The following review considers current concepts concerning the characteristics of DRP1-related mitochondrial division in brain cells during hypoxic-ischemic pathology. The functional role of DRP1 in neurons and astroglia in cerebral ischemia conditions was analyzed. We discuss the potential for regulating DRP1 activity through the selective inhibitor of mitochondrial fission, mdivi-1. The article also presents data on DRP1 involvement in astro- and microglia-mediated intercellular mitochondrial transport. Understanding of the molecular mechanisms responsible for mitochondrial fission during hypoxic-ischemic exposure will allow us to consider DRP1 as an effective therapeutic target for treating conditions with a hypoxic component.

Background: Glucagon-like peptide-1 receptor (GLP1R) agonists, particularly semaglutide, show neuroprotective effects in genetic models of Alzheimer’s disease (AD). However, their delayed and long-term effects in sporadic AD, such as the intracerebroventricular streptozotocin (STZ) injection, remain insufficient. It is unclear how long the effects of GLP1R agonists persist after discontinuation and whether a single course can suppress progressive neurodegeneration. This study aimed to evaluate the delayed effects of semaglutide administration on morphological changes in neurons and glial cells in the hippocampus associated with cognitive impairment in an STZ-induced rat model of AD. Methods: Rats received bilateral intracerebroventricular STZ injections (3 mg/kg) followed by a 5-week course of intraperitoneal administration of semaglutide (0.1 mg/kg, every other day), and were euthanized 60 days after discontinuation of semaglutide administration. Immunomorphological methods were used to detect neuronal, astrocytic and microglial alterations. A novel object recognition test was performed to assess behavioral effects. Results: STZ-treated animals demonstrated cognitive impairments, ventriculomegaly, a significant increase in p-tau protein fluorescence intensity (p = 0.02), a decrease in CA1–CA3 field area (by 23%, p = 0.008), and reduced hippocampal neuronal density. Decreases in TOMM20 (mitochondrial marker) and synaptophysin levels were accompanied by significant glial activation in the hippocampal CA3 field. Semaglutide administration significantly reduced the enlarged ventricular lumen (by 43.5%), decreased p-tau fluorescence intensity, reduced vimentin-positive reactive astrocytes (by 68.4%), and increased synaptophysin fluorescence intensity. Furthermore, it reduced microglial activation (decreasing IBA1 cell density and elongation) and alleviated the disrupted AQP4 distribution. However, semaglutide did not completely halt the neurodegenerative process and showed no effect on the number of doublecortin-positive cells in the dentate gyrus. Conclusions: Hippocampal changes assessment revealed that course administration of semaglutide exerts prolonged effects, attenuating the severity of pathomorphological alterations and behavioral changes in a sporadic AD model after drug discontinuation.

The hippocampus is one of the brain structures most vulnerable to hypoxia. The cellular pool in the hippocampal subgranular zone (SGZ) neurogenic niche is maintained by the adaptive mechanisms, such as functional changes in the mitochondrial respiratory chain complexes and the reactivity of astroglia that provides structural and metabolic support for neurons. To reveal the dynamics of adaptive changes in neurons and glia of the hippocampal dentate gyrus in response to single (60 min) and repeated (8 and 20 bouts) intermittent hypobaric hypoxia exposures (5000 m equivalent to 10.5% O₂), the localization and content of mitochondrial respiratory Complex IV cytochrome c oxidase subunit 1 (MTCO1), astrocyte markers glutamine synthetase (GS) and glial fibrillary acidic protein (GFAP), as well as the immature neuron marker doublecortin (DCX), were studied in low-resistant rats by immunomorphological methods. After a single hypoxic exposure, the MTCO1 content significantly increased in neurons, while after 8 hypoxic episodes, the GS level increased in astrocytes. Changes in the latter were most prominent in the astrocytic processes, indicative of hypoxia-induced GS redistribution. The number of DCX-positive neurons in the SGZ significantly decreased after 20 hypoxic episodes. At the same time, DCX-positive glia-like cells were found in the hippocampal polymorphic layer, while GFAP labeling revealed an increase in the number of astrocytes, which may be partly due to a shift in the direction of cell differentiation in the neurogenic niche. Thus, hypoxia first intensifies mitochondrial respiratory chain activity in the neurons of the hippocampal granular cell layer, followed by the activation of astrocytes that modulate glutamate metabolism. The relationship between the dynamics of adaptive energy metabolism reactions in neurons and glia and changes in neurogenesis after 20 hypoxic episodes suggests that repeated (long-term) hypoxia promotes a shift in the differentiation of SGZ neural progenitors toward astroglia. However, this issue requires further investigation to identify the nature of DCX-positive cells more accurately.