TY - JOUR
T1 - Reproductive and fetal toxicity studies of histamine H3 receptor antagonist DL76 used in mice to prevent maximal electroshock-induced seizure
AU - Bastaki, Salim M.
AU - Abdulrazzaq, Yousef M.
AU - Zidan, Marwan Abdelrahim
AU - Shafiullah, Mohamed
AU - Alaryani, Saif Ghdayer
AU - Alnuaimi, Fatima Awad
AU - Adeghate, Ernest
AU - Mohsin, Sahar
AU - Akour, Amal
AU - Siwek, Agata
AU - Łażewska, Dorota
AU - Kieć-Kononowicz, Katarzyna
AU - Sadek, Bassem
N1 - Publisher Copyright:
Copyright © 2024 Bastaki, Abdulrazzaq, Zidan, Shafiullah, Alaryani, Alnuaimi, Adeghate, Mohsin, Akour, Siwek, Łażewska, Kieć-Kononowicz and Sadek.
PY - 2024
Y1 - 2024
N2 - Introduction: Brain histamine is considered an endogenous anticonvulsant and histamine H1 receptor. H1R antagonists have, in earlier studies, been found to induce convulsions. Moreover, research during the last two decades has provided more information concerning the anticonvulsant activities of histamine H3R (H3R) antagonists investigated in a variety of animal epilepsy models. Methods: Therefore, the in vivo anticonvulsant effect of the H3R antagonist DL76, with proven high in vitro affinity, in vitro selectivity profile, and high in vivo antagonist potency in mice against maximal electroshock (MES)-induced seizures in mice, was assessed. Valproic acid (VPA) was used as a reference antiepileptic drug (AED). In addition, DL76 was tested for its reproductive and fetal toxicity in the same animal species. Results and discussion: Our observations showed that acute systemic administration (intraperitoneal; i.p.) of DL76 (7.5 mg/kg, 15 mg/kg, 30 mg/kg, and 60 mg/kg, i.p.) provided significant and dose-dependent protection against MES-induced seizures in female and male mice. Moreover, the DL76-provided protective effects were comparable to those offered by the VPA and were reversed when animals were co-administered the CNS-penetrant selective H3R agonist R-(α)-methylhistamine (RAM, 10 mg/kg, i.p.). Furthermore, the administration of single (7.5 mg/kg, 15 mg/kg, 30 mg/kg, or 60 mg/kg, i.p.) or multiple doses (3 × 15 mg/kg, i.p.) of H3R antagonist DL76 on gestation days (GD) 8 or 13 failed to affect the maternal body weight of mice when compared with the control mice group. No significant alterations were detected in the average number of implantations and resorptions between the control and DL76-treated groups at the early stages of gestation and the organogenesis period. In addition, no significant differences in the occurrence of skeletal abnormalities, urogenital abnormalities, exencephaly, exomphalos, facial clefts, and caudal malformations were observed. The only significant abnormalities witnessed in the treated groups of mice were in the length of long bones and body length. In conclusion, the novel H3R antagonist DL76 protected test animals against MES-induced seizures and had a low incidence of reproductive and fetal malformation with decreased long bone lengths in vivo, signifying the potential therapeutic value of H3R antagonist DL76 for future preclinical as well as clinical development for use in the management of epilepsy.
AB - Introduction: Brain histamine is considered an endogenous anticonvulsant and histamine H1 receptor. H1R antagonists have, in earlier studies, been found to induce convulsions. Moreover, research during the last two decades has provided more information concerning the anticonvulsant activities of histamine H3R (H3R) antagonists investigated in a variety of animal epilepsy models. Methods: Therefore, the in vivo anticonvulsant effect of the H3R antagonist DL76, with proven high in vitro affinity, in vitro selectivity profile, and high in vivo antagonist potency in mice against maximal electroshock (MES)-induced seizures in mice, was assessed. Valproic acid (VPA) was used as a reference antiepileptic drug (AED). In addition, DL76 was tested for its reproductive and fetal toxicity in the same animal species. Results and discussion: Our observations showed that acute systemic administration (intraperitoneal; i.p.) of DL76 (7.5 mg/kg, 15 mg/kg, 30 mg/kg, and 60 mg/kg, i.p.) provided significant and dose-dependent protection against MES-induced seizures in female and male mice. Moreover, the DL76-provided protective effects were comparable to those offered by the VPA and were reversed when animals were co-administered the CNS-penetrant selective H3R agonist R-(α)-methylhistamine (RAM, 10 mg/kg, i.p.). Furthermore, the administration of single (7.5 mg/kg, 15 mg/kg, 30 mg/kg, or 60 mg/kg, i.p.) or multiple doses (3 × 15 mg/kg, i.p.) of H3R antagonist DL76 on gestation days (GD) 8 or 13 failed to affect the maternal body weight of mice when compared with the control mice group. No significant alterations were detected in the average number of implantations and resorptions between the control and DL76-treated groups at the early stages of gestation and the organogenesis period. In addition, no significant differences in the occurrence of skeletal abnormalities, urogenital abnormalities, exencephaly, exomphalos, facial clefts, and caudal malformations were observed. The only significant abnormalities witnessed in the treated groups of mice were in the length of long bones and body length. In conclusion, the novel H3R antagonist DL76 protected test animals against MES-induced seizures and had a low incidence of reproductive and fetal malformation with decreased long bone lengths in vivo, signifying the potential therapeutic value of H3R antagonist DL76 for future preclinical as well as clinical development for use in the management of epilepsy.
KW - antagonist DL76
KW - anticonvulsant
KW - gestation
KW - histamine H3 receptors
KW - malformation
KW - maximal electroshock
KW - mice
KW - seizures
UR - http://www.scopus.com/inward/record.url?scp=85196298786&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85196298786&partnerID=8YFLogxK
U2 - 10.3389/fphar.2024.1364353
DO - 10.3389/fphar.2024.1364353
M3 - Article
AN - SCOPUS:85196298786
SN - 1663-9812
VL - 15
JO - Frontiers in Pharmacology
JF - Frontiers in Pharmacology
M1 - 1364353
ER -