Expression of Aquaporin-4 Augments Cytotoxic Brain Edema after Traumatic Brain Injury during Acute Ethanol Exposure

Abstract

We previously reported that ethanol consumption affects morbidity and mortality after traumatic brain injury (TBI) by accelerating brain edema via oxidative stress after TBI. Aquaporin-4 (AQP4), a water channel, is involved in brain edema formation. In this study, we found that acute ethanol administration increased AQP4 expression after TBI, leading to severe brain edema in rats. Rats were pretreated with ethanol (3 g/kg) or dl-buthionine-(S,R)-sulfoximine (BSO; 100 mg/kg), an oxidative stressor, before TBI. Acetazolamide, an AQP4 inhibitor, was administered to ethanol-pretreated rats 3 or 12 hours after TBI. Brain edema was increased 24 hours after TBI in both the ethanol- and BSO-pretreated groups. Ethanol pretreatment induced lipid peroxidation 24 hours after TBI. Transcription factors, NF-κB and hypoxia-inducible factor-1α, were activated 3 and 24 hours after TBI in the BSO- and ethanol-pretreated groups, respectively. In the ethanol-pretreated group, AQP4 was accumulated, particularly in astrocyte end feet, 24 hours after TBI. Acetazolamide treatment improved the survival rate to 100% and decreased brain edema and AQP4 in ethanol-pretreated rats. These findings suggest that ethanol induces up-regulation of AQP4, leading to brain edema. The accumulation of AQP4 may play an important role in the augmentation of brain edema after TBI under ethanol consumption.

Neuroinflammation and Neurodegeneration in Adult Rat Brain from Binge Ethanol Exposure: Abrogation by Docosahexaenoic Acid

“…Astroglial cells in culture swell due to ethanol exposure and withdrawal, but previous evidence of blockade by diuretics has been conflicting [59], [60]. However, acceleration of trauma-related cerebral edema by ethanol has been linked to increased AQP4 upregulation and activity, with acetazolamide, presumably through inhibition of AQP4, exerting protection [61]. Herein, binge ethanol-induced AQP4 elevations in brain regions that sustain neurodegeneration, but not in regions known to lack neurodamage, indicate that the water channel could be an important factor in the regioselective neurodegeneration.…”

Ethanol and isolated traumatic brain injury

“…In addition, ethanol has been shown to be associated with respiratory depression, apnoea and hypoxia [3][4][5], which may contribute to secondary insults following TBI. Raised intracranial pressures and acidaemia have also been reported as potential adverse effects of ethanol exposure [6][7][8].…”

Alcohol, Phospholipase A2-associated Neuroinflammation, and ω3 Docosahexaenoic Acid Protection

“…Known connections between increased AQP4 and cytotoxic (cellular) edema [13] led to our considering that alcohol binges were precipitating cerebral edema via potentiation of the water channel, and indeed, initial immunoblots indicated higher AQP4 levels in alcohol-treated brain slices in culture [10]. Other reports have shown that increased AQP4 is important in alcohol’s augmentation of traumatic brain injury and edema [14] and in pro-inflammatory cytokine elevations in lipopolysaccharide-induced neuroinflammation [15]. Thus AQP4, like PLA2 below, can function as a potential neuroinflammatory stimulus.…”