Antagonism of Histamine H3 receptors Alleviates Pentylenetetrazole-Induced Kindling and Associated Memory Deficits by Mitigating Oxidative Stress, Central Neurotransmitters, and c-Fos Protein Expression in Rats.

Abstract

Histamine H3 receptors (H3Rs) are involved in several neuropsychiatric diseases including epilepsy. Therefore, the effects of H3R antagonist E177 (5 and 10 mg/kg, intraperitoneal (i.p.)) were evaluated on the course of kindling development, kindling-induced memory deficit, oxidative stress levels (glutathione (GSH), malondialdehyde (MDA), catalase (CAT), and superoxide dismutase (SOD)), various brain neurotransmitters (histamine (HA), acetylcholine (ACh), γ-aminobutyric acid (GABA)), and glutamate (GLU), acetylcholine esterase (AChE) activity, and c-Fos protein expression in pentylenetetrazole (PTZ, 40 mg/kg) kindled rats. E177 (5 and 10 mg/kg, i.p.) significantly decreased seizure score, increased step-through latency (STL) time in inhibitory avoidance paradigm, and decreased transfer latency time (TLT) in elevated plus maze (all P < 0.05). Moreover, E177 mitigated oxidative stress by significantly increasing GSH, CAT, and SOD, and decreasing the abnormal level of MDA (all P < 0.05). Furthermore, E177 attenuated elevated levels of hippocampal AChE, GLU, and c-Fos protein expression, whereas the decreased hippocampal levels of HA and ACh were modulated in PTZ-kindled animals (all P < 0.05). The findings suggest the potential of H3R antagonist E177 as adjuvant to antiepileptic drugs with an added advantage of preventing cognitive impairment, highlighting the H3Rs as a potential target for the therapeutic management of epilepsy with accompanied memory deficits.

• Authors: Alaa Alachkar, Sheikh Azimullah, Mohamed Lotfy, Ernest Adeghate, Shreesh K Ojha, Rami Beiram, Dorota Łażewska, Katarzyna Kieć-Kononowicz, Bassem Sadek
• Journal: Molecules (Basel, Switzerland) (Molecules) Vol. 25 Issue 7 (Mar 30 2020) ISSN: 1420-3049 [Electronic] Switzerland
• PMID: 32235506 (Publication Type: Journal Article)

Chemical References

• Histamine H3 Antagonists
• Neurotransmitter Agents
• Proto-Oncogene Proteins c-fos
• Pentylenetetrazole

Topics

• Animals
• Epilepsy (chemically induced, drug therapy, metabolism, pathology)
• Gene Expression Regulation (drug effects)
• Hippocampus (metabolism, pathology)
• Histamine H3 Antagonists (pharmacology)
• Kindling, Neurologic (drug effects)
• Male
• Memory Disorders (chemically induced, drug therapy, metabolism, pathology)
• Neurotransmitter Agents (metabolism)
• Oxidative Stress (drug effects)
• Pentylenetetrazole (toxicity)
• Proto-Oncogene Proteins c-fos (biosynthesis)
• Rats
• Rats, Wistar