**3. Conclusion(s)**

**2.6. Activation of multiple neuroimmune genes in human alcoholic brains**

(HMGB1 receptor) has shown an increased level in an alcoholic brain [69].

*2.6.1. Role of microglia*

22 Drug Addiction

**2.7. The brain and immune responses**

chemical changes related to cell death.

In human brain-slice cultures, multiple ethanol-induced cytokines are released. Among all, monocyte chemotactic protein-1 (MCP-1) showed increased levels in the amygdala, nucleus accumbens, VAT and hippocampus [66]. In alcoholic brains, elevated levels of TLR 2, TLR3, TLR4 and HMGB1 (high-mobility group box 1) were found in the orbital frontal cortex (OTC) [67]. Release of HMGB1 leads to disruption of synaptic plasticity which causes hyperexcitability of neurotransmitters due to ethanol exposure. There is an increased level of IL-1β inflammatory marker in an alcoholic brain (hippocampus) causing neuro-degeneration [68]. RAGE

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].

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**).

The interface between the brain and the immune system is bidirectional. Recent findings have revealed that alcohol causes the release of HMGB1 in the gut, which in turn activates TLR4

**Figure 3.** Alcohol-induced elevation of TGF-β1 levels in neuronal cells is accompanied by a host of molecular and

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, synaptic plasticity and synaptic formation. Downregulation of genes by ethanol includes protein synthesis, myelination and the ubiquitin-proteasome pathway. Chronic ethanol exposure increases HMGB1–TLR4 and NF-κB signaling which leads to improved NF-κB target genes' expression. This results in determining neuroimmune responses to ethanol toxicity that releases HMGB1 or directly stimulates TLR and/or NMDA receptors. An epigenetic mechanism will show potential towards drug dependence by changing the DNA protein structure. Microglial cells will arbitrate the effect of alcohol toxicity on neurogenesis. The progression towards the neurobiologic techniques including micro array, QTL and proteomics will provide some anticipation for researching the molecular and cellular mechanisms that act as a keystone for the understanding of neuronal toxicity and enlightening new therapeutic gene targets for this public health burden.

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