Neuroregeneration and neuroprotection: prospects for growth factors and other bioactive substances clinical application

Traumatic injuries, as well as degenerative diseases of the nervous system, are extremely common nowadays, there- fore, in clinical practice the use new methods for their treatment, such as stimulation of reparative neurogene- sis by growth factors, is highly topical. Aim. To review the published results of the experimental use of various growth factors for reparative neurogenesis stimulation and neuroprotection and to evaluate the prospects for their clinical application. Methods. Publications’ search was carried out in open databases of scientific literature, such as PubMed, Cyberleninka and eLIBRARY.RU based on keywords and their combinations: «reparative neuro- genesis», «neuroprotection», «nervous tissue», «neurotro- phic factors», «growth factors», «implantation» (in Russian and English). The search depth is 20 years. Results. The sti mulating and depressing effects of the neurotrophins NGF, CNTF, NF3, NF4, BDNF, GDNF are analysed, as well as the Shh protein’s impact on the regeneration of neu- rons and glial cells of the central and peripheral nervous systems and the specificity of their action on specific cells. The influence of such nonspecific trophic factors as EGF, FGF, IGF-1, VEGF on the viability of cells of the nervous system is described, the results of the enhancement of neurogenesis by using stimulants of erythropoiesis and retinoic acid are given. The results of using various me- thods of growth factors implantation are demonstrated. Conclusions. In the course of the study, it was found that in recent studies, mainly preclinical, both positive and negative results of the neurotrophins and nonspe- cific growth factors application for stimulating reparative neurogenesis and neuroprotection have been experi- mentally achieved. The specificity of their action on vari- ous neurocytes and the dependence of the effect on the chosen route of administration during therapy are noted. It is concluded that additional research is needed to re- solve the issue of recommending these factors for clinical application.

Hydrogen Sulfide Modulates Adult and Reparative Neurogenesis in the Cerebellum of Juvenile Masu Salmon, Oncorhynchus masou

Fish are a convenient model for the study of reparative and post-traumatic processes of central nervous system (CNS) recovery, because the formation of new cells in their CNS continues throughout life. After a traumatic injury to the cerebellum of juvenile masu salmon, Oncorhynchus masou, the cell composition of the neurogenic zones containing neural stem cells (NSCs)/neural progenitor cells (NPCs) in the acute period (two days post-injury) changes. The presence of neuroepithelial (NE) and radial glial (RG) neuronal precursors located in the dorsal, lateral, and basal zones of the cerebellar body was shown by the immunohistochemical (IHC) labeling of glutamine synthetase (GS). Progenitors of both types are sources of neurons in the cerebellum of juvenile O. masou during constitutive growth, thus, playing an important role in CNS homeostasis and neuronal plasticity during ontogenesis. Precursors with the RG phenotype were found in the same regions of the molecular layer as part of heterogeneous constitutive neurogenic niches. The presence of neuroepithelial and radial glia GS+ cells indicates a certain proportion of embryonic and adult progenitors and, obviously, different contributions of these cells to constitutive and reparative neurogenesis in the acute post-traumatic period. Expression of nestin and vimentin was revealed in neuroepithelial cerebellar progenitors of juvenile O. masou. Patterns of granular expression of these markers were found in neurogenic niches and adjacent areas, which probably indicates the neurotrophic and proneurogenic effects of vimentin and nestin in constitutive and post-traumatic neurogenesis and a high level of constructive metabolism. No expression of vimentin and nestin was detected in the cerebellar RG of juvenile O. masou. Thus, the molecular markers of NSCs/NPCs in the cerebellum of juvenile O. masou are as follows: vimentin, nestin, and glutamine synthetase label NE cells in intact animals and in the post-traumatic period, while GS expression is present in the RG of intact animals and decreases in the acute post-traumatic period. A study of distribution of cystathionine β-synthase (CBS) in the cerebellum of intact young O. masou showed the expression of the marker mainly in type 1 cells, corresponding to NSCs/NCPs for other molecular markers. In the post-traumatic period, the number of CBS+ cells sharply increased, which indicates the involvement of H2S in the post-traumatic response. Induction of CBS in type 3 cells indicates the involvement of H2S in the metabolism of extracellular glutamate in the cerebellum, a decrease in the production of reactive oxygen species, and also arrest of the oxidative stress development, a weakening of the toxic effects of glutamate, and a reduction in excitotoxicity. The obtained results allow us to consider H2S as a biologically active substance, the numerous known effects of which can be supplemented by participation in the processes of constitutive neurogenesis and neuronal regeneration.

Hydrogen Sulfide as a Factor of Neuroprotection during the Constitutive and Reparative Neurogenesis in Fish Brain

The H2S-producing systems were studied in trout telencephalon, tectum, and cerebellum at 1 week after eye injury. The results of ELISA analysis have shown a 1.7-fold increase in the CBS expression at 1 week post-injury, as compared to the intact trout. In the ventricular and subventricular regions of trout telencephalon, CBS+ cells, as well as neuroepithelial and glial types, were detected. As a result of injury, the number of CBS+ neuroepithelial cells in the pallial and subpallial periventricular regions of the telencephalon increases. In the tectum, a traumatic damage leads to an increase in the CBS expression in radial glia with a simultaneous decrease in the number of CBS immunopositive neuroepithelial cells detected in intact animals. In the cerebellum, we revealed neuroglial interrelations, in which H2S is probably released from the astrocyte-like cells with subsequent activation of the neuronal NMDA receptors. The organization of the H2S-producing cell complexes suggests that the amount of glutamate produced in the trout cerebellum and its reuptake is controlled with the involvement of astrocyte-like cells, reducing its excitotoxicity. We believe that the increase in the number of H2S-producing cells constitutes a response to oxidative stress, and the overproduction of H2S neutralizes the reactive oxygen species.

Astroglia-mediated regulation of cell development in the model of neurogenic niche in vitro treated with Aβ1-42

Neurogenesis is a complex process which governs embryonic brain development and is importants for brain plasticity throughout the whole life. Postnatal neurogenesis occurs in neurogenic niches that regulate the processes of proliferation and differentiation of stem and progenitor cells under the action of stimuli that trigger the mechanisms of neuroplasticity. Cells of glial and endothelial origin are the key regulators of neurogenesis. It is known that physiological neurogeneses is crucial for memory formation, whereas reparative neurogenesis provides partial repair of altered brain structure and compensation of neurological deficits caused by brain injury. Dysregulation of neurogenesis is a characteristics of various neurodevelopmental and neurodegenerative diseases, particularly, Alzheimer's disease which is very important medical and social problem. In the in vitro model of the neurogenic niche using hippocampal neurospheres as a source of stem/progenitor cells and astrocytes, we studied effects of astrocyte activation on the expression of markers of different stages of cell proliferation and differentiation. We found that aberrant mechanisms of development of stem and progenitor cells, caused by the beta-amyloid (Aβ1-42), can be partially restored by targeted activation of GFAP-expressing cells in the neurogenic niche.