Therapeutic Strategies to Ameliorate Neuronal Damage in Epilepsy by Regulating Oxidative Stress, Mitochondrial Dysfunction, and Neuroinflammation

Brain Sciences, Journal Year: 2023, Volume and Issue: 13(5), P. 784 - 784

Published: May 11, 2023

Epilepsy is a central nervous system disorder involving spontaneous and recurring seizures that affects 50 million individuals globally. Because approximately one-third of patients with epilepsy do not respond to drug therapy, the development new therapeutic strategies against could be beneficial. Oxidative stress mitochondrial dysfunction are frequently observed in epilepsy. Additionally, neuroinflammation increasingly understood contribute pathogenesis Mitochondrial also recognized for its contributions neuronal excitability apoptosis, which can lead loss This review focuses on roles oxidative damage, dysfunction, NAPDH oxidase, blood–brain barrier, excitotoxicity, We therapies used treat prevent seizures, including anti-seizure medications, anti-epileptic drugs, anti-inflammatory therapies, antioxidant therapies. In addition, we use neuromodulation surgery treatment Finally, present role dietary nutritional management epilepsy, ketogenic diet intake vitamins, polyphenols, flavonoids. By reviewing available interventions research pathophysiology this points areas further manage

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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Mitochondrial dysfunction in chronic neuroinflammatory diseases (Review)

International Journal of Molecular Medicine, Journal Year: 2024, Volume and Issue: 53(5)

Published: April 2, 2024

Chronic neuroinflammation serves a key role in the onset and progression of neurodegenerative disorders. Mitochondria serve as central regulators neuroinflammation. In addition to providing energy cells, mitochondria also participate immunoinflammatory response disorders including Alzheimer's disease, Parkinson's multiple sclerosis epilepsy, by regulating processes such cell death inflammasome activation. Under inflammatory conditions, mitochondrial oxidative stress, epigenetics, dynamics calcium homeostasis imbalance may underlying regulatory mechanisms for these diseases. Therefore, investigating related dysfunction result therapeutic strategies against chronic neurodegeneration. The present review summarizes neuroinflammatory diseases current treatment approaches that target

Language: Английский

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Single-Target Versus Multi-Target Drugs Versus Combinations of Drugs With Multiple Targets: Preclinical and Clinical Evidence for the Treatment or Prevention of Epilepsy

Frontiers in Pharmacology, Journal Year: 2021, Volume and Issue: 12

Published: Oct. 27, 2021

Rationally designed multi-target drugs (also termed multimodal drugs, network therapeutics, or multiple ligands) have emerged as an attractive drug discovery paradigm in the last 10–20 years, potential therapeutic solutions for diseases of complex etiology and with significant drug-resistance problems. Such agents that modulate targets simultaneously are developed aim enhancing efficacy improving safety relative to address only a single target combinations single-target drugs. Although this strategy has been proposed epilepsy therapy >25 years ago, my knowledge, one antiseizure medication (ASM), padsevonil, intentionally molecular entity could two different mechanisms. This novel exhibited promising effects numerous preclinical models difficult-to-treat seizures. However, recent randomized placebo-controlled phase IIb add-on trial treatment-resistant focal patients, padsevonil did not separate from placebo its primary endpoints. At about same time, ASM, cenobamate, several controlled trials such patients far surpassed any other newer ASMs. Yet, cenobamate was discovered purely by phenotype-based screening presumed dual mechanism action described recently. In review, I will survey vs. treatment prevention epilepsy. Most clinically approved ASMs already act at targets, but it be important identify validate new more effective drug-resistant eventually may prevent development progression

Language: Английский

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Crosstalk between neuroinflammation and oxidative stress in epilepsy

Frontiers in Cell and Developmental Biology, Journal Year: 2022, Volume and Issue: 10

Published: Aug. 10, 2022

The roles of both neuroinflammation and oxidative stress in the pathophysiology epilepsy have begun to receive considerable attention recent years. However, these concepts are predominantly studied as separate entities despite evidence that neuroinflammatory redox-based signaling cascades significant crosstalk. Oxidative post-translational modifications been demonstrated directly influence function key mediators. Neuroinflammation can further be controlled on transcriptional level regulators NF-KB nrf2 activated by reactive oxygen species. Further, induce increased expression activity NADPH oxidase, leading a highly environment. These factors additionally mitochondria metabolic status neurons glia, which already metabolically stressed epilepsy. Given implication this relationship disease pathology, review explores numerous mechanisms one another context We examine efficacy treatments targeting redox regulation animal human epilepsies literature warrant investigation. Treatment approaches aimed at rectifying aberrant may enable control improve patient outcomes.

Language: Английский

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Beneficial Effects of Capsaicin in Disorders of the Central Nervous System

Molecules, Journal Year: 2022, Volume and Issue: 27(8), P. 2484 - 2484

Published: April 12, 2022

Capsaicin is a natural compound found in chili peppers and used the diet of many countries. The important mechanism action capsaicin its influence on TRPV1 channels nociceptive sensory neurons. Furthermore, beneficial effects cardiovascular oncological disorders have been described. Many recent publications show positive animal models brain disorders. In Alzheimer’s disease, reduces neurodegeneration memory impairment. Parkinson’s disease depression also It has that area infarction improves neurological outcomes stroke. However, both proepileptic antiepileptic epilepsy proposed. These contradictory results may be caused by fact influences not only but different molecular targets such as voltage-gated sodium channels. Human studies helpful treating stroke complications dysphagia. Additionally, this exerts pain-relieving migraine cluster headaches. purpose review to discuss mechanisms central nervous system.

