br Discussion The aim of the present study was to

Discussion The aim of the present study was to extend the list of ASIC ligands and to check if histamine receptors ligands can also affect ASICs. The novel finding is that not only histamine but also thioperamide, 1-metylhistamine and Nα-methylhistamine are active ASIC1a potentiators, while other ligands affected ASIC1a much weaker. H4R antagonist A943931 caused voltage-dependent inhibition, which is likely due to pore block. Homomeric ASIC2a were virtually insensitive not only to histamine [11] but also to the histamine receptor ligands tested in this study. Our present results together with previous data demonstrate that various amine-containing compounds including pharmacological agents and endogenous amines cause subunit-specific modulation of ASICs, which is mediated by at least two different mechanisms. Among the drugs tested we did not see a correlation between their action on histamine receptors and on ASICs. ASIC1a, ASIC2a and ASIC2b subunits have been shown to be abundant in the brain, particularly in the cerebral cortex, hippocampus, cerebellum, striatum, habenula, amygdala and olfactory bulb [19], [20], [21], [22]. A large body of accumulated data shows the involvement of ASICs in various physiological and pathological processes such as pain [23], [24], synaptic plasticity, learning and memory [25], fear and depression [26] and vision [27], [28]. Recently, strong evidence of the direct involvement of ASICs in synaptic transmission was published [12], [13]. Thus, modulation of ASICs by pharmacological agents can affect numerous CNS functions. Our finding that various amine-containing compounds affect ASICs prompts revisiting the pharmacological profile of many drugs used in medicine.
Acknowledgemnts We are grateful to prof. Lev Magazanik for stimulating discussion and valuable comments. The work was supported by Russian Science Foundation grant 16-14-00122.
Introduction Current medical management of acute traumatic 78416 injury (TBI) is primarily supportive, aimed at reducing intracranial pressure and optimizing cerebral perfusion (Levin and Diaz-Arrastia, 2015). There are no pharmacological therapies to date that have been unequivocally demonstrated to improve neurological outcomes in the late phase of TBI (Blennow et al., 2012, Xiong et al., 2010). Neurogenesis contributes to the functional repair of the central nervous system (CNS) through the processes of generation, migration, differentiation, and functional integration of newborn neurons into the pre-existing neuronal network (Zhao et al., 2008). Neurogenesis-related therapies involve (1) the administration of pro-neurogenic factors to boost endogenous mobilization of these neuronal precursors, (2) the transplantation of exogenous stem cells, and (3) a newly developed approach to reprogramming (Blaya et al., 2015, Hallbergson et al., 2003). However, transplantation has several limitations, such as short half-lives, limited diffusion of transplanted cells in CNS parenchyma, prolonged host immune responses, and tumorigenicity (Trounson and McDonald, 2015). The reprogramming approach often requires genetic manipulation, which is not easily accomplished in humans (Li and Chen, 2016). Present pro-neurogenic factors are less aggressive, but most are proteins also having the disadvantage of short half-life and limited penetration of the blood-brain barrier. There is thus a potential value in better therapeutic interventions aimed at supporting the endogenous neurogenic response for neurological recovery from TBI. In particular, specific targets are needed to prevent adverse effects on existing neurons or other cells (Li and Chen, 2016). Accumulating evidence suggests that the histaminergic system may have a role in the regulation of brain injury (Hu and Chen, 2017, Liao et al., 2015). Histamine can increase proliferation and differentiation of neural stem cells (NSCs) derived from fetal rat cortex in vitro (Molina-Hernandez and Velasco, 2008, Rodriguez-Martinez et al., 2012). It has been reported that the action of histamine on neurogenesis is related to its postsynaptic histamine H1 receptor (H1R) or histamine H2 receptor (H2R) (Molina-Hernandez and Velasco, 2008). However, due to the unavailability of conditional knockout mice for H1R or H2R, the role of cell-type-specific histamine receptors in neurogenesis is still unclear. Moreover, the direct application of histamine is clinically limited due to its poor penetration of the blood-brain barrier and its pro-inflammatory effect. By virtue of the extensive CNS localization of the pre-synaptic autoreceptor histamine H3 receptor (H3R), its antagonists produce an almost unique activation of the histaminergic system in the brain (Haas and Panula, 2003).