Mitigating effects of H3 receptor antagonism on cerebellar autophagic pathways and behavioral phenotypes in BTBR T+ tf/J mouse model of autism spectrum disorder

IF 4.2 3区 医学 Q1 PHARMACOLOGY & PHARMACY European journal of pharmacology Pub Date : 2025-03-08 DOI:10.1016/j.ejphar.2025.177481
Nermin Eissa , Petrilla Jayaprakash , Shouq Aljneibi , Abdallah Alsaadi , Shaikha Alzaabi , Dorota Łazewska , Tadeusz Karcz , Katarzyna Kieć-Kononowicz , Bassem Sadek
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Abstract

Accumulation of evidence suggested the involvement of autophagic pathways and their associated AktmTOR (mammalian target of rapamycin) signalling cascade in the pathogenesis of autism spectrum disorder (ASD). Histamine 3 receptors antagonism may be neuroprotective in ASD, as this antagonism modulates autophagy which is reported to be impaired in ASD. Therefore, the effects the novel H3 receptor antagonist E169 (2.5, 5, and 10 mg/kg, i.p.) on short-term memory (STM), long-term memory (LTM), and anxiety level in male Black and Tan BRachyury (BTBR) mice were evaluated using Novel object recognition test (NORT) and open field locomotor (OFT) tests respectively.
In NORT, E169 (2.5 mg/kg, i.p.) significantly improved the memory of tested BTBR mice, and the effects of E169 were similar to those of the reference mTOR inhibitor rapamycin, and were reversed following co-administration with the centrally penetrant H3 receptor agonist (R)-α-methylhistamine (RAMH). Furthermore, E169 enhanced the BTBR memory by inhibiting H3 receptors and regulating the extent of disruption in the expression of cerebellar Akt, mTOR, and LC-3 proteins of treated mice. Moreover, E169 (2.5 mg/kg, i.p.) restored the disturbed anxiety levels and hyperactivity observed in OFT. In summary, the findings indicate that H3 receptor antagonists like E169 could play a role in simultaneously regulating disrupted brain neurotransmitters and the dysregulated cerebellar Akt-mTOR signaling pathway associated with autophagy in neurological diseases.
Therefore, activation of cerebellar autophagy represented by H3 receptor antagonist E169 may serve as an effective pharmacological therapeutic target for the ASD-like behavioral phenotypes and may add new therapeutic management strategy for the multifactorial disorder ASD.
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572
审稿时长
34 days
期刊介绍: The European Journal of Pharmacology publishes research papers covering all aspects of experimental pharmacology with focus on the mechanism of action of structurally identified compounds affecting biological systems. The scope includes: Behavioural pharmacology Neuropharmacology and analgesia Cardiovascular pharmacology Pulmonary, gastrointestinal and urogenital pharmacology Endocrine pharmacology Immunopharmacology and inflammation Molecular and cellular pharmacology Regenerative pharmacology Biologicals and biotherapeutics Translational pharmacology Nutriceutical pharmacology.
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Editorial Board Timosaponin AⅢ inhibits ectopic lipid deposition and enhances the browning of white adipose tissue. Dihydromyricetin attenuates intervertebral disc degeneration by inhibiting NLRP3 inflammasome activation via the Keap1/Nrf2/HO-1 pathway. Mitigating effects of H3 receptor antagonism on cerebellar autophagic pathways and behavioral phenotypes in BTBR T+ tf/J mouse model of autism spectrum disorder Physiological implications of the Slack channel in the central and peripheral nervous systems
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