Antidiabetic drug as potent protection in ischemic brain injury

Abstract

Ischemic brain injury is among the leading causes of human deaths and disabilities. An acute reduction in cerebral blood flow results energy failure, glutamate release, ionic disbalance, oxidative stress, mitochondrial damage, neuroinflammation and cell death. Multiple attempts have been made to develop neuroprotective treatments by using glutamatergic activity inhibitors, ion channel modulators, free radical scavengers, antiinflammatory agents, etc., but none of them has been approved as an efficient medicine for ischemic stroke treatment yet. Imeglimin is a novel oral antidiabetic drug approved for treatment of type 2 diabetes that among other potential effects also alters mitochondrial processes. To provide insight into the pharmacological properties of imeglimin we aimed to assess the effect of intraperitoneal injection (109 µg/kg) on ischemic brain injury in different age groups: young (2-3 months-old), middle-aged (10 months-old) and aged (24 months-old) rats, and to determine whether imeglimin directly affects brain mitochondrial functions. Imeglimin treatment 24 h before in vitro global cerebral ischemia in acute brain slices reduced infarct size only in young and middle-aged rat groups. Elucidating the mechanism of neuroprotection, we found that direct addition of imeglimin to isolated mitochondria of 2-3 months-old and 10 months-old rat brains suppressed NADH-linked oxidative phosphorylation and enzymatic activity of respiratory chain complexes I. The opposite stimulating effect on complex II activity was observed within the same groups as previously mentioned. In the aged group (24 months) imeglimin had no effect in reducing cerebral infarct size or directly modulating mitochondrial respiratory and enzymatic functions. In conclusion, we expanded knowledge about potential effects of imeglimin in the brain by demonstrating a direct stimulating effect on mitochondrial complex II activity and an age-dependent its beneficial effects on brain under in vitro ischemia.