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.

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“…In fact, recent findings from our investigation group revealed that hypoxia-ischemia triggers ROS elevation in neuron-like cell lines. Treatment with edaravone enhanced cell viability and decreased ROS levels, likely attributable to its free radical-scavenging characteristics [27]. Various studies have also observed reductions in antioxidant levels in both depressed patients and animal models of depression [21,28].…”

Will edaravone become a new complex treatment for diabetes?

“…За допомогою аналізів життєздатності клітин, аналізу морфології та виявлення продукції АФК Silva D. та співавт. (2022) виявили, що едаравон здатен послабити індуковане пошкодження клітин гіпоксією і киснево-глю-козною недостатністю [17]. У порівнянні з іншими препаратами (перампанел і метформін) едаравон виявився найефективнішим у послабленні подій, спричинених гіпоксієюішемією, і найбезпечнішим, оскільки він не виявляв значної цитотоксичності, навіть у високих концентраціях, і індукував зниження АФК [17].…”

Neuroprotective effect and possible mechanism of edaravone in rat models of spinal cord injury: a protocol for a systematic review and meta-analysis

“…Because of the reliable safety and e cacy, it has been approved for the treatment of amyotrophic lateral sclerosis in Japan and the United States [12]. Recently, emerging studies have attempted to the explore edaravone in extended areas, such as diabetes, oncology and cardiovascular diseases [13][14][15][16]. Given the critical role of ROS in SCI, edaravone is also nding its new application scope in ied of SCI.…”