Neuroprotective and Neuroregenerative Effects of Shikonin-mediated Inhibition of NF-κB/Stat3 in Alcoholic Encephalopathy

Abstract

Background: Targeting intracellular signaling molecules in nervous tissue progenitors is a promising basis for the development of novel neurodegenerative disease therapy approaches. Naphthoquinone shikonin from the root of Lithospermum erythrorhizon is known to have inhibitory effects on NF-κB and STAT3. Objective: This study aimed to explore the influence of shikonin on the functioning of progenitors of nervous tissue and its neuroprotective properties in the modeling of alcoholic encephalopathy (AE). Methods: Experiments were performed on C57B1/6 male mice. AE was modeled by prolonged intragastric administration of ethanol. We studied the exploratory behavior and conditioned reflex activity in laboratory animals, as well as the functioning of neural stem cells (NSCs) and neuronal committed progenitors (NCPs) of the subventricular zone of the cerebral hemispheres. NCPs were obtained using the immunomagnetic separation method. The direct in vitro effects of the shikonin on the colony-forming capacity of progenitors, their proliferative activity, and intensity of specialization were compared with the effects of synthetic NF-κB and STAT3 inhibitors. Results: Results of in vitro experiments showed that the influence of phytochemicals was similar to the effects of synthetic NF-κB and STAT3 inhibitors. Shikonin stimulated the proliferation of NSCs and NCPs. In vivo shikonin administration caused the normalization of exploratory behavior and conditioned reflex activity of mice with AE. These effects developed after an increase in NSCs and NCPs content in the subventricular zone of the cerebral hemispheres due to an increase in their proliferative activity. The intensity of specialization of progenitors was also accelerated. Conclusion: The findings indicated the promise of developing a novel approach to the treatment of AE based on shikonin-mediated inhibiting of NF-κB/STAT3.