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Ivermectin Exerts Anticonvulsant Effects Against Status Epilepticus Induced by Lithium-Pilocarpine in Rats via GABAA Receptor and Neuroinflammation Modulation: Possible Interaction of Opioidergic Pathways and KATP Channel with Nitrergic System

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Abstract

Status epilepticus (SE) is a critical medical emergency marked by persistent or rapidly repeating seizures, posing a threat to life. Using the lithium-pilocarpine-induced SE model, we decide to evaluate the anti-seizure effects of ivermectin as a positive allosteric modulator of GABAA receptor and the underlying mechanisms involved. Lithium chloride was injected intraperitoneally at a dose of 127 mg/kg, followed by the administration of pilocarpine at a dose of 60 mg/kg after a 20-h interval in order to induce SE. Subsequently, the rats received varying amounts of ivermectin (0.3, 1, 3, 5, and 10 mg/kg, i.p.) 30 min before the onset of SE. To study the underlying molecular mechanisms, we had pharmacological interventions of diazepam (1 mg/kg), glibenclamide and nicorandil as ATP-sensitive potassium channel blocker and opener (both 1 mg/kg, i.p.), naltrexone and morphine, as opioid receptor antagonist and agonist (1 mg/kg and 0.5 mg/kg, i.p., respectively). In addition, three nitric oxide inhibitors, namely, L-NAME (10 mg/kg, i.p.), 7-NI (30 mg/kg, i.p.), and aminoguanidine (100 mg/kg, i.p.), were administered to the rats in the experiment. Finally, we use ELISA and western blotting, respectively, to examine the amounts of pro-inflammatory cytokines (TNF-α and IL-1β), nitrite, and GABAA receptors in the rat hippocampal tissue. The study found that ivermectin, at doses of 3, 5, and 10 mg/kg, exerts anti-seizure effects and decrease Racine’s scale SE score. Interestingly glibenclamide and naltrexone reduced the anti-seizure effects of ivermectin, and from other hand diazepam, nicorandil, morphine, L-NAME, 7-NI, and aminoguanidine, enhance the effects when co-administrated with subeffective dose of ivermectin. Additionally, the study found that ivermectin decreased the elevated levels of TNF-α and IL-1β following SE, while increased the reduced expression of GABAA receptors. Overall, these findings suggest that ivermectin has anti-seizure effects in a SE seizure which may be mediated by the modulation of GABAergic, opioidergic, and nitrergic pathways and KATP channels.

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Data Availability

The dataset of the present study are available from the corresponding author on reasonable request.

Abbreviations

SE:

Status epilepticus

KATP channel:

ATP-sensitive potassium channel

TNF-α:

Tumor necrosis factor-alpha

IL-1β:

Interleukin-1β

ASMs:

Anti-seizure medications

NO:

Nitric oxide

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Acknowledgements

Special thanks to Iran National Science Foundation (INSF) and Gilaranco for their support.

Funding

This work was supported by a grant from Experimental Medicine Research Center, Tehran University of Medical Sciences (grant no. 1401-1-101-57147).

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Authors and Affiliations

  1. Experimental Medicine Research Center, Tehran University of Medical Sciences, P.O. Box 13145-784, Tehran, Iran

    Mohammad Amin Manavi, Samaneh Toutounchian, Sahar Afsahi, Zahra Ebrahim Soltani, Razieh Mohammad Jafari & Ahmad Reza Dehpour

  2. Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

    Samaneh Toutounchian, Sahar Afsahi, Zahra Ebrahim Soltani, Razieh Mohammad Jafari & Ahmad Reza Dehpour

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  1. Mohammad Amin Manavi
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Contributions

In this study every member respectively performed these responsibilities:

Mohammad Amin Manavi (Supervising animal study, writing the article and analyses the data), Samaneh Toutounchian (performing animal study), Sahar Afsahi (performing animal study), Zahra Ebrahim Soltani (Consulted methods, editing critically the assay), Razieh Mohammad Jafari (Consulted methods, editing critically the assay), Ahmad Reza Dehpour (supervised and principal investigator).

Corresponding authors

Correspondence to Razieh Mohammad Jafari or Ahmad Reza Dehpour.

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All experimental steps were performed according to the authorized instructions of animal care and ethics of Tehran University of Medical Sciences (IR.TUMS.AEC.1401.028). We confirm that we have read the journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

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Highlights

• Ivermectin exhibits anti-seizure effects in rat models of status epilepticus, reducing seizure duration and delaying onset

• Ivermectin increases GABAA receptors expression, potentially contributing to its anti-seizure properties

• Ivermectin reduces hippocampal TNF-α and IL-1β levels, suggesting a role in neuroinflammation modulation

• Ivermectin’s anti-seizure effects are potentiated by inhibitors of nitric oxide synthase, leading to a decrease in brain NO levels

• The anti-seizure effects of ivermectin are influenced by KATP channels and the opioidergic pathways with possible interaction of nitrergic system

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Manavi, M.A., Toutounchian, S., Afsahi, S. et al. Ivermectin Exerts Anticonvulsant Effects Against Status Epilepticus Induced by Lithium-Pilocarpine in Rats via GABAA Receptor and Neuroinflammation Modulation: Possible Interaction of Opioidergic Pathways and KATP Channel with Nitrergic System. Mol Neurobiol (2024). https://doi.org/10.1007/s12035-024-04061-3

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