Perampanel attenuates oxidative stress and pyroptosis following subarachnoid hemorrhage via the SIRT3/FOXO3α pathway

Abstract

Subarachnoid hemorrhage (SAH) occurs most commonly after rupture of an aneurysm, resulting in high disability and mortality due to the absence of effective therapy. Its subsequent stage, early brain injury (EBI), promotes the sustainable development of injury in the brain and ultimately leads to poor prognosis. As a new antiepileptic drug, the effect of perampanel on EBI after SAH is unknown. Pyroptosis, a process of inflammatory programmed cell death, has been confirmed in most studies to play a substantial role in aggravating SAH-post EBI. Similarly, oxidative stress is closely involved in neuronal pyroptosis and the pathophysiological mechanism of SAH-post EBI, leading to a devastating outcome for SAH patients. Nonetheless, no studies have been conducted to determine whether perampanel reduces pyroptosis and oxidative stress in the context of SAH-induced EBI. Rat SAH model via endovascular perforation was constructed in this study, to assess the neuroprotective effect of perampanel on SAH-post EBI, and to clarify the possible molecular mechanism. By means of the neurological score, brain edema detection, FJB staining, immunofluorescence, WB, ELISA, and ROS assay, we found that perampanel can improve neuroscores and reduce brain edema and neuronal degeneration at 24 h after SAH; we also found that perampanel reduced oxidative stress, neuronal pyroptosis, and inhibition of the SIRT3-FOXO3α pathway at 24 h after SAH. When 3-TYP, an inhibitor of SIRT3, was administered, the effects of perampanel on the SIRT3-FOXO3a pathway, antioxidant stress, and neuronal pyroptosis were reversed. Taken together, our data indicate that perampanel attenuates oxidative stress and pyroptosis following subarachnoid hemorrhage via the SIRT3/FOXO3α pathway. This study highlights the application value of perampanel in subarachnoid hemorrhage and lays a foundation for clinical research and later transformation of perampanel in SAH.

The role of Foxo3a in neuron-mediated cognitive impairment

“…Additionally, the anti-malarial drug 8-aminoquinoline has demonstrated robust biological activity in improving neuronal mitochondrial function through the SIRT1/3-Foxo3a pathway ( Ruankham et al, 2023 ). Perampanel, a widely prescribed antiepileptic medication, has shown efficacy in inhibiting neuronal damage following subarachnoid hemorrhage by targeting the SIRT3/Foxo3a signaling cascade ( Yang et al, 2023 ). Furthermore, several candidate small molecules targeting neuronal Foxo3a signaling, including 3,14,19-triacetylandrographolide ( Zhou et al, 2024 ), creatine ( Leem et al, 2024 ), carboxy-terminal modulator protein ( Miyawaki et al, 2009 ), estradiol ( Jover-Mengual et al, 2010 ), and Ferulic acid ( Picone et al, 2013 ), have surfaced.…”