Abstract
Background
Non-deleterious episodes of seizure preconditioning can efficiently increase the brain’s resistance to the consequent severe status epilepticus (SE). In the present investigation, we intended to elucidate further (i) the effects of preconditioning with pentylenetetrazole (PTZ) in the lithium-pilocarpine model of SE in male rats, along with (ii) the possible contribution of opioid, N-Methyl-D-aspartate (NMDA) receptors, and nitric oxide (NO) signaling transduction.
Methods
In male Wistar rats, the SE was incited by lithium administration (127 mg/kg, ip) 20 h before pilocarpine (60 mg/kg, ip). PTZ preconditioning was induced via a low-dose injection of PTZ (25 mg/kg) for 5 repeated days. To investigate the underlying signaling pathway, naltrexone (NTX; a non-specific opioid receptor antagonist), MK-801 (NMDA antagonist), L-NAME (a non-specific nitric oxide synthase (NOS) inhibitor), aminoguanidine (AG; a specific inducible NOS inhibitor), and 7-Nitroindazole (7-NI; a specific neuronal NOS inhibitor) were administered 15 min before PTZ injection.
Results
Preconditioning with PTZ successfully ameliorates the increased SE scores due to lithium-pilocarpine-induced SE (p < 0.05). None of the drugs given without PTZ preconditioning had an impact on SE outcomes. The observed anti-convulsant effect of PTZ preconditioning is reversed by the opioid receptor antagonists and NOS inhibitors. Conversely, the NMDA receptor antagonist enhanced the anti-convulsion activity caused by PTZ preconditioning. Quantifying nitrite level in the hippocampus showed a significant NO level decline in the PTZ-preconditioned animals.
Conclusions
Therefore, PTZ preconditioning generates endogenous protection against SE, possibly through targeting opioid/NMDA receptors and NO signaling transduction in the animal model of lithium-pilocarpine-induced SE.
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Data availability
All data were generated in-house, and no paper mill or other ways of manipulating research materials were used. All data generated or analyzed during this study are included in this published article and its supplementary material S1 (SE scores and biochemical measurements) and S2 (mortality rate). The Prism files, including the data analysis and figures, are available in supplementary material S3–S5.
Abbreviations
- AG:
-
Aminoguanidine
- ANOVA:
-
Analysis of variance
- Ca2 + :
-
Calcium
- EEG:
-
Electroencephalographic
- eNOS:
-
Endothelial nitric oxide synthase
- FSH:
-
Follicle-stimulating hormone
- GABA:
-
Gamma-aminobutyric acid
- iNOS:
-
Inducible nitric oxide synthase
- ip:
-
Intraperitoneal
- KA:
-
Kainic acid
- LH:
-
Luteinizing hormone
- L-NAME:
-
L-NG-Nitro-Larginine methyl ester hydrochloride
- NIH:
-
National Institutes of Health
- NMDA:
-
N-Methyl-D-aspartate
- nNOS:
-
Neuronal nitric oxide synthase
- NO:
-
Nitric oxide
- NOS:
-
Nitric oxide synthase
- NTX:
-
Naltrexone
- OD:
-
Optical density
- PCOS:
-
Polycystic ovary syndrome
- PTZ:
-
Pentylenetetrazole
- SD:
-
Standard deviation
- SE:
-
Status epilepticus
- 7-NI:
-
7-Nitroindazole
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Acknowledgements
This study was supported by a grant from the Tehran University of Medical Sciences (TUMS) and Iran National Sciences Foundation (INSF) (Grant No. 96002757).
Funding
A grant supported this study from the Tehran University of Medical Sciences (TUMS) and Iran National Sciences Foundation (INSF) (Grant No. 96002757).
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ARD: conceptualization, resources, methodology, supervision, writing, review and editing, FE and MS: investigation, project administration, writing original draft, methodology, formal analysis, review and editing, AA: project administration, methodology, writing, review and editing, NR: review and editing, PD: review and editing.
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All animal experiments were performed in agreement with the Guidelines for the Care and Use of Laboratory Animal Ethics Committee of Tehran University of Medical Sciences (Ethical code: IR.TUMS.MEDICINE.REC.1399.579) as well as the National Institutes of Health (NIH publication NO. 85–23; revised 1985).
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Eslami, F., Shayan, M., Amanlou, A. et al. Pentylenetetrazole preconditioning attenuates severity of status epilepticus induced by lithium-pilocarpine in male rats: evaluation of opioid/NMDA receptors and nitric oxide pathway. Pharmacol. Rep 74, 602–613 (2022). https://doi.org/10.1007/s43440-022-00387-8
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DOI: https://doi.org/10.1007/s43440-022-00387-8