The AMPAR antagonist perampanel protects the neurovascular unit against traumatic injury via regulating Sirt3

Abstract

Introduction Perampanel is a highly selective and noncompetitive α‐amino‐3 ‐hydroxy‐5‐methyl‐4‐isoxazole propionate receptor (AMPAR) antagonist, which has been used as an orally administered antiepileptic drug in more than 55 countries. Recently, perampanel was shown to exert neuroprotective effects in hemorrhagic and ischemic stroke models via regulating blood–brain barrier (BBB) function. Aim Here, the protective effects of perampanel were investigated in an in vitro neurovascular unit (NVU) system established using a triple cell co‐culture model (neurons, astrocytes, and brain microvascular endothelial cells) and in an in vivo traumatic brain injury (TBI) model. Results Neurons in the NVU system exhibit a more mature morphological phenotype compared with neurons cultured alone, and the co‐culture system mimicked an impermeable barrier in vitro. Perampanel protects the NVU system against traumatic and excitotoxic injury, as evidenced by reduced lactate dehydrogenase (LDH) release and apoptotic rate. Treatment with perampanel attenuated lipid peroxidation and expression of inflammatory cytokines. In addition, perampanel increased Sirt3 protein expression, enhanced the activities of mitochondrial enzyme IDH2 and SOD2, and preserved BBB function in vitro. Knockdown of Sirt3 using specific siRNA (Si‐Sirt3) partially reserved the effects of perampanel on neuronal injury and BBB function. Treatment with perampanel in vivo attenuated brain edema, preserved neurological function, inhibited apoptosis and microglia activation after TBI. Furthermore, perampanel increased the expression of Sirt3 and preserved BBB function after TBI. The effect of perampanel on BBB function and brain edema was abolished by knockdown of Sirt3 in vivo. Conclusion Our results indicate that the noncompetitive AMPAR antagonist perampanel protects the NVU system and reduces brain damage after TBI via activating the Sirt3 cascades.

Blood-Brain Barrier Dysfunction Amplifies the Development of Neuroinflammation: Understanding of Cellular Events in Brain Microvascular Endothelial Cells for Prevention and Treatment of BBB Dysfunction

“…Metformin ( Takata et al, 2013 ), pitavastatin ( Morofuji et al, 2010 ), siponimod ( Spampinato et al, 2021 ), and cilostazol ( Horai et al, 2013 ) possess the ability to strengthen brain endothelial barrier properties through modulating intracellular signaling in physiological conditions. Minocycline ( Yang et al, 2015 ), alogliptin ( Hao et al, 2019 ), zafirlukast ( Zeng et al, 2020 ), siponimod ( Spampinato et al, 2021 ), memantine ( Zhu et al, 2019 ), cilostazol ( Horai et al, 2013 ; Takeshita et al, 2014 ), candesartan ( So et al, 2015 ), perampanel ( Chen et al, 2021 ), lithium ( Ji et al, 2021 ), omarigliptin ( Du and Wang, 2020 ) and 5′-azacytidine ( Kalani et al, 2014 ) restore the barrier function dependently of specific pathological conditions (e.g., hypoxia, etc.). Ruxolitinib ( Takata et al, 2019 ) inhibits activation of pericytes to release inflammatory mediators, resulting in restoration of the BBB.…”

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

“…Glutamate is the most important and widely distributed excitatory neurotransmitter in the brain and predominantly binds to alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), kainate, and N-methyl-D-aspartate ionotropic receptors ( 23 ). Overexpression of glutamate and overactivation of its receptors contribute to neuroinflammation, tissue damage, or neuronal death following ICH, traumatic brain injury, or acute and chronic pain ( 24 , 25 ). Perampanel is a noncompetitive antagonist of AMPA receptor (AMPAR), a subtype of ionotropic glutamate receptor ( 26 ).…”

“…Perampanel is a noncompetitive antagonist of AMPA receptor (AMPAR), a subtype of ionotropic glutamate receptor ( 26 ). Previous studies have revealed that perampanel can exert neuroprotective effects and improve brain injury outcomes after traumatic brain injury, and its mechanisms of action may be related to neuronal necroptosis and antioxidative and anti-inflammatory activity ( 24 , 27 , 28 ). However, the effects of perampanel on ICH in vitro or in vivo remain unclear, and whether the underlying molecular mechanisms involve neuronal necroptosis and neuroinflammation has not been investigated.…”

Effects of Lipotoxicity in Brain Microvascular Endothelial Cells During Sirt3 Deficiency-Potential Role in Comorbid Alzheimer’s Disease

“…These effects were lost following the silencing of Sirt3. AMPAR antagonist perampanel has been shown to protect NVU by a mechanism involving Sirt3 ( Chen et al, 2021 ). However, the role of sirtuins have not been examined under conditions of comorbid AD.…”