Vol 12, No 4 (2018)

The concept of specific receptors is the basis of the modern pharmacology of neurotransmitters. This article describes the works of Tigran Mel’kumovich Turpaev (1918–2003), during which a receptor protein was isolated for the first time. The centenary of the birth of this outstanding researcher is marked by the organization of an international conference “Physiology and Biochemistry of Signaling Systems”.

The idea on the possibility of intracellular neurotransmitter receptor localization exists already more than half a century, however it remains disputable until now. The data on such neurotransmitter receptors’ localization in unicellular organisms, early (pre-nervous) embryos and in adult cells, including neurons are summarized in the present paper. These data were obtained both using pharmacological experiments with pairs of hydrophilic and lipophilic analogues of transmitter receptor ligands, by direct ligand microinjection into the cells, and also as by labelled ligand binding and using electrophysiological methods. The data on the intracellular localization of transmitter receptors provokes to critically evaluate the current understanding of the origin of transmitter substances and corresponding receptors. It is suggested that they were formed as the result of the evolution of function of systems that originally were coupled to the processes of intracellular syntheses but not to cellular interactions.

We review the role of dopamine in the mechanisms of development of primary headaches, including migraine. Some data are given about the involvement of various types of dopamine receptors in the regulation of cranial blood flow and control of nociceptive transmission in the trigeminal nerve system. We discuss the role of the basal ganglia in the neurobiology of cephalgias. One part of the review is focused on dopaminergic drugs that may be used in the therapy of migraine.

Rapamycin is a strong inducer of autophagy which binds with its target protein mTOR and causes inhibition of biosynthetic and mitotic cell activities. The review considers neuroprotective properties of autophagy induction by rapamycin. The most important feature of the neurodegenerative diseases is the accumulation of specific proteins, such as amyloid-β, α-synuclein, huntingtin, etc. Their accumulation is associated with the weakening of the cellular function of the protein quality control provided by the ubiquitin-proteasomal system and autophagy, including chaperone-mediated autophagy. In many cases, activation of autophagy by rapamycin is able to restore the quality control of proteins and organelles, to attenuate the accumulation of pathogenic proteins. Mechanisms of rapamycin therapeutic effects include activation of the clearance of neurons from pathogenic material and induction of both autophagosomal segregation of cellular material and the lysosomal flux by activating TFEB factor, which is the inductor of the lysosomal biogenesis. Short-term treatment with rapamycin has a positive therapeutic effect in models of acute brain injury (trauma, ischemia, hypoxia). Inhibition of neurodegeneration requires long-term therapy. Neuroprotective effect of rapamycin is higher if started at young age. Good results are achieved by prolonged treatment with rapamycin in intermittent mode.

Hydrogen sulfide (H₂S) is an endogenously synthesized gaseous transmitter that participates in the regulation of the cardiovascular system and has a cardioprotective effect under ischemia–reperfusion conditions. Here, we studied possible mechanisms of the interaction of H₂S and muscarinic acetylcholine receptors in the regulation of mice atrium contractility in the isometric conditions. We show that sodium hydrosulfide (NaHS), an exogenous donor of H₂S, caused dose-dependent and reversible depression of the contractile force in the concentration range from 1 μM to 5 mM. The negative inotropic effect of NaHS did not change after the activation of muscarinic acetylcholine receptors by carbachol. However, we observed that the negative inotropic effect of carbachol increased after preliminary application of NaHS. The application of the reducing agent dithiothreitol did not change the effects of carbachol, which indicated that the effects of NaHS was not related to a direct action on the disulfide bonds of the receptor’s protein subunits. The increased effects of carbachol after NaHS application were not prevented by the inhibition of intracellular signaling pathway that mediated activation of M-cholinergic receptors, including adenylate cyclase, guanylate cyclase, and NO-synthase. However, an increase in the carbachol negative inotropic effect was not observed when ATP-dependent potassium channels were inhibited by glibenclamide. In its turn, activation of ATPdependent potassium channels by diazoxide resulted in an increase in carbachol negative inotropic action in the atrial myocardium of mice similar to the effect of NaHS. Our data indicate that the enhanced negative inotropic effect of carbachol under the action of H₂S in the mouse atrium was mediated by the activation of ATP-dependent potassium channels.

Hyperproduction and disturbance of the protein conformation of α-synuclein that are associated with the formation of aggregated forms, which have a neurotoxic effect, are the key link in the mechanisms of the pathogenesis of synucleinopathies, which are chronic progressive neurodegenerative diseases. We studied the effects of chronic intranasal administration of fibrillar forms of α-synuclein on the processes of neurogenesis in the hippocampus, the content of dopaminergic neurons in the substantia nigra, motor and exploratory activity, short- and long-term memory, and anxiety in ageing animals. The experiments were performed with 12-month-old male C57Bl/6 mice, which were administered intranasally once a day with a solution of α-synuclein fibrils or physiological solution for 14 days. Behavioral experiments included the Open field, novel object recognition, passive avoidance, and elevated plus maze tests. We used antibodies against bromodeoxyuridine, doublecortin, and tyrosine hydroxylase to stain proliferating cells, immature neurons, and dopaminergic nerve cells. We found that α-synuclein fibrils do not cause significant changes in indices of neurogenesis, the number of proliferating cells and immature neurons in the hippocampal dentate gyrus; nor do they have a significant effect on exploratory behavior, short- and long-term memory, and anxiety in mice. However, animals that were treated with fibrils of α-synuclein had a significant increase in the number of dopaminergic neurons in the substantia nigra pars compacta and an increase in some indices of general motor activity. We compared the data on the effects of α-synuclein fibrils and the results of a previous study of the action of α-synuclein oligomers under the conditions of a similar experimental protocol. We discuss possible mechanism of the revealed effect of α-synuclein fibrils on dopaminergic neurons of the substantia nigra of ageing mice.

Depressive disorder is considered as an important medico-social problem due to its severity, chronic nature, and high level of clinical polymorphism. The precise biological mechanism of this pathology is still unknown. The latest data confirms the role of the glutamatergic system in the pathogenesis of depression. Here, 79 patients with depressive disorders (50 diagnosed with a “single depressive episode” and 29 with “recurrent depressive disorder”) who were treated with selective serotonin reuptake inhibitors (SSRIs) and 27 healthy control donors underwent complex clinical and biochemical examinations. The depression severity at the baseline and on the 14th and 28th days of treatment, as well as during remission, was evaluated using the 17-item Hamilton Depression Rating Scale (HDRS-17). The therapy response was evaluated using the CGI-I scale. The blood serum glutamate concentration was measured at the baseline. The concentration of glutamate was significantly higher in the group of patients compared to the controls. No difference in this parameter was observed between groups of patients. A positive correlation between the severity of depression at the 28th day and the glutamate concentration was found in the groups of patients with recurrent depressive disorder. No association between glutamate concentration and the CGI-I scale score, as well as remission, was found. A high glutamate level in blood serum of patients with depressive disorders could be an indicator of glutamatergic system dysregulation. This value in the future may be used as a predictor of the effectiveness of SSRI treatment in patients with recurrent depressive disorder.