β (IL-1β) secretion, and IL-1β is a master cytokine regulating inflammatory response. Importantly, ethanol-promoted IL-1β secretion is inhibited in the developing cerebellum of N-PKR−/− mice. Thus, RAX/PKR interaction and PKR activation regulate ethanol neurotoxicity in the developing cerebellum, which may involve ethanol-induced neuroinflammation. Further, PKR could be a possible target for pharmacological intervention to prevent or treat fetal alcohol spectrum disorder (FASD).

Exposure of neonatal rats to alcohol has differential effects on neuroinflammation and neuronal survival in the cerebellum and hippocampus

“…Previous studies have demonstrated that binge-like exposure to high levels of alcohol is effective at inducing neuronal cell loss in the rodent brain [ 4 ]. Additionally, binge-like, heavy alcohol-exposure paradigms in the early postnatal period have been shown to be more effective in generating a robust neuroimmune response [ 24 – 26 ] when compared to more moderate but long-term exposures [ 34 ]. Importantly, heavy alcohol exposure during late pregnancy has been documented in humans [ 35 , 36 ].…”

“…Additionally, studies in models of third trimester-equivalent alcohol exposure have demonstrated elevations in pro-inflammatory cytokines in multiple brain regions [ 23 , 24 ], which were long-lasting in some cases [ 25 ] and widespread signs of neuronal loss [ 4 ]. Moreover, blunting neuroinflammation correlated with decreased neuronal loss [ 26 , 24 ] and improved performance in hippocampal-dependent tasks [ 25 ]. Based on these results, it was concluded that neuroimmune activation contributes to neuronal loss across several brain regions.…”

Impacts on prenatal development of the human cerebellum: a systematic review

“…These findings may support the possible benefit of early abstinence for fetal growth measures including cerebellar growth. Although there is no comparable animal data available, decreased cerebellar weight and cerebellar neuronal loss was recorded due to ethanol induced neurotoxicity [45]. Alcohol-induced cerebellar alterations may result from underlying mechanisms, such as excitotoxicity, nutritional deficiencies, growth factor alterations, glial abnormalities, apoptosis, oxidative stress and compromised energy production [46].…”

Double‐stranded RNA‐dependent protein kinase signalling and paradigms of cardiometabolic syndrome

“…Besides dsRNA, endoplasmic reticulum (ER) stress, mechanical stress, high‐fat diet, pathogens, environmental stress, haeme limitation, cytokines (TNF‐α, IL‐1β) and irradiation also possess the ability to activate PKR . In addition, researchers have found that the PACT is a plausible cellular activator of PKR which can cause the PKR phosphorylation , while others have demonstrated that protein kinase R (PKR)‐associated protein X (RAX), murine counterpart for PACT , is accountable for the activation of PKR at cellular level, when stimulated by any extracellular stress stimuli . Table shows the list of some PKR activators that are associated with the substrate phosphorylation and physiological process linked with substrate phosphorylation.…”