perampanel and Cognitive-Dysfunction

Pathological accumulation of Aβ oligomers has been linked to neuronal networks hyperexcitability, potentially underpinned by glutamatergic AMPA receptors (AMPARs) dysfunction. We aimed to investigate whether the non-competitive block of AMPARs was able to counteract the alteration of hippocampal epileptic threshold, and of synaptic plasticity linked to Aβ oligomers accumulation, being this glutamate receptor a valuable specific therapeutic target. In this work, we showed that the non-competitive AMPARs antagonist perampanel (PER) which, per se, did not affect physiological synaptic transmission, was able to counteract Aβ-induced hyperexcitability. Moreover, AMPAR antagonism was able to counteract Aβ-induced hippocampal LTP impairment and hippocampal-based cognitive deficits in Aβ oligomers-injected mice, while retaining antiseizure efficacy. Beside this, AMPAR antagonism was also able to reduce the increased expression of proinflammatory cytokines in this mice model, also suggesting the presence of an anti-inflammatory activity. Thus, targeting AMPARs might be a valuable strategy to reduce both hippocampal networks hyperexcitability and synaptic plasticity deficits induced by Aβ oligomers accumulation.

Topics: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Amyloid beta-Peptides; Animals; Cerebral Amyloid Angiopathy; Cognition; Cognitive Dysfunction; Excitatory Amino Acid Antagonists; Hippocampus; Mice; Receptors, AMPA

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

Cognitive dysfunctions are frequent in patients with epilepsy. This comorbidity significantly alters their quality of life and plays an important role in their therapeutic management. Perampanel is a noncompetitive antagonist of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors and is considered a new generation AED (antiepileptic drug) with limited impact on cognitive functions.The aims of this study were to evaluate the efficacy of perampanel as first add-on therapy and its impact on cognitive functions and quality of life in patients with epilepsy followed for 6 months at the Neurology Division of "A. Cardarelli" Hospital in Naples (Italy).

Topics: Adult; Anticonvulsants; Cognitive Dysfunction; Drug Therapy, Combination; Epilepsy; Female; Humans; Male; Middle Aged; Nitriles; Pyridones; Quality of Life; Retrospective Studies; Treatment Outcome; Young Adult

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

Drug-resistant epilepsy (DRE) occurs commonly in gliomas, possibly due to a shared mechanism of AMPA-activation involving both seizure activity and tumor growth. We tested the AMPA-receptor blocker perampanel (PER) in patients with DRE in low- and high-grade gliomas. Seizure response was defined as 50% drop in seizure frequency or as seizure-freedom. Cognitive function was examined by computerized test on cognitive speed (CTCS), which is sensitive to the type of cognitive dysfunction associated with epilepsy and use of anticonvulsants. Treatment policy included reduction of dose or discontinuation of one or more concurrent AEDs, once a seizure-free response was observed. Twelve patients were included patients, median age 41 years, 9 men versus 3 women and 6 months median duration of follow-up. An objective seizure response (75%) was observed in 9 (75%) out of 12 patients: 50%-seizure response in 3, seizure-freedom in 6, which is plainly more than seen with other types of DRE. Side-effects occurred in six patients. Cognitive function as examined by CTCS improved in six out of eight associated withlowering of concurrent AEDs. The final median dose of PER was 8 mg (varying between 2 and 12 mg). These results of an objective seizure response in 9 (75%) out of 12 patients treated by PER in DRE may be interpreted as a surrogate-marker of tumor response secondary to AMPA blockade, advancing confirmation by MR imaging. These results warrant further study of PER on tumor activity in gliomas.

Topics: Adult; Aged; Anticonvulsants; Cognitive Dysfunction; Dose-Response Relationship, Drug; Drug Resistant Epilepsy; Female; Follow-Up Studies; Glioma; Humans; Male; Middle Aged; Nitriles; Pyridones; Seizures; Treatment Outcome

The objective of this work was to review systematically the efficacy and tolerability of perampanel (PER) in residential patients of an epilepsy center.. We adopted an industry-independent noninterventional retrospective evaluation on the basis of the paper and electronic records complemented by personal information on the part of the treating neurologists. All patients (N=26, 15 females, mean age: 30, range 21-55years) started on PER from its introduction to the market in September 2012 until December 15th 2013 were included. Evaluation was carried out after 6, 12, and 24months of PER treatment. Changes in seizure frequency were calculated as the number of seizures during three months on PER compared to a three-month baseline period. The Clinical Global Impression Scale served as an instrument to record changes in seizure intensity beyond numerical values. Adverse effects were documented by means of the Liverpool Adverse Events Profile.. Most patients had structural or metabolic epilepsy, 2 patients suffered from Lennox-Gastaut syndrome, 2 from other symptomatic generalized epilepsy. All patients had grade III drug-resistant epilepsy. All patients had additional cognitive deficits of different degree. The retention rates were 61.5% after 6months, 46.2% after 12months, and 42.3% after 24months. The responder rates were 11.5% after 6months, 23.1% after 12months, and 7.7% after 24months. Partial responders (positive CGI and/or seizure reduction <50%) included, the respective values were 26.9%, 38.5%, and 23.1%. Only 1 patient was seizure free at 12months (but not at 24months). A loss of efficacy in the second year of treatment was suspected but the decrease of the responder rate could also be ascribed to a number of different circumstances. Adverse effects in the psychiatric field like irritability, aggression, increased sensitivity, and suicidal ideation/behavior occurred in 50% of the patients. They were the main reason to discontinue PER.. After one year of treatment PER showed reasonable efficacy in a particularly difficult-to-treat population. Psychiatric adverse effects forced discontinuation in many cases.

Topics: Adult; Aggression; Anticonvulsants; Cognitive Dysfunction; Drug Resistant Epilepsy; Female; Humans; Irritable Mood; Male; Middle Aged; Nitriles; Pyridones; Retrospective Studies; Suicidal Ideation; Time Factors; Treatment Outcome; Young Adult