perampanel and Stroke

Stroke is a common cause of epilepsy that may be mediated via glutamate dysregulation. There is currently no evidence to support the use of antiseizure medications as primary prevention against poststroke epilepsy. Perampanel has a unique antiglutamatergic mechanism of action and may have antiepileptogenic properties. This study aims to evaluate the efficacy and safety of perampanel as an antiepileptogenic treatment in patients at high risk of poststroke epilepsy.. Up to 328 patients with cortical ischaemic stroke or lobar haemorrhage will be enrolled, and receive their first treatment within 7 days of stroke onset. Patients will be randomised (1:1) to receive perampanel (titrated to 6 mg daily over 4 weeks) or matching placebo, stratified by stroke subtype (ischaemic or haemorrhagic). Treatment will be continued for 12 weeks after titration. 7T MRI will be performed at baseline for quantification of cerebral glutamate by magnetic resonance spectroscopy and glutamate chemical exchange saturation transfer imaging. Blood will be collected for measurement of plasma glutamate levels. Participants will be followed up for 52 weeks after randomisation.The primary study outcome will be the proportion of participants in each group free of late (more than 7 days after stroke onset) poststroke seizures by the end of the 12-month study period, analysed by Fisher's exact test. Secondary outcomes will include time to first seizure, time to treatment withdrawal and 3-month modified Rankin Scale score. Quality of life, cognitive function, mood and adverse events will be assessed by standardised questionnaires. Exploratory outcomes will include correlation between cerebral and plasma glutamate concentration and stroke and seizure outcomes.. This study was approved by the Alfred Health Human Research Ethics Committee (HREC No 44366, Reference 287/18).. ACTRN12618001984280; Pre-results.

Topics: Brain Ischemia; Clinical Trials, Phase II as Topic; COVID-19; Double-Blind Method; Humans; Nitriles; Pyridones; Quality of Life; Randomized Controlled Trials as Topic; SARS-CoV-2; Stroke; Treatment Outcome

Patients in Japan often have difficulty in screening and selecting chronic-care and rehabilitation hospitals for transfer because of the high cost and unavailability of new antiseizure medications, such as perampanel and lacosamide. To investigate whether the requirement for perampanel and lacosamide interfered with patients' hospital transfer by comparing the number of days required for hospital transfer. Data were obtained from patients 1) who were diagnosed with intracerebral hemorrhage or cerebral infarction, 2) who were treated with antiseizure medications for epilepsy, and 3) who were transferred to another hospital. The main outcome measures were the length of hospital stay and days from the last seizure to hospital transfer.Ninety-four eligible patients were divided into those treated with perampanel or lacosamide (n = 18) and those treated with other agents (n = 76). The mean length of hospital stay and days from the last seizure to hospital transfer were 52.9 and 45.4 d in the perampanel and lacosamide group, and 32.7 and 28.6 d in the other medication group (p < 0.001). The mean antiseizure medication costs and total drug costs were U.S. $4.88 and $6.85 in the perampanel/lacosamide group and U.S. $1.94 and $4.41 in the other medication group (p < 0.001, p = 0.007), respectively. Considering antiseizure medication availability and cost in the transfer destination hospital is important when choosing medications for patients requiring hospital transfer from an acute-care hospital.

Topics: Hospitals; Humans; Japan; Lacosamide; Retrospective Studies; Seizures; Stroke

The present study evaluates the effect of modulating α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor (AMPAR) by inhibiting them in the acute phase and activating them in the sub-acute phase on post-stroke recovery in middle cerebral artery occlusion (MCAo) model of stroke in rats. After 90 min of MCAo, perampanel (an AMPAR antagonist, 1.5 mg/kg i.p) and aniracetam (an AMPA agonist, 50 mg/kg i.p.) were administered for different durations after MCAo. Later, after obtaining the best time point for the antagonist and the agonist treatment protocols, sequential treatment with perampanel and aniracetam were given, and the effect on neurological damage and post stroke recovery were assessed. Perampanel and aniracetam significantly protected MCAo-induced neurological damage and diminished the infarct percentage. Furthermore, treatment with these study drugs improved the motor coordination and grip strength. Sequential treatment with perampanel and aniracetam reduced the infarct percentage as assessed by MRI. Moreover, these compounds diminished the inflammation via reducing the levels of pro-inflammatory cytokines (TNF-α, IL-1β) and increasing the levels of anti-inflammatory cytokine (IL-10) along with reductions in GFAP expression. Moreover, the neuroprotective markers (BDNF and TrkB) were found to be significantly increased. Levels of apoptotic markers (Bax, cleaved-caspase-3; Bcl2 and TUNEL positive cells) and neuronal damage (MAP-2) were normalized with the AMPA antagonist and agonist treatment. Expressions of GluR1 and GluR2 subunits of AMPAR were significantly enhanced with sequential treatment. The present study thus showed that modulation of AMPAR improves neurobehavioral deficits and reduces the infarct percentage through anti-inflammatory, neuroprotective and anti-apoptotic effects.

