Perampanel, an AMPAR antagonist, alleviates experimental intracerebral hemorrhage‑induced brain injury via necroptosis and neuroinflammation

Abstract

Spontaneous intracerebral hemorrhage (ICH) is a subtype of stroke with high mortality and morbidity due to the lack of effective therapies. The alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist perampanel has been reported to alleviate early brain injury following subarachnoid hemorrhage and traumatic brain injury by reducing reactive oxygen species, apoptosis, autophagy, and necroptosis. Necroptosis is a caspase-independent programmed cell death mechanism that serves a vital role in neuronal cell death following ICH. However, the precise role of necroptosis in perampanel-mediated neuroprotection following ICH has not been confirmed. The present study aimed to investigate the neuroprotective effects and potential molecular mechanisms of perampanel in ICH-induced early brain injury by regulating neural necroptosis in C57BL/6 mice and in a hemin-induced neuron damage cell culture model. Mortality, neurological score, brain water content, and neuronal death were evaluated. The results demonstrated that perampanel treatment increased the survival rate and neurological score, and increased neuron survival. In addition, perampanel treatment downregulated the protein expression levels of receptor interacting serine/threonine kinase (RIP) 1, RIP3, and mixed lineage kinase domain like pseudokinase, and of the cytokines IL-1β, IL-6, TNF-α, and NF-κB. These results indicated that perampanel-mediated inhibition of necroptosis and neuroinflammation ameliorated neuronal death in vitro and in vivo following ICH. The neuroprotective capacity of perampanel was partly dependent on the PTEN pathway. Taken together, the results of the present study demonstrated that perampanel improved neurological outcomes in mice and reduced neuronal death by protecting against neural necroptosis and neuroinflammation.

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

“…However, they had no impact on cell viability at medium concentrations and were cytotoxic at higher concentrations (more than 50 µM) and more prolonged treatments (more than 24 h), particularly for perampanel. Although not as efficient as edaravone, metformin and perampanel also can increase cell viability, which is in line with data from previous studies [ 30 , 31 ]. Although these effects of perampanel were particularly obvious when using the MTT assay, which we have demonstrated to be more precise and sensitive to small changes in both cell lines, they were similar to those obtained with the other viability assays used in the present study.…”

“…Whereas in higher concentrations, it decreases cell viability and increases ROS production. Thus, it seems that when in low doses, perampanel may protect neuronal cells from hypoxia and OGD, potentially due to its capability of reducing neuronal overexcitation [ 13 ], necroptosis, and neuroinflammatory events [ 30 ]. However, it seems that to be efficient, perampanel needs to be administered in low concentrations and simultaneously with hypoxic events.…”

Necrosulfonamide Alleviates Acute Brain Injury of Intracerebral Hemorrhage via Inhibiting Inflammation and Necroptosis

“…A series of agents aimed at ameliorating necroptosis have improved neurological results in ICH ( Shen et al, 2017 ; Yang et al, 2021 ). Necrosulfonamide (NSA) is a specific inhibitor of MLKL.…”

Ulinastatin alleviates early brain injury after intracerebral hemorrhage by inhibiting necroptosis and neuroinflammation via MAPK/NF-κB signaling pathway

“…The present study also demonstrated that UTI can alleviate brain edema, improve neurological function, relieve neuroinflammation response, and decrease hippocampal neuronal damage and necroptosis. Yang 49 reported that necroptosis and neuroinflammation were important mechanisms to lead EBI after ICH, and inhibition of these mechanisms can improve neurological outcomes, and reduce neuronal damage. Pan 50 also indicated that antinecroptosis chemical necrostatin-1 can suppress apoptosis and autophagy in mice ICH model.…”