Date of Award
Doctor of Philosophy (PhD)
Pharmacology and Therapeutics
Bassem Shaban Sadek
Shreesh K. Ojha
Epilepsy is a common chronic neurological disorder accompanied by cognitive impairment. Available antiepileptic drugs (AEDs) have not been reported to have ameliorative effects on epilepsy-associated memory impairment. The potential of histamine H3 receptors (H3R) in several neuropsychiatric diseases, including epilepsy and Alzheimer’s disease, is well recognized. In this study, a series of H3R antagonists (1-16) were screened for their in vivo anticonvulsant effect in several acute-induced seizures in rats. Moreover, the procognitive effect of the most promising H3R antagonist was investigated in dizocilpine (DIZ)-induced amnesic effect applying several behavioral memory tests. Furthermore, the most promising H3R antagonist was assessed for its simultaneous anticonvulsant and procognitive effect and its modulatory effect on levels of oxidative stress markers, several hippocampal neurotransmitters, and c-fos protein expression in the PTZ model. Finally, the promising H3R antagonist was examined for its anticonvulsant effect in PLC-induced SE and its ability to mitigate SE incidence.
The Observed results indicated that H3R antagonist 4 (10 mg/kg i.p.) significantly exhibited high protection in maximum electroshock (MES)-induced seizures facilitated through histaminergic neurotransmission and activation of post-synaptically located H1R and full protection in the PTZ-acute induced seizures, Moreover, H3R antagonist 4 (5 mg/kg i.p.) showed a procognitive effect that was abrogated with RAM co-injection in all behavioral memory tests. Additionally, treatment with H3R antagonist 4 showed a simultaneous anticonvulsant and procognitive effect in addition to antioxidant effect in PTZ- acute and -chronic models. Furthermore, chronic treatment with H3R antagonist 4 (5 mg/kg i.p.) modified histamine, acetylcholine, and glutamate release, and reduced hippocampal c-fos activation. In addition, RAMadministration reversed the protective effects provided by H3R antagonist 4 in PTZ chronic model. Moreover, and in PLC-induced SE, systemic administration of H3R antagonist 4 (10 mg/kg i.p.) mitigated the severity of SE and exhibited antioxidant effect in the hippocampus of the treated rats, facilitated through the histaminergic neurotransmission. The observed findings recommend that the newly developed H3R antagonist 4 provides antiepileptic, memory-enhancing, and antioxidant properties in a PTZ-induced kindling model of epilepsy and provides neuroprotection in a preclinical PLC-induced SE in rats, highlighting the histaminergic system as a potential therapeutic target for the management of epilepsy with accompanied memory deficits.
Alachkar, Alaa Imad, "ANTICONVULSANT AND PROCOGNITIVE EFFECT OF NONIMIDAZOLE HISTAMINE H3R RECEPTOR ANTAGONISTS /INVERSE AGONISTS IN EXPERIMENTAL ANIMAL MODELS" (2020). Dissertations. 122.