Topics: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Anti-Inflammatory Agents; Infarction, Middle Cerebral Artery; Ischemic Stroke; Models, Theoretical; Neuroprotective Agents; Rats; Receptors, AMPA; Stroke

Ischemic stroke is a leading cause of death and disability worldwide. Additionally, neonatal ischemia is a common cause of neonatal brain injury, resulting in cerebral palsy with subsequent learning disabilities and epilepsy. However, there is currently a lack of effective treatments available for patients with perinatal ischemic stroke. In this study, we investigated the effect of perampanel (PER)-loaded poly lactic-co-glycolic acid (PLGA) by targeting microglia in perinatal stroke.. After formation of focal ischemic stroke by photothrombosis in P7 rats, PER-loaded PLGA was injected intrathecally. Proinflammatory markers (TNF-α, IL-1β, IL-6, COX2, and iNOS) and M2 polarization markers (Ym1 and Arg1) were evaluated. We investigated whether PER increased M2 microglial polarization in vitro.. PER-loaded PLGA nanoparticles decreased the pro-inflammatory cytokines compared to the control group. Furthermore, they increased M2 polarization.. PER-loaded PLGA nanoparticles decreased the size of the infarct and increased motor function in a perinatal ischemic stroke rat model. Pro-inflammatory cytokines were also reduced compared to the control group. Finally, this development of a drug delivery system targeting microglia confirms the potential to develop new therapeutic agents for perinatal ischemic stroke.

Topics: Animals; Animals, Newborn; Brain; Brain Injuries; Brain Ischemia; Cytokines; Ischemic Stroke; Microglia; Nitriles; Pyridones; Rats; Stroke

Perampanel (PER), a noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor antagonist, clinically used for seizure control, has been reported to exert neuroprotective effects in experimental models of neurodegenerative diseases. However, few studies have investigated the therapeutic effects of PER in brain injury including stroke. Our aim was to investigate the neuroprotective potential of PER using a rat transient middle cerebral artery occlusion (MCAO) model. Sprague-Dawley rats underwent 90-min MCAO followed by intraperitoneal PER administration at a dose of 1.5 mg/kg. Infarct volumes, neurological deficits, and immunological analyses were performed at 7 days after MCAO. PER significantly reduced infarct volumes (p < 0.05) and improved motor function (p < 0.05) compared with vehicle. Immunological analysis showed that PER significantly inhibited microglial activation, pro-inflammatory cytokine expression, and oxidative stress compared with vehicle. Moreover, PER suppressed neurodegeneration in the cortical ischemic boundary zone, via downregulation of Bcl-2-associated x and upregulation of Bcl-extra-large with Akt activation. In addition, post-stroke secondary neuronal damage and cognitive impairments, using the Y-maze test, were assessed 30 days after MCAO. PER significantly improved spatial working memory, which was accompanied by hippocampal CA1 neuronal loss and cortical thinning, compared with vehicle. These results indicate that PER attenuates infarct volumes and motor function deficits possibly through its anti-inflammatory, antioxidant, and anti-apoptotic activities, mediated via activation of phosphatidylinositol 3-kinase (PI3K)/Akt pathways in the acute ischemic phase, and further ameliorates post-stroke cognitive impairments via the suppression of secondary neuronal damage in the chronic ischemic phase.

Topics: Animals; Cognitive Dysfunction; Excitatory Amino Acid Antagonists; Infarction, Middle Cerebral Artery; Male; Maze Learning; Nitriles; Pyridones; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Recovery of Function; Stroke

The blood-brain barrier (BBB) is formed by brain endothelial cells, and decreased BBB integrity contributes to vasogenic cerebral edema and increased mortality after stroke. In the present study, we investigated the protective effect of perampanel, an orally active noncompetitive AMPA receptor antagonist, on BBB permeability in an in vitro ischemia model in murine brain endothelial cells (mBECs). The results showed that perampanel significantly attenuated oxygen glucose deprivation (OGD)-induced loss of cell viability, release of lactate dehydrogenase, and apoptotic cell death in a dose-dependent manner. Perampanel treatment did not alter the expression and surface distribution of various glutamate receptors. Furthermore, the results of calcium imaging showed that perampanel had no effect on OGD-induced increase in intracellular Ca(2+) concentrations. Treatment with perampanel markedly reduced the paracellular permeability of mBECs after OGD in different time points, as measured by transepithelial electrical resistance assay. In addition, the expression of claudin-5 at protein level, but not at mRNA level, was increased by perampanel treatment after OGD. Knockdown of claudin-5 partially prevented perampanel-induced protection in cell viability and BBB integrity in OGD-injured mBECs. These data show that the noncompetitive AMPA receptor antagonist perampanel affords protection against ischemic stroke through caludin-5 mediated regulation of BBB permeability.

Topics: Animals; Blood-Brain Barrier; Brain; Brain Edema; Cell Membrane Permeability; Cells, Cultured; Claudin-5; Endothelial Cells; Glucose; Ischemia; Mice, Inbred C57BL; Nitriles; Oxygen; Pyridones; Receptors, AMPA; Stroke