Mito-TEMPO, a Mitochondria-Targeted Antioxidant, Improves Cognitive Dysfunction due to Hypoglycemia: an Association with Reduced Pericyte Loss and Blood-Brain Barrier Leakage

Abstract

Hypoglycemia is associated with cognitive dysfunction, however, the exact mechanisms have not been elucidated. Our previous study found that severe hypoglycemia can lead to cognitive dysfunction in a type 1 diabetes (T1D) mouse model after severe hypoglycemia. Thus, the aim of this study was to further investigate whether the mechanism of severe hypoglycemia leading to cognitive dysfunction is related to oxidative stress-mediated pericyte loss and blood-brain barrier leakage. A streptozotocin T1D model, using male C57BL/6J mice, was used to induce hypoglycemia. The brain tissue was stained, ROS and ATP were determined, and cognitive function was tested using the Morris water maze. Also, an in vitro glucose deprivation model was constructed. The results show that blood-brain barrier (BBB) leakage after hypoglycemia is associated with excessive activation of oxidative stress and mitochondrial dysfunction due to glucose deprivation/reperfusion. Interventions using the mitochondria-targeted antioxidant Mito-TEMPO in both in vivo and in vitro models reduced mitochondrial oxidative stress, decreased pericyte loss and apoptosis, and attenuated BBB leakage and neuronal damage, ultimately leading to improved cognitive function.

The Role of NRF2 in Cerebrovascular Protection: Implications for Vascular Cognitive Impairment and Dementia (VCID)

“…First, pericytes participate in BBB maintenance, which is highly dependent on redox balance. In a mouse model of hypoglycemia-mediated cognitive dysfunction, both pericyte loss and BBB leakage were restored by Mito-TEMPO, a mitochondria-targeted antioxidant shown to reduce ROS in pericyte cultures [198]. Indeed, in a mouse traumatic brain injury model, TNFα-related oxidative stress and inflammation were responsible for pericyte loss, BBB damage, and vasogenic edema [199].…”

Pericyte Loss in Diseases

“…Additionally, TEM has proven useful in visualizing the interaction between pericytes and endothelium [199]. Furthermore, TEM has been widely applied to identify pericyte changes in various tissues affected by different diseases [174,[200][201][202].…”

Associations Among Microvascular Dysfunction, Fatty Acid Metabolism, and Diabetes

“…Fatty acid metabolism disorders affect pericytes, disrupting their function and survival through mitochondrial dysfunction and oxidative stress [26]. Pericyte loss leads to increased microvascular permeability, impaired blood flow regulation, and decreased capillary density, thereby contributing to microcirculatory disorders in diabetes [27][28][29][30].…”