Influence of Alcohol on Intracerebral Hemorrhage: From Oxidative Stress to Glial Cell Activation

Abstract

The intricate relationship between alcohol consumption and intracerebral hemorrhage (ICH) presents a nuanced field of study, especially concerning the dose-dependent impact on secondary brain injury (SBI). Recognizing the established risks associated with heavy drinking, this review delves deeper into the less understood territories of low to moderate alcohol consumption. By systematically analyzing recent studies, we uncover critical insights into how varying alcohol intake levels modulate ICH risk through mechanisms such as microglial activation, oxidative stress, and the protective potential of polyphenols. This analysis extends beyond the hypertensive effects of heavy alcohol use to explore the complex molecular pathophysiology involved in alcohol-related ICH. Our findings indicate that while heavy alcohol use unequivocally exacerbates ICH risk, moderate consumption and its associated polyphenols may offer neuroprotective effects against SBI, albeit within a finely balanced threshold. This review highlights the significant gaps in current understanding and underscores the urgent need for targeted research to elucidate these complex interactions. Through this comprehensive examination, we aim to inform more nuanced public health policies and intervention strategies, taking into account the diverse effects of alcohol consumption on ICH risk.

Keywords: alcohol consumption; alcohol intoxication; alcoholism; intracerebral hemorrhage.

Figure 1

Consumption, absorption, and metabolism of alcohol. Consumption of alcohol (expressed as grams of ethanol per day) among different regions around the world is shown on the left of the figure. Alcohol is primarily absorbed in the small intestine (80%) and stomach (20%), with 2–5% excreted unchanged via breath, sweat, and urine. The rest, 95–98% of ethanol, is metabolized in the liver through two pathways: oxidative and non-oxidative. The oxidative pathway involves alcohol dehydrogenase (ADH) in the cytosol converting ethanol to acetaldehyde and further metabolism to acetate by aldehyde dehydrogenase 2 (ALDH2) in the mitochondria. Cytochrome P450 2E1 (CYP2E1) and catalase also play roles in ethanol metabolism, especially at higher consumption levels. In the non-oxidative pathway, ethanol forms fatty acid ethyl ester (FAEE) or phosphatidyl ethanol, catalyzed by FAEE synthase and phospholipase D. The metabolites from both pathways enter the circulation, impacting peripheral organs.

Figure 2

ICH is initiated by the rupture of blood vessels in the brain, leading to red blood cell (RBC) leakage and hematoma formation, facilitated by clotting factors like thrombin, fibrin, and fibrinogen. The subsequent SBI involves erythrocyte lysis, releasing Hb, which is broken down into heme and iron (Fe²⁺), triggering oxidative stress through various reactive oxygen species (ROS). This process activates microglia and astrocytes, with TLRs playing a role in their activation. The initial event causes direct neuronal damage and edema, further exacerbating tissue damage. Additionally, circulating macrophages infiltrate the injury site, differentiating into pro-inflammatory M1 and anti-inflammatory M2 macrophages, releasing a mix of cytokines.

Figure 3

This representative figure delineates the multifaceted interactions between alcohol consumption patterns and brain injury subsequent to ICH. It maps out the cascade from alcohol-induced microglia activation and complement system engagement to the generation of ROS, mitochondrial damage, and apoptosis. It further illustrates systemic effects, including neuroendocrine responses, highlighting the extensive influence of alcohol on both brain pathology and peripheral organ systems in the context of ICH. For a detailed understanding, please refer to Section 11.

Figure 4

Alcohol consumption, categorized as chronic mild–moderate, chronic heavy, or acute heavy (binge drinking), has varying impacts on ICH. ICH is divided into deep ICH, primarily caused by small vessel disease due to hypertension and platelet dysfunction as well as lobar ICH, influenced by cerebral amyloid angiopathy (CAA) and atherosclerosis. Both types involve SBI mechanisms like oxidative stress, neuroinflammation, mitochondrial dysfunction, endothelial dysfunction, and cell apoptosis. Chronic heavy alcohol consumption exacerbates all these SBI mechanisms. Acute heavy consumption contributes to oxidative stress, neuroinflammation, endothelial dysfunction, and apoptosis but not mitochondrial dysfunction. In contrast, chronic mild–moderate consumption can be protective, reducing neuroinflammation and CAA by lowering low-density lipoprotein-cholesterol (LDL-c).