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Possible Interaction of Opioidergic and Nitrergic Pathways in the Anticonvulsant Effect of Ivermectin on Pentylenetetrazole-Induced Clonic Seizures in Mice

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Abstract

Ivermectin (IVM) is an antiparasitic drug that primarily works by the activation of GABAA receptors. The potential pharmacological pathways behind the anti-convulsant effect of IVM haven’t yet been identified. In this study, intravenous injection of pentylenetetrazole (PTZ)-induced clonic seizure in mice was investigated in order to assess the possible influence of IVM on clonic seizure threshold (CST). We also look at the function of the Opioidergic and nitrergic pathways in IVM anticonvulsant action on clonic seizure threshold. IVM (0.5, 1, 5, and 10 mg/kg, i.p.) raised the PTZ-induced CST, according to our findings. Furthermore, the ineffective dose of nitric oxide synthase inhibitors (L-NAME 10 mg/kg, i.p.), and (7-NI 30 mg/kg, i.p.) or opioidergic system agonist (morphine 0.25 mg/kg, i.p.) were able to amplify the anticonvulsive action of IVM (0.2 mg/kg, i.p.). Moreover, the anticonvulsant effect of IVM was reversed by an opioid receptor antagonist (naltrexone 1 mg/kg, i.p.). Furthermore, the combination of the ineffective dose of morphine as an opioid receptor agonist with either L-NAME (2 mg/kg, i.p.) or 7-NI (10 mg/kg, i.p.) and with an ineffective dose of IVM (0.2 mg/kg, i.p.) had a significant anticonvulsant effect. Taken together, IVM has anticonvulsant activity against PTZ-induced clonic seizures in mice, which may be mediated at least in part through the interaction of the opioidergic system and the nitric oxide pathway.

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Data Availability

Enquiries about data availability should be directed to the authors.

Abbreviations

PTZ:

Pentylenetetrazole

CST:

Clonic seizure threshold

IVM:

Ivermectin

NO:

Nitric oxide

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Acknowledgements

This study was financially supported by Department of Pharmacology, Tehran University of Medical Sciences, Tehran, Iran [Grant No. 1400-3-367-54764]. Special thanks to Iran National Science Foundation (INSF) for their support.

Funding

Funding was provided Iran National Science Foundation (Grant No. 1400-3-367-54764).

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Author notes

  1. Sina Jourian, Mohammad Rahimi and Mohammad Amin Manavi have contributed equally as first authors.

Authors and Affiliations

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

    Sina Jourian, Mohammad Rahimi, Mohammad Amin Manavi, Mohammad-Taha Pahlevan-Fallahy, Razieh Mohammad Jafari & Ahmad Reza Dehpour

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

    Sina Jourian, Mohammad Rahimi, Mohammad-Taha Pahlevan-Fallahy & Ahmad Reza Dehpour

  3. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran

    Mohammad Amin Manavi

  4. The Chapman University School of Pharmacy (CUSP), Irvine, CA, USA

    Ali Amini

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Contributions

In this study every member respectively performed these responsibilities: SJ (Following animal study), MR (Following animal study), MAM (Supervision of Experiments on Animals, writing some parts of article, analyzing the data, and critically editing the assay), M-TP-F (Writing some parts of article, critically editing the assay), RMJ (Consulted methods, critically editing the assay), AA (Editing the assay), ARD (Supervised and principal investigator, editing assay).

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Correspondence to Razieh Mohammad Jafari or Ahmad Reza Dehpour.

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Jourian, S., Rahimi, M., Manavi, M.A. et al. Possible Interaction of Opioidergic and Nitrergic Pathways in the Anticonvulsant Effect of Ivermectin on Pentylenetetrazole-Induced Clonic Seizures in Mice. Neurochem Res 48, 885–894 (2023). https://doi.org/10.1007/s11064-022-03804-9

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