Repurposed Edaravone, Metformin, and Perampanel as a Potential Treatment for Hypoxia–Ischemia Encephalopathy: An In Vitro Study

Abstract

Hypoxia–ischemia encephalopathy results from the interruption of oxygen delivery and blood flow to the brain. In the developing brain, it can lead to a brain injury, which is associated with high mortality rates and comorbidities. The hippocampus is one of the brain regions that may be affected by hypoxia–ischemia with consequences on cognition. Unfortunately, clinically approved therapeutics are still scarce and limited. Therefore, in this study, we aimed to test three repurposed drugs with good pharmacological properties to evaluate if they can revert, or at least attenuate, the deleterious effects of hypoxia–ischemia in an in vitro model. Edaravone, perampanel, and metformin are used for the treatment of stroke and amyotrophic lateral sclerosis, some forms of epileptic status, and diabetes type 2, respectively. Through cell viability assays, morphology analysis, and detection of reactive oxygen species (ROS) production, in two different cell lines (HT-22 and SH-SY5Y), we found that edaravone and low concentrations of perampanel are able to attenuate cell damage induced by hypoxia and oxygen-glucose deprivation. Metformin did not attenuate hypoxic-induced events, at least in the initial phase. Among these repurposed drugs, edaravone emerged as the most efficient in the attenuation of events induced by hypoxia–ischemia, and the safest, since it did not exhibit significant cytotoxicity, even in high concentrations, and induced a decrease in ROS. Our results also reinforce the view that ROS and overexcitation play an important role in the pathophysiology of hypoxia–ischemia brain injury.