Chronic alcohol consumption is characterized by disturbances of neuroplasticity. Brain-derived neurotrophic factor (BDNF) is believed to be critically involved in this process. Here we aimed to review actual experimental and clinical data related to BDNF participation in neuroplasticity in the context of alcohol dependence. As has been shown in experiments with rodents, alcohol consumption is accompanied by the brain region-specific changes of BDNF expression and by structural and behavioral impairments. BDNF reverses aberrant neuroplasticity observed during alcohol intoxication. According to the clinical data parameters associated with BDNF demonstrate close correlation with neuroplastic changes accompanying alcohol dependence. In particular, the rs6265 polymorphism within the BDNF gene is associated with macrostructural changes in the brain, while peripheral BDNF concentration may be associated with anxiety, depression, and cognitive impairment. Thus, BDNF is involved in the mechanisms of alcohol-induced changes of neuroplasticity, and polymorphisms within the BDNF gene and peripheral BDNF concentration may serve as biomarkers, diagnostic or prognostic factors in treatment of alcohol abuse.

Background: The development of cholinergic deficit is considered an early sign of a number of pathological conditions, including Alzheimer’s disease. Cholinergic dysfunction underlies cognitive decline associated with both normal aging and Alzheimer’s disease. Objective: Here, we studied a possible mechanism of functional impairment of cholinergic neurons using an olfactory bulbectomy model. Methods: Male mice were subjected to olfactory bulbectomy or sham surgery. Three weeks after that they were trained in Morris water maze and then euthanized one month after surgery. The cholinergic indices as well as the indices of oxidative stress were studied using immunohistochemistry, western blot and ELISA. Gene expression was studied using RT-qPCR. Results: The experimental treatment was followed by impaired learning of a standard spatial task in a water maze. This was associated with a decrease in the number of cells containing choline acetyltransferase (ChAT), in relation to total number of neurons in the medial septum and lower ChAT enzymatic activity in the hippocampus. However, the levels of mRNAs of ChAT, vesicular ACh transporter and acetylcholine esterase remained unchanged in bulbectomized mice compared to sham-operated animals. These alterations were preceded by the accumulation of protein-bound carbonyls, indicating oxidative damage of proteins, whereas oxidative damage of nucleic acids was not detected. Conclusion: We assume that in olfactory bulbectomy model, oxidative damage of proteins may cause cholinergic dysfunction rather than irreversible neuronal damage. These data indicate that cholinergic neurons of the basal forebrain are very sensitive to oxidative stress, which may be responsible for the appearance of early cognitive decline in Alzheimer’s disease.

Polymorphic variant rs738409 within the PNPLA3 gene associates with alcoholic liver cirrhosis (ALC) in heavy drinkers of various ancestry but has not yet been established in the Russian population characterized by high incidence of ALC. PNPLA3 rs738409 involvement in the inflammatory process has been proposed as one of the mechanisms of liver dysfunction. Relationship between the PNPLA3 polymorphism and the biochemical markers of inflammation in patients with ALC remains unclear. The current study revealed the association between the rs738409 polymorphism, liver cirrhosis and serum cytokines in heavy drinkers in the Russian population. The serum levels of IL6, IL10, IL8, and CCL2 along with PNPLA3 rs738409 polymorphism were determined in heavy drinkers (AA, n=71) and heavy drinkers with diagnosed liver cirrhosis (ALC, n=110). All of the recruited individuals were Caucasians and belonged to the Russian population. Heavy drinkers carrying PNPLA3 rs738409 CG or CG+GG genotypes as compared with CC genotype carriers or G allele as compared with C allele carriers had significant risk of ALC. In ALC levels of interleukins and CCL2 increased as compared with AA. PNPLA3 rs738409 CC carriers had lower cirrhosis stage as compared with CG+GG carriers, however there were no differences of IL6, IL10, IL8 or CCL2 levels between G allele carriers and non-carriers in heavy drinkers. Thus, in the Russian population heavy drinkers carrying PNPLA3 rs738409 G allele are at higher risk of ALC, however the presence of rs738409 allele does not influence the serum cytokine levels.

Peripheral brain-derived neurotrophic factor (BDNF) levels increase during alcohol abstinence in dependent subjects. Meanwhile, the genetic determinants of circulating BDNF this context are poorly understood. Studies of associations between circulating BDNF and single nucleotide polymorphisms (SNPs) of the corresponding gene are mainly restricted by the most studied BDNF SNP rs6265. A recent genome-wide association study demonstrated that the BDNF-related SNP rs75945125 is associated with serum BDNF. However, it is unknown whether this SNP is associated with changes in peripheral BDNF levels in the context of alcohol abstinence. We aimed to assess the association of the BDNF-related SNPs rs75945125 and rs6265 with changes in serum BDNF levels after alcohol withdrawal and the corresponding clinical manifestations. A total of 132 inpatients diagnosed with alcohol withdrawal syndrome were enrolled in the study. Serum BDNF levels were assessed on 2nd, 7th, and 21st days after alcohol withdrawal. Alcohol withdrawal syndrome severity, craving severity, affective symptoms, and cognitive impairment were assessed on 7th and 21st days. BDNF SNPs rs75945125 and rs6265 were genotyped using real-time PCR. BDNF concentrations in the carriers of the rs75945125 C allele on 21st day were higher as compared with TT genotype carriers. BDNF SNP rs75945125 C allele carriers had a longer duration of problem drinking, consumed a lesser volume of alcohol in the last 3 months, and had lower severity of withdrawal syndrome on 7th day compared with TT genotype carriers. BDNF levels were moderated by rs75945125 and rs6265, as well as by the interaction of rs75945125 × rs6265, whereas only the interaction of rs75945125 × rs6265 had an effect on depression scores during abstinence. Thus, the trajectory of serum BDNF changes during alcohol abstinence is determined by both rs75945125 and rs6265. Moreover, BDNF gene-related SNPs are associated with the clinical parameters of alcohol dependence and withdrawal. The longitudinal design without a control group and the relatively small sample size are the limitations of this study. Future studies on the revealed interactions are warranted.