Neuropharmacology
Research areas:
- Investigation of the mechanisms of non-quantum acetylcholine release
- Investigation of the mechanisms of action of a new class of inhibitors of acetylcholine esterase
- Investigation of the role of the kinetics of the neurotransmitter secretion in the reliability of synaptic transmission
- Research of the molecular mechanisms of regulation of endogenous neurotransmitter release from the nerve terminals
- Investigation of mechanisms of the blocking receptor-channel complex of postsynaptic membrane
Main results of studies:
1. It was found that the release of neurotransmitter from synaptic vesicles is accompanied by the formation of the “directed” micro-flow which could enhance the efficiency of neurotransmitter action on receptors of the target cell, ensuring the reliability of synaptic excitation.
2. It was shown that magnesium ions could reduce the intensity of non-quantal neurotransmitter release. It was proved that extracellular calcium was necessary to implement non-quantal release of neurotransmitter, but the participation of extracellular calcium ions in the process of non-quantal secretion was not direct and was not mediated by their entry via calcium channels, as in the case with quantal secretion. At the same time, the sensitivity of non-quantal mechanism of neurotransmitter release to magnesium ions was specific and was not related to the ability of these ions to block calcium channels. (The results were included in the list of the main achievements of RAS in 2009).
3. The mechanism of autoregulation of non-quantal release of acetylcholine was found in the neuromuscular synapse of mammalians activated by both main neurotransmitter acetylcholine and glutamate, co-released in a free form from the nerve terminal as a co-mediator or formed by the hydrolysis of neuropeptide N-acetylaspartylglutamate in the synaptic cleft. (The results were included in the list of the main achievements of RAS in 2007.)
4. It was found that the inhibition of butyrylcholinesterase changed the amplitude and time parameters of postsynaptic responses after blockade of acetylcholinesterase, the main enzyme responsible for rapid hydrolysis of neurotransmitter, demonstrating that butyrylcholinesterase was localized in close proximity to release sites (These results were included in the list of the main achievements of RAS in 2009).
5. For the first time it was shown that, in contrast to classical acetylcholinesterase inhibitors, a new class of inhibitors of this enzyme, derivatives of 6-methyluracil, inactivated functional synaptic acetylcholinesterase more effectively in synapses of locomotor muscles compared to synapses of diaphragm muscle, pointing to the distinction of cholinesterase properties in synapses of muscles of different functional types. Screening of some compounds of this class according to their ability to inhibit acetylcholinesterase in different organs revealed the reagents facilitating the synaptic transmission in neuromuscular junction at doses not causing any side-effects associated with acetylcholinesterase inactivation in heart and smooth muscles. This allows considering these compounds as potential medical tools for treatment of myasthenia gravis and other syndromes of pathological muscle weakness.
6. The essential physiological role of the previously unexplored way of modulation of synaptic transmission by altering the kinetics of the release of quanta of neurotransmitter was proved. In some cases, this mechanism was the leading one in providing the reliable neuromuscular transmission, and the modulation of this mechanism could be important for overcoming the synaptic defects in certain types of pathology. (The results were included in the list of the main achievements of RAS in 2002.)
7. The leading role of calcium ions and cyclic AMP in the modulation of the kinetics of neurosecretion, particularly, the correlation between their intracellular level and the synchrony of the neurotransmitter release, was revealed.
8. When comparing the mechanisms of action of substances used in clinical practice (mecamylamine, chlorhexidine, demifosfon), it was established that these compounds were the blockers of cholinoceptive complexes with different mechanisms of action including the slow blocking of opened ion channels, the “trapping” block of the channel and allosteric modulation of the receptor-channel complex. On the basis of the experimental studies and mathematical modeling, the algorithm allowing to determine the mechanism of action of different modulators was developed.
