| Abstrakt: |
Potential mechanisms for the realization of the neuroprotective action of nicotinamide during acute lethal short-term hypoxia were evaluated based on current knowledge about its effect on metabolic processes. Attention was drawn to the role of mitochondrial dysfunction and excitotoxicity followed by axonal degeneration and apoptosis of neurocytes and neuroglia during the development of an inflammatory response in trauma and cerebral ischemia. A decrease in the level of ATP in the cells during hypoxia affects the generation of the mitochondrial membrane potential, promotes an increase in membrane permeability, the release of NAD from mitochondria, the entry of sodium into the cell, and the development of intracellular edema. Activation of poly (ADP-ribose)-polymerase 1, induced by DNA damage during reoxygenation, reduces the level of NAD in the cell as a substrate for its reaction and causes dysfunction of the respiratory mitochondrial complex. High doses of nicotinamide have neuroprotective properties in traumatic brain injury, ischemia and stroke, as well as in neurodegenerative Alzheimer's, Parkinson's and Huntington's diseases. It is generally accepted that the neuroprotective effect of nicotinamide, firstly, is because, being a substrate for the synthesis of nicotinamide mononucleotide and NAD+, it can maintain and prevent the NAD+ content decrease under conditions of acute hypoxia. Secondly, nicotinamide, being a blocker of poly (ADP-ribose) polymerase 1, can provide the required level of NAD+ in the cell and reduce its use in the reactions with this polymerase. Thirdly, nicotinamide is a substrate for NAD+ synthesis and maintains the NAD+/NADH complex, which is important for the functioning of the antioxidant system of the mitochondrial respiratory chain under conditions of acute hypoxia. It is doubtful that these mechanisms are sufficient to implement the action of nicotinamide for the reason that there was no decrease in the level of NAD in mitochondria during the death of animals under conditions of short-term lethal hypoxia. A variant of the mechanism of nicotinamide action through GABA/benzodiazepine receptors, which causes inhibition of the activation of neurocyte glutamate receptors during acute hypoxia, was considered. In hypoxia, there is an excessive hyperactivation of glutamate receptors and the development of acute cellular hypoxia, which leads to cell death from overexcitation (excitotoxicity). Nicotinamide reduces the death of neurocytes from excitotoxicity by acting on benzodiazepine receptors. GABA agonists prevent the effect of glutamate during excitotoxicity in this way. [ABSTRACT FROM AUTHOR] |
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