Tauopathy is a group of neurodegenerative diseases associated with abnormal phosphorylation and aggregation of microtubule-associated tau protein. There are currently no disease-modifying therapies for the treatment of tauopathies, however, substantial evidence has shown that there is a major role of neuroinflammation in the disease progression. According to the literature, ionizing radiation (IR) may serve as an effective tool for managing neuroinflammation. In this study, we investigated effects of the combined IR (γ-rays and carbon-12 nuclei) on locomotor abilities and microglial activation markers in the brain of Tau P301S mice, a transgenic model for tauopathy. Irradiation resulted in the improvement of behavioral symptoms in mice: increased endurance and locomotor activity in the early symptomatic and terminal stages of the disease, respectively. At the same time, irradiation led to increase in the levels of both pro-inflammatory and anti-inflammatory cytokines in the cerebellum and, to a lesser extent, in the hippocampus of the irradiated animals. The obtained data indicate a significant modulatory effect of IR on the innate immune system, highlighting high potential of radiotherapy as a new strategy for neurodegenerative disease treatment.

Neuroinflammation can be an important factor of many disorders in central nervous system (CNS) including cognitive dysfunction, affective disorders, and addictive behavior associated with prenatal alcohol exposure and presented in early adulthood. In this study we used an experimental rodent model of prenatal alcohol (PA) exposure (consumption of a 10% ethanol solution by female Wistar rats throughout pregnancy), multiplex immunofluorescence analysis of interleukins (IL-1α, IL-1β, IL-3, IL-6, IL-9, and IL-12), tumor necrosis factor (TNF-α), and chemokine CCL5, as well as quantitative real-time PCR to assess the level of cytokine mRNAs in the prefrontal cortex of the sexually mature (PND60) offspring – male and female rats with prenatal alcohol intoxication and control animals. Significant decrease in the content of TNF-α and interleukins IL-1β, IL-3, IL-6, IL-9 was detected in the prefrontal cortex of male, but not in the female PA offspring. Importantly, PA males also showed decrease in the level of TNF-α mRNA in the prefrontal cortex by 45% compared to the control males, which may underlie the detected decrease in its content. Taken together, our study demonstrates that a number of neuroimmune factors are regulated in a sex-specific manner in the prefrontal cortex and are differentially affected in males and females by the prenatal exposure to alcohol. Sex factor must be taken into account when conducting further translational studies of the fetal alcohol spectrum disorders and developing new methods for prevention and therapy.

As shown by a genome-wide association study (GWAS), the Bridging Integrator 1 (BIN1) gene is the second most important genetic locus associated with Alzheimer’s disease risk, after apolipoprotein E (APOE). Amphiphysin 2 (Bin1), encoded by this gene, is an adaptor protein involved in the regulation of synaptic vesicular transport and neurotransmission. In Alzheimer’s disease patients, Bin1 protein expression was found to be altered in several regions of the brain, including the hippocampus, which may affect Tau-dependent neurologic conditions and disease progression. This review presents current data on the structure, functions, and potential role of Bin1 in the pathogenesis of cognitive impairment of varying severity, as well as the potential use of allelic polymorphisms of the BIN1 gene for diagnosing cognitive impairment and assessing AD risk.

Recent Phase 3 clinical trials of selective kappa-opioid (KOP) receptor antagonists aticaprant and navacaprant failed to demonstrate sufficient clinical efficacy in treatment-resistant depression (TRD). This highlights a critical gap in current strategies that target opioid-mediated hedonic suppression. We propose two hypotheses to explain these setbacks: (1) neutral antagonists are inherently ineffective in blocking constitutively active KOP receptor hyperactivation and (2) the nociceptin opioid (NOP) receptor provides functional redundancy that compensates for KOP receptor blockade. Gaining insights from paralogous compensation in drug-resistant tumors, we argue for shifting from selective opioid antagonists to dual KOP/NOP receptor blockers to meaningfully improve reward function. This concept provides a theoretical framework for overcoming clinical resistance where selective KOP targeting with neutral antagonists has failed. Thus, we advocate for the development of opioid inverse agonists (such as nor-BNI, CAS: 105618-26-6), pan-antagonists (such as AT-076, CAS: 1657028-64-2), and combinations of selective blockers.