*2.6.1. Role of microglia*

Exposure to alcohol causes activation of microglia along with the proinflammatory cytokines, leading to neuronal inflammation and toxicity [70]. Alcohol exposure causes accumulation of microglia in the brain which occurs through activation of TLRs leading to increased HMGB1 expression [71]. Alcohol-induced neuronal apoptosis leads to stimulation of the transcription factor AP-1 and release of IL-1β, IL-6 and transforming growth factor β (TGF-β1) [71]. An in vitro study revealed that microglial TNF-α production plays an important role in neuronal toxicity [72]. Neuronal cell death occurred due to chronic alcohol exposure which leads to upregulation of the NF-κB expression, which in turn leads to release of TNF-α resulting in neuronal apoptosis [73].

resulting in an increased gut permeability. As a result, there is activation of proinflammatory cytokines in the liver, which leads to induction of TNF-α and other cytokines in the blood. Researchers found that LPS induced increases in serum TNF-α as well as proinflammatory cytokines, leading to induction of the gene in the brain [77]. This proinflammatory cytokines in the blood are then transported across the blood–brain barrier (BBB) by their receptors [78]. For example, 2 to 3 g/kg ethanol when administered into the stomach results in the activation of innate immune response in the gut [79]. This damages the tight junction present in the gut resulting in an opening of the sites where gut bacteria and their endotoxins (LPS) can easily enter the blood stream leading to the liver, where they can activate proinflammatory cytokines (**Figure 4**). Increased proinflammatory cytokines responses, which affects the brain through TNF-α and other cytokines [80]. The brain response to the proinflammatory cytokine MCP-1 is quite longer than that found in the liver and blood [81]. An in vivo study showed an increased LPS induction of proinflammatory cytokines (TNF-α, IL-1β and MCP-1) only in the brain but not in the liver and blood after ten daily doses of alcohol [81]. In the liver, the researcher suggested that the anti-inflammatory cytokine (IL-10) inhibits NF-κB which was increased after 1 week of ethanol treatment but decreased in the brain [81]. After 10 days of ethanol (5g/kg/day) administration to mice model, this study showed sensitization to TLR3 agonist Poly:IC which induces proinflammatory cytokines in the brain for 24 hours [74].

Effect of Alcohol on Brain Development http://dx.doi.org/10.5772/intechopen.73693 23

**Figure 4.** Alcohol influences neuroimmune signaling via its effects on the gut.

Alcohol is an anxiolytic and soothing drug. Chronic alcohol consumption leads to determined molecular and cellular modification in the brain system. It is comprehensible that GABA and glutamate neurotransmitters play a crucial role in alcohol toxicity, neuronal toxicity and neuronal cell death. Ethanol exposure triggers the activation of various gene expressions involved in apoptosis, in oxidative stress and in the cell cycle. Upregulation of genes by ethanol includes heat shock proteins and proteins related to synaptic neurotransmission,

**3. Conclusion(s)**

In vivo studies in the cortical and hippocampus region of the brain showed increased levels of NADPH oxidase, superoxide and microglial activation, which is correlated with alcoholinduced ROS production [74]. In vitro studies revealed that upon alcohol exposure, microgliaconditioned cells showed increased ROS production and induced oxidative stress in cultured hypothalamic neuronal cells; this leads to neuronal apoptosis [75]. Alcohol-induced elevation of TGF-β1 levels in neuronal cells is accompanied by a host of molecular and chemical changes such as increase in E2F1 protein expression, mitochondrial proapoptotic proteins bak, bad and bcl-xs and E2F1 protein expression and simultaneously decrease in cyclin D1, cyclin-dependent kinase-4 expression and antiapoptotic protein bcl-2 leading to neuronal apoptosis [76] (**Figure 3**).
