Anticonvulsant effect of (±) citronellal possibly through the GABAergic and voltage-gated sodium channel receptor interaction pathways: In vivo and in silico studies

Neurochemistry International, Journal Year: 2024, Volume and Issue: 175, P. 105704 - 105704

Published: Feb. 22, 2024

Language: Английский

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New epilepsy therapies in development

Nature Reviews Drug Discovery, Journal Year: 2024, Volume and Issue: 23(9), P. 682 - 708

Published: July 22, 2024

Language: Английский

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New GABA-Targeting Therapies for the Treatment of Seizures and Epilepsy: II. Treatments in Clinical Development

CNS Drugs, Journal Year: 2023, Volume and Issue: 37(9), P. 781 - 795

Published: Aug. 21, 2023

The inhibitory neurotransmitter γ-aminobutyric acid (GABA) plays an important role in the modulation of neuronal excitability, and a disruption GABAergic transmission contributes to pathogenesis some seizure disorders. Although many currently available antiseizure medications do act at least part by potentiating transmission, there is opportunity for further research aimed developing more innovative GABA-targeting therapies. present article summarises evidence on number such treatments clinical development. These can be broadly divided into three groups. first group consists positive allosteric modulators GABAA receptors includes Staccato® alprazolam (an already marketed benzodiazepine being repurposed epilepsy as potential rescue inhalation treatment prolonged repetitive seizures), α2/3/5 subtype-selective agents darigabat ENX-101, orally active neurosteroids ETX155 LPCN 2101. A second comprises two drugs non-neurological indications, which could include bumetanide, diuretic agent that has undergone trials phenobarbital-resistant neonatal seizures rationale development this indication under debate, ivermectin, antiparasitic drug investigated randomised double-blind trial focal epilepsy. last series highly therapies, namely interneurons (NRTX-001) delivered via stereotactic cerebral implantation mesial temporal lobe epilepsy, antisense oligonucleotide (STK-001) upregulating NaV1.1 currents restoring function interneurons, tested patients with Dravet syndrome, adenoviral vector-based gene therapy (ETX-101) scheduled investigation syndrome. Another agent, subcutaneously administered neuroactive peptide (NRP2945) reportedly upregulates expression receptor α β subunits investigated, Lennox–Gastaut syndrome other epilepsies proposed indications. diversity current pipeline underscores strong interest GABA system target new To date, limited data are these investigational studies required assess their value addressing unmet needs management.

Language: Английский

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Impairments of GABAergic transmission in hippocampus mediate increased susceptibility of epilepsy in the early stage of Alzheimer’s disease

Cell Communication and Signaling, Journal Year: 2024, Volume and Issue: 22(1)

Published: Feb. 22, 2024

Abstract Background Patients with Alzheimer’s disease (AD) are often co-morbid unprovoked seizures, making clinical diagnosis and management difficult. Although it has an important role in both AD epilepsy, abnormal γ-aminobutyric acid (GABA)ergic transmission is recognized only as a compensative change for glutamatergic damage. Neuregulin 1 (NRG1)-ErbB4 signaling can promote GABA release suppress epileptogenesis, but its effects on cognition still controversial. Methods Four-month-old APPswe/PS1dE9 mice (APP mice) were used animal models the early stage of this study. Acute/chronic chemical-kindling epilepsy established pentylenetetrazol. Electroencephalogram Racine scores performed to assess seizures. Behavioral tests emotion. Electrophysiology, western blot immunofluorescence detect alterations synapses, GABAergic system components NRG1-ErbB4 signaling. Furthermore, NRG1 was administrated intracerebroventricularly into APP then antiepileptic cognitive evaluated. Results had increased susceptibility resulting hippocampal synaptic damage impairment. Electrophysiological analysis revealed decreased hippocampus. This involved reduction number parvalbumin interneurons (PV + Ins) levels synthesis transport. We also found impaired which mediated by PV Ins loss. And administration could effectively reduce seizures improve four-month-old mice. Conclusion Our results indicated that hyperexcitability, further excitation/inhibition imbalance, promoted epileptogenesis AD. Appropriate down-regulate seizure rescue function. study provided potential direction intervening co-morbidity epilepsy.

