Characterization of substantia nigra neurogenesis in homeostasis and dopaminergic degeneration: beneficial effects of the microneurotrophin BNN-20

Stem Cell Research & Therapy

Ioannis Charalampopoulos¹  Achilleas Gravanis¹  Fevronia Angelatou²  Aggeliki Dimopoulou²  Konstantinos Botsakis²  Theodora Mourtzi³  Charalampos Salodimitris⁴  Ilias Kazanis⁴  Dimitrios Dimitrakopoulos⁴  Dimitrios Kakogiannis⁴  Danai Kassandra Meri⁴  Maria Anesti⁵  Nikolaos Matsokis⁶ 

[1] Department of Pharmacology, Medical School, University of Crete, 71500, Heraklion, Greece;Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, 70013, Heraklion, Greece;Department of Physiology, Medical School, University of Patras, 26504, Patras, Greece;Department of Physiology, Medical School, University of Patras, 26504, Patras, Greece;Lab of Developmental Biology, Department of Biology, University of Patras, 26500, Patras, Greece;Lab of Developmental Biology, Department of Biology, University of Patras, 26500, Patras, Greece;Lab of Developmental Biology, Department of Biology, University of Patras, 26500, Patras, Greece;Lab of Human and Animal Physiology, Department of Biology, University of Patras, 26500, Patras, Greece;Lab of Human and Animal Physiology, Department of Biology, University of Patras, 26500, Patras, Greece;

关键词: Neurogenesis;    Adult brain;    Dopaminergic;    Substantia nigra;    Parkinson’s disease;    Weaver mouse;    Microneurotrophin;    BNN-20;    Neurotrophic;    Subependymal zone;   

DOI  :  10.1186/s13287-021-02398-3

来源: Springer

【 摘 要 】

BackgroundLoss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) underlines much of the pathology of Parkinson’s disease (PD), but the existence of an endogenous neurogenic system that could be targeted as a therapeutic strategy has been controversial. BNN-20 is a synthetic, BDNF-mimicking, microneurotrophin that we previously showed to exhibit a pleiotropic neuroprotective effect on the dopaminergic neurons of the SNpc in the “weaver” mouse model of PD. Here, we assessed its potential effects on neurogenesis.MethodsWe quantified total numbers of dopaminergic neurons in the SNpc of wild-type and “weaver” mice, with or without administration of BNN-20, and we employed BrdU labelling and intracerebroventricular injections of DiI to evaluate the existence of dopaminergic neurogenesis in the SNpc and to assess the origin of newborn dopaminergic neurons. The in vivo experiments were complemented by in vitro proliferation/differentiation assays of adult neural stem cells (NSCs) isolated from the substantia nigra and the subependymal zone (SEZ) stem cell niche to further characterize the effects of BNN-20.ResultsOur analysis revealed the existence of a low-rate turnover of dopaminergic neurons in the normal SNpc and showed, using three independent lines of experiments (stereologic cell counts, BrdU and DiI tracing), that the administration of BNN-20 leads to increased neurogenesis in the SNpc and to partial reversal of dopaminergic cell loss. The newly born dopaminergic neurons, that are partially originated from the SEZ, follow the typical nigral maturation pathway, expressing the transcription factor FoxA2. Importantly, the pro-cytogenic effects of BNN-20 were very strong in the SNpc, but were absent in other brain areas such as the cortex or the stem cell niche of the hippocampus. Moreover, although the in vitro assays showed that BNN-20 enhances the differentiation of NSCs towards glia and neurons, its in vivo administration stimulated only neurogenesis.ConclusionsOur results demonstrate the existence of a neurogenic system in the SNpc that can be manipulated in order to regenerate the depleted dopaminergic cell population in the “weaver” PD mouse model. Microneurotrophin BNN-20 emerges as an excellent candidate for future PD cell replacement therapies, due to its area-specific, pro-neurogenic effects.

【 授权许可】

CC BY