Language: Английский

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Lipid-Based Nanocarriers for Neurological Disorders: A Review of the State-of-the-Art and Therapeutic Success to Date

Pharmaceutics, Journal Year: 2022, Volume and Issue: 14(4), P. 836 - 836

Published: April 11, 2022

Neurodegenerative disorders including Alzheimer’s, Parkinson’s, and dementia are chronic advanced diseases that associated with loss of neurons other related pathologies. Furthermore, these involve structural functional defections the blood-brain barrier (BBB). Consequently, advances in medicines therapeutics have led to a better appreciation various pathways development neurodegenerative disorders, thus focusing on drug discovery research for targeted therapy central nervous system (CNS). Although BBB functions as shield prevent toxins blood from reaching brain, delivery CNS is hindered by its presence. Owing this, formulation approaches, use lipid-based nanocarriers, been proposed address shortcomings permeation CNS-targeted therapy, showing potential carriers translation into clinical use. Nevertheless, date, none nanocarriers has granted market authorization following successful completion all stages trials. While aforementioned benefits using underscores need fast-track their translational practice, technological be initiated achieve appropriate capacity scale-up production affordable dosage forms.

Language: Английский

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Dogs as a Natural Animal Model of Epilepsy

Frontiers in Veterinary Science, Journal Year: 2022, Volume and Issue: 9

Published: June 22, 2022

Epilepsy is a common neurological disease in both humans and domestic dogs, making dogs an ideal translational model of epilepsy. In species, epilepsy complex brain characterized by enduring predisposition to generate spontaneous recurrent epileptic seizures. Furthermore, as humans, status epilepticus one the more emergencies with not single but group disorders broad array clinical signs, age onset, underlying causes. Brain imaging suggests that limbic system, including hippocampus cingulate gyrus, often affected canine epilepsy, which could explain high incidence comorbid behavioral problems such anxiety cognitive alterations. Resistance antiseizure medications significant problem human so can be used study mechanisms drug resistance develop novel therapeutic strategies benefit species. Importantly, are large enough accommodate intracranial EEG responsive neurostimulation devices designed for humans. Studies have reported ictal interictal events remarkably similar those occurring Continuous (24/7) recordings select >1 year provided rich dataset unprecedented length studying seizure periodicities developing new methods forecasting. The data presented this review substantiate excellent several facets research. techniques inducing seizures laboratory discussed related advances. development vagus nerve stimulation therapy drug-resistant people was based on series studies induced Dogs naturally or provide large-animal models bridge gap between rodents therapies. because dog only preclinical species medicine also potential patient pet, research serves veterinary medicine.

Language: Английский

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Recent advances in pharmacotherapy for epilepsy

Current Opinion in Neurology, Journal Year: 2023, Volume and Issue: 36(2), P. 77 - 85

Published: Feb. 10, 2023

Purpose of review Epilepsy affects 70 million people worldwide and is a significant cause morbidity early mortality. The mainstay therapy oral medications. drug development escalating, driven by continued resistance in up to third epilepsy patients. Treatment now focuses on discovery novel mechanisms action syndrome-specific therapies Recent findings Difficult-to-treat related conditions including tuberous sclerosis complex (TSC), Lennox Gastaut syndrome (LGS) Dravet (DS) have been the target recent developments. Disease-modifying for TSC with vigabatrin at onset first electroencephalographic epileptiform changes, rather than after clinical seizure, has demonstrated strongly positive seizure developmental outcomes. Fenfluramine, approved DS and, more recently, LGS, robust data supporting efficacy, safety/tolerability, as well mortality, quality life cognitive function. Rescue expanded include better tolerated benzodiazepines form nasal midazolam valium. Cenobamate, first-in-class inactivator persistent voltage-gated sodium channel adult partial epilepsy, exceptional efficacy tolerability will be children generalized adults. Summary repertoire available rapidly expanding, includes disease-modifying agents extraordinary fenfluramine cenobamate.

Language: Английский

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Animal Models of Drug-Resistant Epilepsy as Tools for Deciphering the Cellular and Molecular Mechanisms of Pharmacoresistance and Discovering More Effective Treatments

Cells, Journal Year: 2023, Volume and Issue: 12(9), P. 1233 - 1233

Published: April 24, 2023

In the last 30 years, over 20 new anti-seizure medicines (ASMs) have been introduced into market for treatment of epilepsy using well-established preclinical seizure and models. Despite this success, approximately 20–30% patients with drug-resistant (DRE). The current approach to ASM discovery DRE relies largely on drug testing in various model systems that display varying degrees resistance. recent attempts made include more etiologically relevant models evaluation a investigational drug. Such played an important role advancing greater understanding at mechanistic level hypothesis as experimental evidence becomes available. This review provides critical discussion pharmacology adult focal allow selection responders nonresponders those pharmacoresistance per se two or ASMs. addition, animal major genetic epilepsies is discussed. Importantly, addition chemical compounds, several discussed here can be used evaluate other potential therapies such neurostimulation, dietary treatments, gene therapy, cell transplantation. also discusses challenges associated identifying novel absence mechanisms contribute DRE. Finally, lessons learned from profile recently approved highly efficacious broad-spectrum cenobamate.

Language: Английский

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