Turning a Drug Target into a Drug Candidate: A New Paradigm for Neurological Drug Discovery?

Mann, Harry-Jack; Hearnden, Olivia K.; Sattelle, David B.

doi:10.1002/bies.202000011

Cited by 4 publications

(3 citation statements)

References 86 publications

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“…It is known that the release of glutamate plays an important role in epilepsy (Chen et al 2023a ). Buckingham et al found an inhibitory glutamate receptor in invertebrates, which does not exist in vertebrates (Buckingham et al 2020 ). Modifying this exogenous receptor and introducing it into the human body can serve as a tool for studying neural circuits, achieving targeted therapy for epilepsy.…”

Section: Drug Therapy Targeting Neural Circuits In Epilepsymentioning

confidence: 99%

Unraveling the Neural Circuits: Techniques, Opportunities and Challenges in Epilepsy Research

Xiao,

Li,

Kong

et al. 2024

Cell Mol Neurobiol

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Epilepsy, a prevalent neurological disorder characterized by high morbidity, frequent recurrence, and potential drug resistance, profoundly affects millions of people globally. Understanding the microscopic mechanisms underlying seizures is crucial for effective epilepsy treatment, and a thorough understanding of the intricate neural circuits underlying epilepsy is vital for the development of targeted therapies and the enhancement of clinical outcomes. This review begins with an exploration of the historical evolution of techniques used in studying neural circuits related to epilepsy. It then provides an extensive overview of diverse techniques employed in this domain, discussing their fundamental principles, strengths, limitations, as well as their application. Additionally, the synthesis of multiple techniques to unveil the complexity of neural circuits is summarized. Finally, this review also presents targeted drug therapies associated with epileptic neural circuits. By providing a critical assessment of methodologies used in the study of epileptic neural circuits, this review seeks to enhance the understanding of these techniques, stimulate innovative approaches for unraveling epilepsy's complexities, and ultimately facilitate improved treatment and clinical translation for epilepsy. Graphical Abstract

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Section: Drug Therapy Targeting Neural Circuits In Epilepsymentioning

confidence: 99%

Unraveling the Neural Circuits: Techniques, Opportunities and Challenges in Epilepsy Research

Xiao,

Li,

Kong

et al. 2024

Cell Mol Neurobiol

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“…Because the glutamate-gated chloride channels of invertebrates are absent from vertebrate genomes, it has been suggested to introduce this exogenous, inhibitory, L-glutamate receptor into vertebrate neuronal circuits either as a tool to study neural networks or as a treatment for epilepsy. 21,69 Dimitri Kullmann and colleagues mutated a glutamate-gated chloride channel to impart an increased L-glutamate sensitivity and expressed it in excitatory neurons of rats, using a chemogenetic approach. 70 This exerted an antiseizure effect in the pilocarpine and tetanus toxin seizure models in rats.…”

Section: Mechanisms Of Action Of Ivermectinmentioning

confidence: 99%

Is the antiparasitic drug ivermectin a suitable candidate for the treatment of epilepsy?

Löscher

2023

Epilepsia

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There are only a few drugs that can seriously lay claim to the title of “wonder drug,” and ivermectin, the world's first endectocide and forerunner of a completely new class of antiparasitic agents, is among them. Ivermectin, a mixture of two macrolytic lactone derivatives (avermectin B1a and B1b in a ratio of 80:20), exerts its highly potent antiparasitic effect by activating the glutamate‐gated chloride channel, which is absent in vertebrate species. However, in mammals, ivermectin activates several other Cys‐loop receptors, including the inhibitory γ‐aminobutyric acid type A and glycine receptors and the excitatory nicotinic acetylcholine receptor of brain neurons. Based on these effects on vertebrate receptors, ivermectin has recently been proposed to constitute a multifaceted wonder drug for various novel neurological indications, including alcohol use disorders, motor neuron diseases, and epilepsy. This review critically discusses the preclinical and clinical evidence of antiseizure effects of ivermectin and provides several arguments supporting that ivermectin is not a suitable candidate drug for the treatment of epilepsy. First, ivermectin penetrates the mammalian brain poorly, so it does not exert any pharmacological effects via mammalian ligand‐gated ion channels in the brain unless it is used at high, potentially toxic doses or the blood–brain barrier is functionally impaired. Second, ivermectin is not selective but activates numerous inhibitory and excitatory receptors. Third, the preclinical evidence for antiseizure effects of ivermectin is equivocal, and at least in part, median effective doses in seizure models are in the range of the median lethal dose. Fourth, the only robust clinical evidence of antiseizure effects stems from the treatment of patients with onchocerciasis, in which the reduction of seizures is due to a reduction in microfilaria densities but not a direct antiseizure effect of ivermectin. We hope that this critical analysis of available data will avert the unjustified hype associated with the recent use of ivermectin to control COVID‐19 from recurring in neurological diseases such as epilepsy.

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“…Several mechanisms of action are considered for IVM. The primary mechanism of action is related to the glutamate-gated chloride channels [ 6 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

Anticonvulsant effects of ivermectin on pentylenetetrazole- and maximal electroshock-induced seizures in mice: the role of GABAergic system and KATP channels

Manavi¹,

Jafari²,

Shafaroodi³

et al. 2022

Heliyon

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Turning a Drug Target into a Drug Candidate: A New Paradigm for Neurological Drug Discovery?

Cited by 4 publications

References 86 publications

Unraveling the Neural Circuits: Techniques, Opportunities and Challenges in Epilepsy Research

Unraveling the Neural Circuits: Techniques, Opportunities and Challenges in Epilepsy Research

Is the antiparasitic drug ivermectin a suitable candidate for the treatment of epilepsy?

Anticonvulsant effects of ivermectin on pentylenetetrazole- and maximal electroshock-induced seizures in mice: the role of GABAergic system and KATP channels

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