2. Academic Validation
  3. Ivabradine possesses anticonvulsant and neuroprotective action in mice

Ivabradine possesses anticonvulsant and neuroprotective action in mice

  • Biomed Pharmacother. 2019 Jan;109:2499-2512. doi: 10.1016/j.biopha.2018.11.096.
Talita Matias Barbosa Cavalcante 1,  José de Maria Albuquerque De Melo Júnior 2,  Lia Bastos Lopes 3,  Matheus Costa Bessa 4,  Jéssica Gurgel Santos 5,  Luna Costa Vasconcelos 6,  Antônio Eufrásio Vieira Neto 7,  Lucas Teixeira Nunes Borges 8,  Marta Maria França Fonteles 9,  Adriano José Maia Chaves Filho 10,  Danielle Macêdo 11,  Adriana Rolim Campos 12,  Carlos Clayton Torres Aguiar 13,  Silvânia Maria Mendes Vasconcelos 14
Affiliations

Affiliations

  • 1 Neuropsychopharmacology Laboratory, Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará (UFC), Fortaleza, CE, Brazil. Electronic address: talitamatias12@hotmail.com.
  • 2 Experimental Biology Center (NUBEX), University of Fortaleza (UNIFOR), CE, Brazil. Electronic address: josedemariamelo@gmail.com.
  • 3 Experimental Biology Center (NUBEX), University of Fortaleza (UNIFOR), CE, Brazil. Electronic address: liabastoslopes2014@gmail.com.
  • 4 Experimental Biology Center (NUBEX), University of Fortaleza (UNIFOR), CE, Brazil. Electronic address: matheusbessa@edu.unifor.br.
  • 5 Experimental Biology Center (NUBEX), University of Fortaleza (UNIFOR), CE, Brazil. Electronic address: jessicagurgel8@gmail.com.
  • 6 Neuropsychopharmacology Laboratory, Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará (UFC), Fortaleza, CE, Brazil. Electronic address: lunacv94@gmail.com.
  • 7 Experimental Biology Center (NUBEX), University of Fortaleza (UNIFOR), CE, Brazil; Department of Biochemistry and Molecular Biology, Federal University of Ceará (UFC), Fortaleza, CE, Brazil. Electronic address: antonionetoeng@alu.ufc.br.
  • 8 Neuropsychopharmacology Laboratory, Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará (UFC), Fortaleza, CE, Brazil. Electronic address: lucastnb@outlook.com.
  • 9 Neuropsychopharmacology Laboratory, Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará (UFC), Fortaleza, CE, Brazil. Electronic address: martafonteles@yahoo.com.br.
  • 10 Neuropsychopharmacology Laboratory, Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará (UFC), Fortaleza, CE, Brazil. Electronic address: adrianoafilho@hotmail.com.
  • 11 Neuropsychopharmacology Laboratory, Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará (UFC), Fortaleza, CE, Brazil. Electronic address: daniellesilmacedo@gmail.com.
  • 12 Experimental Biology Center (NUBEX), University of Fortaleza (UNIFOR), CE, Brazil. Electronic address: adrirolim@unifor.br.
  • 13 Neuropsychopharmacology Laboratory, Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará (UFC), Fortaleza, CE, Brazil; Experimental Biology Center (NUBEX), University of Fortaleza (UNIFOR), CE, Brazil. Electronic address: claytontorresaguiar@gmail.com.
  • 14 Neuropsychopharmacology Laboratory, Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará (UFC), Fortaleza, CE, Brazil. Electronic address: silvania_vasconcelos@yahoo.com.br.
PMID: 30551511 DOI: 10.1016/j.biopha.2018.11.096
Abstract

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.

Keywords

GABA(A) receptor; Gamma-Aminobutyric acid; Ivabradine; Pentylenetetrazole; Picrotoxin; Seizure.

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