ABSTRACT
Alcohol abuse can result in significant alterations to the structure of the brain and ultimately to behavioral dysfunctions. Epidemiological studies have shown that alcoholism is closely associated with impaired memory and judgment. However, the degree of deficit (brain injury) depends on factors such as the age of onset, duration of heavy drinking, continuous versus periodic (binge) drinking and the typical amount consumed per session. In recent years, neuroinflammation has been proposed as one of the alcoholism-induced neuropathological mechanisms, since increased levels of microglial markers are observed in the brains of both post-mortem human alcoholics and various alcohol-treated animals, from newborn or adolescent rodents to adult rodents. Many studies have investigated how microglia modulate alcohol-induced behavioral changes such as cognitive deficits, abnormal locomotor activity, motor impairment and mood disturbance. Importantly, we try to characterize and compare the distinct features in different ethanol (EtOH)-induced neurodegenerative disease (NDD) models. Moreover, mounting evidence indicates that in response to certain environmental toxins, microglia can become over-activated under oxidative stress, releasing pro-inflammatory mediators that cause central nervous system (CNS) disease. The molecular mechanisms involve free radical formation and the release of pro-inflammatory cytokines that are detrimental to neighboring neurons and interfere with the molecules regulating cell-cell interactions. The identification and understanding of the cellular and molecular mechanisms of microglial activation are described, as well as multiple downstream targets, in different alcohol-treated animal models. This review might contribute to the development of treatments and/or therapeutic agents that can reduce or eliminate the deleterious effects of alcohol-induced NDD.
Subject(s)
Aging , Alcoholism/pathology , Cognition/drug effects , Ethanol/toxicity , Microglia/drug effects , Neurodegenerative Diseases/pathology , Aging/pathology , Aging/psychology , Alcoholism/complications , Alcoholism/psychology , Animals , Cell Death/drug effects , Disease Models, Animal , Humans , Microglia/pathology , Motor Activity/drug effects , Neurodegenerative Diseases/chemically induced , Neurodegenerative Diseases/metabolism , Neurodegenerative Diseases/psychology , Oxidative Stress/drug effects , Social BehaviorABSTRACT
Recent studies have shown that oligomeric amyloid-ß (oAß) peptide can potentially activate microglia in addition to inducing more potent neurotoxicity compared with fibrillar Aß (fAß); however, its mechanisms of action remain unclear. This study was designed to investigate the possible mechanisms involved in the microglial activation induced by oAß in BV-2 microglial cells. The results showed that oAß induced activated properties of microglia, including higher proliferative capacity as well as increased production of reactive oxygen species, nitric oxide (NO), tumor necrosis factor-α (TNF-α), and interleukin-1ß (IL-1ß). NADPH oxidase inhibitors [diphenylene iodonium (DPI) and apocynin (4-hydroxy-3-methoxy-acetophenone)] prevented the microglial activation induced by oAß, suggesting that NADPH oxidase activation was involved in microglial activation. In addition, TNF-α and IL-1ß, which are massively released by activated microglia, significantly induced the activation of microglia, thereby resulting in the production of NO and proliferation of microglia, respectively. These effects could be inhibited by diphenylene iodonium and apocynin, indicating a self-cycle regulated by NADPH oxidase in microglial activation in response to oAß. In conclusion, microglial activation induced by oAß is possibly mediated by NADPH oxidase, suggesting that oAß, which is normally considered a neurotoxin, may also lead to indirect neuronal damage through the pro-inflammation activation of microglia in Alzheimer's disease and that NADPH oxidase could be a potential target to prevent oAß-induced inflammatory neurodegeneration.