Language: Английский

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Established and emerging GABAA receptor pharmacotherapy for epilepsy

Frontiers in Pharmacology, Journal Year: 2024, Volume and Issue: 15

Published: Feb. 21, 2024

Drugs that modulate the GABA A receptor are widely used in clinical practice for both long-term management of epilepsy and emergency seizure control. In addition to older medications have well-defined roles treatment epilepsy, recent discoveries into structure function led development newer compounds designed maximise therapeutic benefit whilst minimising adverse effects, whose position within pharmacologic armamentarium is still emerging. will remain a cornerstone foreseeable future and, this article, we provide an overview mechanisms efficacy established emerging pharmacotherapies.

Language: Английский

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Cenobamate as an Early Adjunctive Treatment in Drug-Resistant Focal-Onset Seizures: An Observational Cohort Study

CNS Drugs, Journal Year: 2024, Volume and Issue: 38(9), P. 733 - 742

Published: Aug. 3, 2024

Cenobamate (CNB) is a new antiseizure medication (ASM) to treat drug-resistant, focal-onset seizures. Data on its use in early therapy lines are not yet available, and clinicians frequently consider CNB be later ASM drug choice. We investigated the efficacy safety of as an adjunctive treatment The study population were patients with seizures who initiated after they did respond two or three lifetime ASMs, including all prior concomitant ASMs. These matched (1:2) by sex, age, seizure frequency controls any other than CNB. All participants participated Mainz Epilepsy Registry. evaluated retention rate 12 months each control group. In addition, freedom response (reduction ≥ 50% from baseline) estimated. included 231 aged 44.4 ± 15.8 years. Of these, 33.3% (n = 77) CNB, 19.0% 44) valproate (VPA), 17.3% 40) lacosamide (LCS), 16.4% 38) levetiracetam (LEV), 13.9% 32) topiramate (TPM). highest since beginning was observed (92.0%), compared LCS (80.0%), LEV (73.3%), VPA (68.2%), TPM (62.5%) (p < 0.05). Seizure also best (19.5% 71.4%, respectively) ASMs (8.3% 52.5%, respectively; p No significant differences adverse events between observed. Our provides evidence that effective good profile This data should support medical decision making management refractory epilepsy. NCT05267405.

Language: Английский

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Antisocial personality disorder:Failure to balance excitation/inhibition?

Neuropharmacology, Journal Year: 2025, Volume and Issue: unknown, P. 110321 - 110321

Published: Jan. 1, 2025

Language: Английский

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From barbiturates to ganaxolone: The importance of chirality in drug development and in understanding the actions of old and new antiseizure medications

Pharmacology & Therapeutics, Journal Year: 2025, Volume and Issue: unknown, P. 108808 - 108808

Published: Feb. 1, 2025

Out of 37 antiseizure medications (ASMs) currently in the market, 17 are chiral molecules and an additional one (oxcarbazepine) is a prodrug compound licarbazepine. Of ASMs, six (ethosuximide, fenfluramine, methsuximide, mephobarbital, stiripentol vigabatrin) marketed as racemates, remainder licensed enantiomerically pure medicines. note, all ASMs introduced prior to 1990 were racemates. Stiripentol, fenfluramine vigabatrin only racemic approved by FDA >10 years after release regulatory guidelines on development Despite fact that pharmacokinetic pharmacodynamic differences between enantiomers have been recognized for decades, importance chirality understanding biological actions not widely appreciated, many recent publications refer these if they single molecular entity. In present article, we provide critical review developed 1920s, when mephobarbital was introduced, 2022, last ASM (ganaxolone) approved. We summarize available data stereoselective pharmacokinetics pharmacodynamics also discuss aspects related introduction medicines within current scenario Europe U.S., focusing stiripentol, examples different approaches. identified number knowledge gaps relevant use drugs epilepsy, including remarkable lack published information comparative pharmacokinetics, toxicity activity most ASMs. The clinical discussed, together with rationale follow-up compounds potentially improved efficacy, safety commercial viability.

Language: Английский

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Mechanistic and therapeutic relationships of traumatic brain injury and γ-amino-butyric acid (GABA)

Pharmacology & Therapeutics, Journal Year: 2024, Volume and Issue: 256, P. 108609 - 108609

Published: Feb. 16, 2024

Language: Английский

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Adjunctive cenobamate in people with focal onset seizures: Insights from the Italian Expanded Access Program

Epilepsia, Journal Year: 2024, Volume and Issue: 65(10), P. 2909 - 2922

Published: Aug. 14, 2024

This study was undertaken to assess the effectiveness/tolerability of adjunctive cenobamate, variations in load concomitant antiseizure medications (ASMs) and predictors clinical response people with focal epilepsy.

Language: Английский

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