The inflammatory footprints of alcohol-induced oxidative damage in neurovascular components

Abstract

Microvessels, the main components of the blood-brain barrier (BBB) are vulnerable to oxidative damage during alcohol-induced stress. Alcohol produces oxidative damage within the vessels and in the brain. Using our animal model of catheter implant into the common carotid artery (CCA), we trace the footprints of alcohol-induced oxidative damage and inflammatory process at the BBB and into the brain. The uniqueness of the finding is that ethanol causes oxidative damage in all neurovascular components by activating NADPH oxidase and inducible nitric oxide synthase in the brain. It is not the oxidants but the ethanol that traverses through the BBB because we found that the highly reactive peroxynitrite does not cross the BBB. Thus, oxidative damage is caused at the site of oxidant production in the microvessels and in the brain. Our data indicate that acetaldehyde (the primary metabolite of ethanol) is the inducer/activator of these enzymes that generate oxidants in brain neurovascular cells. Evidence for alcohol-induced BBB damage is indicated by the alterations of the tight junction protein occludin in intact microvessels. Importantly, we demonstrate that the site of BBB oxidative damage is also the site of immune cells aggregation in the microvessels, which paves the path for inflammatory footprints. These findings reveal the underlying mechanisms that ethanol-elicited BBB oxidative damage initiate the brain vascular inflammatory process, which ultimately leads to neuroinflammation.

Induction of oxidative and nitrosative damage leads to cerebrovascular inflammation in an animal model of mild traumatic brain injury induced by primary blast

“…Labeled cells were infused into the right common carotid artery (2 × 10 6 cells per rat) using 27.5 G needle (see Alikunju et al, (13), for the detailed protocol). Adhesion and infiltration of these cells were detected in intact brain microvessels under fluorescent microscope.…”

“…We have shown that cerebral vascular integrity (the BBB) is very sensitive to oxidative stress during substance of abuse (11, 12). Ensuing oxidative damage of the BBB leads to neuroinflammation and neuronal degeneration (13–15). Understanding of underlying molecular and biochemical mechanisms will help define the characteristic biomarkers of cerebral vascular injury and be able to formulate a preventive strategy to mitigate the adverse acute effects of blast exposure and related chronic neurological complications.…”

“…The 15-point Glascow Coma Scale (GCS) (19) defines severity of traumatic brain injury as mild TBI (13–15), moderate TBI (9–12), severe TBI (3–8), and vegetative state TBI (3). Mild TBI (mTBI) considered in this work is defined as loss of consciousness for less than 24 hours (20).…”

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

“…Specifically, alcohol oxidation by brain cytosolic catalase is a possible ROS-producing route, as is inducible cytochrome P4502E1 in endoplasmic reticulum ([29]. Also, alcohol-dependent microglial activation leading to increased brain NADPH oxidase activity and resultant ROS generation has been implicated in prolonged alcohol exposure [30]. However, the above alcohol-ROS generating possibilities have been examined largely in acute and chronic alcohol rodent models that utilize non-binge alcohol intake or administration (liquid diets, water, vapor chamber)—models that do not generally entail the repetitive, highly elevated blood alcohol levels and nadirs of binge administration/intoxication.…”

Alcohol exposure after mild focal traumatic brain injury impairs neurological recovery and exacerbates localized neuroinflammation

“…Nevertheless, our data comprise the outcomes of all experimental groups in order to understand the overall associations between the expression of neuroinflammatory markers and NSS, not necessarily the effect of TBI/Alcohol alone on either of those markers. It is also important to know that this association does not indicate a causal relationship and other potential factors should be considered including acetaldehyde, the metabolic by-product of alcohol metabolism, as it is highly toxic and can activate enzymes such as NADPH oxidase and inducible nitric oxidase synthase, causing oxidative damages on neurovascular cells with subsequent neuroinflammation (Alikunju et al, 2011). Since there is no significant main effect of TBI on body weight gain when compared to sham controls, we conclude that mild TBI produced in our model does not affect subsequent feeding and nutrition.…”