**1. Introduction**

Alcohol is a sedative agent and is pharmacologically similar to other hypnotic drugs, which makes it a potential candidate for abuse worldwide. In Western, European, and North American populations, the percentage of alcoholics among the adult population varies from 2% to 12% [1]. Alcohol and its derivatives promote physiological, behavioral, and cognitive dysfunctions in consumers [2], so worldwide alcohol dependence is considered to be a serious health issue in the modern world [3]. Ethanol has shown strong neurodegenerative consequences in experimental animal brains [4,5]. The neurodegenerative effects are associated with neuroinflammation, apoptotic cell death [6], and

<sup>†</sup> These authors contributed equally to this paper.

synaptic dysfunction [7,8]. Moreover, it has been shown that the consumption of alcohol leads to the generation of free radicals and to the chain reaction of lipid peroxidation that causes damage to the brain and other vital organs [9,10]. To combat the challenges of free radical generation, a potent antioxidant defense mechanism is of crucial importance. In the journey to find a novel, potent, and effective antioxidant system, naturally occurring compounds have always drawn more attention because of their ease of availability, safety, and efficacy. Many natural compounds and their derivatives have shown efficacy in the management of different neurological disorders [11–13], and are under consideration and evaluation for these disorders. Curcumin, a compound known to inhibit neuroinflammation, reduces plaque deposition in AD (Alzheimer's Disease) models and improves vascular dysfunction [14]. It has been shown to antagonize many steps in the inflammatory cascade [15], including the suppression of nuclear factor-B, iNOS (Inducible nitric oxide synthase), and JNK (c-Jun N-terminal kinases) [13,16]. Moreover, it has shown the best antioxidant effects in mice [17]. It has shown effectiveness against the MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) model of Parkinson's disease [18] and the MCAO (middle cerebral artery occlusion) animal model of the ischemic brain [19]. Based on the promising therapeutic potentials of naturally occurring curcumin, we hypothesized that chronic curcumin administration may inhibit ethanol-induced neurodegeneration and memory impairment in mice, by regulating reactive oxygen species (ROS), toll-like receptor-4 (TLR4), and Receptor for advanced glycation end products (RAGE)-mediated neuroinflammation, while p-JNK and p-NF-kB triggered the release of cytokines and synaptic dysfunction. The main target of the current study is oxidative stress, regulated by nuclear factor erythroid-2 (Nrf2; an endogenous antioxidant enzyme), and neuroinflammation, initiated by the activation of the innate immune response, mostly tailored by the activation of TLR4 and RAGE, playing a role in recognizing the microbial-associated molecular patterns initiating and modulating the immune response. The activation of the TLR4 signaling promotes the phosphorylation of NF-kB, thereby promoting the inflammatory effects [20]. The signals generated by both the RAGE and TLR4 receptors funnel to the same pathway of neuroinflammation [21]. Compounds counteracting the abnormal ROS generation, inhibition of TLR4/RAGE, and inhibition of the phosphorylation of JNK/NF-kB signaling may render protection to the brain against the mediators of neurodegeneration. Here, we have made an attempt to explore the underlying neuroprotective mechanisms of chronic curcumin administration against ethanol-induced neurodegeneration and memory impairment, by targeting the oxidative stress, neuroinflammation, and apoptotic cell death.
