The Potent and Selective Histamine H3 Receptor Antagonist E169 Counteracts Cognitive Deficits and Mitigates Disturbances in the PI3K/AKT/GSK-3β Signaling Pathway in MK801-Induced Amnesia in Mice

The role of histamine H3 receptors (H3Rs) in memory and the prospective H3R antagonists pharmacological control neurodegenerative disorders, e.g., Alzheimer’s disease (AD), is well-accepted. Therefore, procognitive effects acute systemic administration antagonist E169 (2.5–10 mg/kg, i.p.) on MK801-induced amnesia C57BL/6J mice using novel object recognition test (NORT) were evaluated. (5 mg) provided a significant memory-improving effect short- long-term impairments NORT. mg)-provided comparable to those observed with reference phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 abrogated agonist (R)-α-methylhistamine (RAMH). Additionally, our results demonstrate that ameliorated deficits by antagonism H3Rs modulation level disturbance expression PI3K, Akt, GSK-3β proteins, signifying mitigated Akt-mTOR signaling pathway hippocampus tested mice. Moreover, revealed did not alter anxiety levels locomotor activity animals open field tests, demonstrating performances improved following NORT are unrelated changes emotional response or spontaneous activity. In summary, these obtained suggest potential such as E169, good silico physicochemical properties stable retained key interactions docking studies at H3R, simultaneously modulating disturbed brain neurotransmitters imbalanced related AD.