Ivabradine possesses anticonvulsant and neuroprotective action in mice

[Display omitted] •IVA attenuated the seizure behavior induced by PTZ and PICRO.•IVA reduced brain MDA levels.•IVA prevented the increase in cleaved caspase-3 expression induced by PTZ and PICRO.•IVA demonstrated a high affinity and chemical compatibility to GABAA receptor. We analyzed whether ivabr...

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Published in:	Biomedicine & pharmacotherapy Vol. 109; pp. 2499 - 2512
Main Authors:	Cavalcante, Talita Matias Barbosa, De Melo, José de Maria Albuquerque, Lopes, Lia Bastos, Bessa, Matheus Costa, Santos, Jéssica Gurgel, Vasconcelos, Luna Costa, Vieira Neto, Antônio Eufrásio, Borges, Lucas Teixeira Nunes, Fonteles, Marta Maria França, Chaves Filho, Adriano José Maia, Macêdo, Danielle, Campos, Adriana Rolim, Aguiar, Carlos Clayton Torres, Vasconcelos, Silvânia Maria Mendes
Format:	Journal Article
Language:	English
Published:	France Elsevier Masson SAS 01-01-2019 Elsevier
Subjects:	GABAA receptor Gamma-Aminobutyric acid Ivabradine Pentylenetetrazole Picrotoxin Seizure Seizure Pentylenetetrazole Picrotoxin GABAA receptor Gamma-Aminobutyric acid Ivabradine GABA(A) receptor
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Summary:	[Display omitted] •IVA attenuated the seizure behavior induced by PTZ and PICRO.•IVA reduced brain MDA levels.•IVA prevented the increase in cleaved caspase-3 expression induced by PTZ and PICRO.•IVA demonstrated a high affinity and chemical compatibility to GABAA receptor. We analyzed whether ivabradine (IVA), a hyperpolarization-activated cyclic nucleotide-gated (HCN) channel blocker, clinically used for angina and arrhythmia, had anticonvulsant, antioxidant and neuroprotective properties against classical seizure models. Potential molecular targets to IVA anticonvulsant effects were evaluated by molecular docking. Mice were treated with IVA (1, 10 or 20 mg/kg, IP) for 3 days, and 30 min after the last administration were injected with pentylenetetrazole (PTZ - 85 mg/kg, IP), pilocarpine (PILO 400 mg/kg, SC), picrotoxin (PICRO 10 mg/kg, IP). The following measures were performed: presence of seizures, latency for the first seizure, latency for death, percentage of survival. Antioxidant activity was investigated by determination of lipid peroxidation (MDA), reduced glutathione (GSH) and nitrite levels in the prefrontal cortex (PFC), hippocampus and striatum (ST). Immunohistochemistry analysis for cleaved caspase-3, a pro-apoptotic and degenerative marker, in hippocampal subregions namely cornu ammonis (CA)1, CA3 and dentate gyrus (DG), were also performed. IVA attenuated PTZ- and PICRO-induced seizures while presented an antioxidant effect in all brain areas studied. IVA markedly reduced cleaved caspase-3 expression in the CA1 and DG region of PICRO- and PTZ-treated mice, respectively. Molecular docking demonstrated that IVA has high energetic affinity and binding compatibility for GABAA receptor without causing channel obstruction. However, no reproducibility in the binding of IVA to N-methyl-d-aspartate (NMDA) receptor was detected. In conclusion, IVA has anticonvulsant, antioxidant and neuroprotective effects against PTZ- and PICRO-induced seizures. Also, a high affinity of IVA to GABAA receptor was predicted, representing a potential underlying mechanism to these observable effects.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0753-3322 1950-6007
DOI:	10.1016/j.biopha.2018.11.096