perampanel and Brain-Injuries--Traumatic

Perampanel is a highly selective and non-competitive α-amino-3-hydroxy- 5 -methyl-4-isoxazole propionate (AMPA) receptor (AMPAR) antagonist, which has been licensed as an orally administered antiepileptic drug in more than 55 countries. Recently, perampanel was found to exert neuroprotective effects in hemorrhagic and ischemic stroke models.. In this study, the protective effect of perampanel was investigated.. The protective effect of perampanel was investigated in an in vitro Traumatic Neuronal Injury (TNI) model in primary cultured cortical neurons.. We found that perampanel significantly preserved morphological changes, attenuated lactate dehydrogenase (LDH) release and inhibited caspase-3 activation after TNI. The TNI-induced necroptosis, as evidenced by flow cytometry, was markedly reduced by perampanel treatment. The results of western blot showed that perampanel decreased the expression and phosphorylation of the necroptotic factors, receptor protein interacting kinase 1 (RIPK1) and RIPK3. In addition, treatment with perampanel increased the phosphorylation of Akt and GSK3β in a time-dependent manner up to 24 h after TNI. Treatment with the Akt inhibitor LY294002 partially reversed the protective effects of perampanel.. Our present data suggest that necroptosis plays a key role in the pathogenesis of neuronal death after TNI, and that perampanel might have therapeutic potential for patients with Traumatic Brain Injury (TBI).

Topics: Animals; Brain Injuries, Traumatic; Glycogen Synthase Kinase 3 beta; Necroptosis; Neurons; Neuroprotective Agents; Nitriles; Phosphorylation; Proto-Oncogene Proteins c-akt; Pyridones; Rats; Rats, Sprague-Dawley; Receptor-Interacting Protein Serine-Threonine Kinases; Receptors, AMPA; Signal Transduction

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.. 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.. 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.. Our results indicate that the noncompetitive AMPAR antagonist perampanel protects the NVU system and reduces brain damage after TBI via activating the Sirt3 cascades.

Topics: Animals; Blood-Brain Barrier; Brain Injuries, Traumatic; Coculture Techniques; Excitatory Amino Acid Antagonists; Female; Male; Neuroprotective Agents; Neurovascular Coupling; Nitriles; Pregnancy; Pyridones; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Sirtuins

Traumatic brain injury (TBI) is a major cause of death and physical as well as cognitive disability for which an effective treatment option remains to be identified. Evidence in preclinical models has indicated that antagonists of the α-amino-3-hydroxy-5-methyl-4-isozazole propionate (AMPA) receptor exert neuroprotective effects after mechanical injury in vitro and in vivo. In particular, 2-(2-oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl)benzonitrile hydrate (perampanel), a selective AMPA receptor antagonist with good bioavailability, was recently shown to therapeutically protect against the sequelae of TBI in the rodent controlled cortical impact model. However, this model induces a largely focal injury and is less representative of diffuse injury components that occur in TBI resulting from acceleration/deceleration forces. Here, we investigated the neuroprotective effects of perampanel in the rodent lateral fluid percussion injury model (LFPI), which produces both focal and diffuse injury. Pre- or post-injury administration of perampanel in male adult rats attenuated the injury-induced increase in the pro-apoptotic bax/bcl-xL ratio in the hippocampus; reduced impairments in learning and memory, assessed by the Morris water maze test; and reduced impairments in reward-seeking behavior, assessed by a female encounter test. Although additional studies are needed to determine the sex-related differences in the neuroprotective effects, these results provide support for the therapeutic potential of perampanel in TBI.

Topics: Animals; bcl-2-Associated X Protein; bcl-X Protein; Brain Injuries, Traumatic; Cognition; Cognitive Dysfunction; Disease Models, Animal; Excitatory Amino Acid Antagonists; Hippocampus; Male; Maze Learning; Neuroprotective Agents; Nitriles; Pyridones; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Spatial Memory; Treatment Outcome

Traumatic brain injury (TBI) is among the most debilitating neurological disorders with inadequate therapeutic options. It affects all age groups globally leading to post-TBI behavioral challenges and life-long disabilities requiring interventions for these health issues. In the current study, C57BL/6J mice were induced with TBI through the weight-drop method, and outcomes of acutely administered ketamine alone and in combination with perampanel were observed. The impact of test drugs was evaluated for post-TBI behavioral changes by employing the open field test (OFT), Y-maze test, and novel object recognition test (NOR). After that, isolated plasma and brain homogenates were analyzed for inflammatory modulators, i.e., NF-

Topics: Animals; Behavior, Animal; Brain; Brain Injuries, Traumatic; Disease Models, Animal; Inflammation; Ketamine; Male; Maze Learning; Metabolomics; Mice; Mice, Inbred C57BL; Neuroprotection; Neuroprotective Agents; NF-kappa B p50 Subunit; Nitric Oxide Synthase Type II; Nitriles; Pyridones; Recognition, Psychology; Spatial Memory

Perampanel is a novel α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor (AMPAR) antagonist, approved in over 35 countries as an adjunctive therapy for the treatment of seizures. Recently, it was found to exert protective effects against ischemic neuronal injury in vitro. In the present study, we investigated the potential protective effects of perampanel in a traumatic brain injury (TBI) model in rats. Oral administration with perampanel at a dose of 5 mg/kg exerted no major organ-related toxicities. We found that perampanel significantly attenuated TBI-induced brain edema, brain contusion volume, and gross motor dysfunction. The results of Morris water maze test demonstrated that perampanel treatment also improved cognitive function after TBI. These neuroprotective effects were accompanied by reduced neuronal apoptosis, as evidenced by decreased TUNEL-positive cells in brain sections. Moreover, perampanel markedly inhibited lipid peroxidation and obviously preserved the endogenous antioxidant system after TBI. In addition, enzyme-linked immunosorbent assay (ELISA) was performed at 4 and 24 h after TBI to evaluate the expression of inflammatory cytokines. The results showed that perampanel suppressed the expression of pro-inflammatory cytokines TNF-α and IL-1β, whereas increased the levels of anti-inflammatory cytokines IL-10 and TGF-β1. These data show that the orally active AMPAR antagonist perampanel affords protection against TBI-induced neuronal damage and neurological dysfunction through anti-oxidative and anti-inflammatory activity.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Brain Injuries, Traumatic; Inflammation Mediators; Lipid Peroxidation; Male; Nitriles; Pyridones; Rats; Rats, Sprague-Dawley; Receptors, AMPA