Mitochondrial dysfunction in cerebrovascular pathology as a target for pharmacological modulation: focus on benzodiazepines

Abstract

Mitochondrial dysfunction (MD) is recognized as one of the key pathobiochemical mechanisms in the development of cerebrovascular diseases, neurodegenerative processes and cognitive disorders. In destructive and degenerative brain diseases, there is a disruption of the mitochondrial respiratory chain, energy metabolism, and cellular ionic homeostasis, with elevated intracellular calcium levels, glutamate induced excitotoxicity, nitrosative and oxidative stress and neuronal injury. Mitochondria, which play a central role in cellular energy supply, are identified as the primary source of reactive oxygen species (ROS). The term "mitochondrial dysfunction" now encompasses a typical pathological process without strict etiological or nosological specificity.
MD is characterized by impaired respiratory chain function, reduced ATP production, excessive ROS accumulation, mitochondrial pore opening, calcium homeostasis disruption, and activation of neuronal apoptosis. These alterations lead to neuronal structural damage, decreased energy potential, impaired cognitive function, and reduced neuroplasticity. The issue is particularly relevant in the context of ischemic brain injury, trauma, chronic hypoxia, and post-hypoxic conditions.
The purpose of the study – is to analyze and summarize data from scientific literature and our own results regarding the role of MD in cerebrovascular pathology and to determine approaches to its
pharmacological correction. This article emphasizes the central role of mitochondria in pathological processes and highlights the importance of pharmacological correction of MD. It explores the mechanisms by which adaptive cellular factors such as HIF-1 and molecular chaperones Hsp70 regulate mitochondrial metabolism and contribute
to neuronal protection. Current therapeutic approaches are discussed, including the use of antioxidants, antihypoxants, energy-modulating agents, neuropeptides, and particularly peripheral benzodiazepine receptor (TSPO) modulators. Benzodiazepine derivatives such as Gidazepam®, Phenazepam®, and Cinazepam (levana) demonstrate mitoprotective properties by reducing ROS production, increasing mitochondrial membrane potential, modulating pore opening, and elevating Hsp70 levels. TSPO, located on the outer mitochondrial membrane, plays a critical role in apoptosis regulation, steroidogenesis, and cellular stress responses, making it a promising pharmacological target. The potential use of benzodiazepines in autism spectrum disorders (ASD) is also of growing interest. Thus, benzodiazepine derivatives capable of modulating TSPO and mitochondrial function may represent valuable components of combined neuroprotective strategies in cerebrovascular pathology. Further researches are needed to establish their clinical efficacy and safety in neurology, neurosurgery,
and neurocritical care