Date of Award

4-2016

Document Type

Thesis

Degree Name

Master of Science in Medical Sciences (MSMS)

Department

Medical Education

First Advisor

Dr. Bassem Sadek

Second Advisor

Professor Chris Howarth

Third Advisor

Professor Paul Chazot

Abstract

To determine the potential of histamine H3 receptor (H3R) ligands as new antiepileptic and procognitive drugs, aromatic ether derivatives (1-12) belonging to the nonimidazole class of ligands, with high in-vitro binding affinity at human H3R, were tested for their in-vivo anticonvulsive activity in maximal electroshock (MES)-, pentylenetetrazole (PTZ)-, and strychnine (STR)-induced seizure models in male adult rats having phenytoin (PHT) and valproic acid (VPA) as the reference antiepileptic drugs, pitolisant (PIT) as the standard H3R antagonist/inverse agonist, and donepezil (DOZ) as a reference procognitive drug. Among the H3R ligands (1-12) tested in the current project, H3R antagonist 4 showed significant and dose dependent reduction in the duration of tonic hind limb extension (THLE) subsequent to acute systemic administration (5, 10, and 15 mg/kg, i.p.). Importantly, the protective action observed for H3R antagonist 4 in MES-induced seizure was comparable to that of the reference antiepileptic drug phenytoin (PHT), and was also reversed when rats were pretreated with the CNS penetrant pyrilamine (PYR) (10 mg/kg, i.p.), or with the selective H3R agonist R-(α)-methylhistamine (RAMH) (10 mg/kg, i.p.). Furthermore, the procognitive studies indicate that acute pre-training systemic administration of H3R antagonist 4 (2.5 mg/kg, i.p.) facilitated acquisition, whereas pre-testing acute administration of 4 (5 and 10 mg/kg, i.p.) improved retrieval. Interestingly, the procognitive effect of 4 on retrieval was completely abrogated when rats were pretreated with the centrally-acting H2R antagonist zolantidine (ZOL) but not the centrally acting H1R antagonist PYR, indicating that histaminergic pathways through activation of H2Rs appear to be participating in neuronal circuits involved in the retrieval processes. Taken together, our results show that H3R antagonist 4 demonstrates anticonvulsant properties in the MES-induced seizure model and improves cognitive performance through actions on different memory stages. Therefore, H3Rs may have implications for the treatment of degenerative disorders associated with impaired memory function and may represent a novel therapeutic pharmacological target to tackle cognitive problems associated with the chronic use of antiepileptic drugs.

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