Targeted Inhibition of NF-kappa B to Facilitate Neural Repair in Alcoholic Encephalopathy

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Abstract
Recent evidence indicating that ethanol-induced neurodegeneration disrupts the function of neural stem cells (SCs) and other brain progenitor populations provides a strong pathogenetic rationale for developing drugs with neuroregenerative properties. The aim of the present investigation was to elucidate the effect of an inhibitor of Nuclear Factor kappa B (NF-kappa B, NF-κB) on both the neuropsychiatric profile and the neural progenitor cell pool within the brains of a preclinical model of alcoholic encephalopathy (AE). JSH-23 (Sigma-Aldrich, Germany), with activity guaranteed by the manufacturer, was used as an NF-κB inhibitor. The experimental protocol involved inducing alcoholic encephalopathy (AE) in C57BL/6 mice. To evaluate the effects of the NF-kappa B inhibitor JSH-23, we assessed cognitive performance via the open field test and the retention of a conditioned passive avoidance reflex (CPAR). Concurrently, in vitro assays were conducted to determine the content and functional activity of multipotent SCs and committed neuronal progenitors (NPs) derived from the subventricular zone (SVZ). Furthermore, we analyzed the secretion of progenitor-active growth factors by distinct neuroglial subpopulations. The administration of JSH-23 after AE induction corrected impairments in both exploratory behavior and CPAR reproducibility in mice with AE. This cognitive recovery was accompanied by a significant increase in the population of neuronal SCs and committed NPs within the SVZ. On day 7, these cell populations reached 152.6% and 211.1% of the corresponding levels in untreated AE animals. Furthermore, both progenitor types exhibited enhanced proliferative activity and differentiation intensity. This was paralleled by an increase in growth factor production by oligodendrocytes, which rose to 174.3% and 190.8% of control values (mice with AE without treatment) on days 3 and 7 following JSH-23 treatment. These results support further investigation into the possibility of using NF-κB blockers as a basis for the development of novel neuroregenerative therapies for AE.

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