Potential of using JNK and p53 as novel drug targets for the treatment of alcoholic encephalopathy

ABSTRACT

Objectives: Investigating novel therapies for alcoholic encephalopathy (AE) would be part of the implementation of the concept of targeted pharmacological control of intracellular signalisation in regeneration-competent cells. This study aimed to explore the involvement of JNK and p53 in the implementation of the functions of different types of regeneration-competent cells of nervous tissue in alcoholic neurodegeneration (AN). Materials and Methods: The studies were conducted on C57B1/6 mice. AN was modelled in vitro and in vivo. The effects of the JNK and p53 inhibitors on the realisation of neural stem cell (NSC) and neuronal-committed progenitor (NCP) functions (their colony-forming ability, proliferative activity and intensity of specialisation), as well as on the secretion of neurotrophins by astrocytes, oligodendrocytes and microglial cells were studied. Individual cell fractions were prepared using an immunomagnetic separation method. Results: We showed that JNK and p53 stimulate the proliferation and specialisation of intact NSCs. An inversion of the role of these signalling molecules in the regulation of NSC proliferation in the conditions of modelling AN was revealed. It has been found that JNK and p53 are not involved in regulating the functions of NCP. The ambiguous role of JNK and p53 in the production of neurotrophic growth factors by different types of neuroglia cells was also found. Increased secretion of neurotrophins by oligodendrocytes and microglia during the blockade of JNK and p53 under conditions of exposure to ethanol cells was revealed. Conclusion: The results suggest the prospect of exploring the possibility of using JNK and/or p53 inhibitors as novel drugs to treat AE.