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Review

Targeting Microglia in Neuroinflammation: H3 Receptor Antagonists as a Novel Therapeutic Approach for Alzheimer’s Disease, Parkinson’s Disease, and Autism Spectrum Disorder

1
Department of Pharmacology & Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
2
Zayed Center for Health Sciences, United Arab Emirates University, Al-Ain P.O. Box 1551, United Arab Emirates
3
Department of Biomedical Sciences, College of Health Sciences, Abu Dhabi University, Abu Dhabi P.O. Box 59911, United Arab Emirates
4
Department of Biopharmaceutics and Clinical Pharmacy, School of Pharmacy, The University of Jordan, Amman 11942, Jordan
5
Centre for Global Health Research, Saveetha Medical College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai 602105, India
6
Centre of Research Impact and Outcome, Chitkara University, Rajpura 140401, India
7
School of Bioengineering & Biosciences, Lovely Professional University, Phagwara 144411, India
8
Department of Biotechnology, School of Applied & Life Sciences (SALS), Uttaranchal University, Dehradun 248007, India
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Pharmaceuticals 2024, 17(7), 831; https://doi.org/10.3390/ph17070831
Submission received: 15 May 2024 / Revised: 20 June 2024 / Accepted: 21 June 2024 / Published: 25 June 2024

Abstract

Histamine performs dual roles as an immune regulator and a neurotransmitter in the mammalian brain. The histaminergic system plays a vital role in the regulation of wakefulness, cognition, neuroinflammation, and neurogenesis that are substantially disrupted in various neurodegenerative and neurodevelopmental disorders. Histamine H3 receptor (H3R) antagonists and inverse agonists potentiate the endogenous release of brain histamine and have been shown to enhance cognitive abilities in animal models of several brain disorders. Microglial activation and subsequent neuroinflammation are implicated in impacting embryonic and adult neurogenesis, contributing to the development of Alzheimer’s disease (AD), Parkinson’s disease (PD), and autism spectrum disorder (ASD). Acknowledging the importance of microglia in both neuroinflammation and neurodevelopment, as well as their regulation by histamine, offers an intriguing therapeutic target for these disorders. The inhibition of brain H3Rs has been found to facilitate a shift from a proinflammatory M1 state to an anti-inflammatory M2 state, leading to a reduction in the activity of microglial cells. Also, pharmacological studies have demonstrated that H3R antagonists showed positive effects by reducing the proinflammatory biomarkers, suggesting their potential role in simultaneously modulating crucial brain neurotransmissions and signaling cascades such as the PI3K/AKT/GSK-3β pathway. In this review, we highlight the potential therapeutic role of the H3R antagonists in addressing the pathology and cognitive decline in brain disorders, e.g., AD, PD, and ASD, with an inflammatory component.
Keywords: microglia; neuroinflammation; cytokines; H3R antagonists; neurogenesis; amyloid beta (Aβ); α-synuclein; Alzheimer’s disease; Parkinson’s disease; autism spectrum disorder microglia; neuroinflammation; cytokines; H3R antagonists; neurogenesis; amyloid beta (Aβ); α-synuclein; Alzheimer’s disease; Parkinson’s disease; autism spectrum disorder

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MDPI and ACS Style

Thomas, S.D.; Abdalla, S.; Eissa, N.; Akour, A.; Jha, N.K.; Ojha, S.; Sadek, B. Targeting Microglia in Neuroinflammation: H3 Receptor Antagonists as a Novel Therapeutic Approach for Alzheimer’s Disease, Parkinson’s Disease, and Autism Spectrum Disorder. Pharmaceuticals 2024, 17, 831. https://doi.org/10.3390/ph17070831

AMA Style

Thomas SD, Abdalla S, Eissa N, Akour A, Jha NK, Ojha S, Sadek B. Targeting Microglia in Neuroinflammation: H3 Receptor Antagonists as a Novel Therapeutic Approach for Alzheimer’s Disease, Parkinson’s Disease, and Autism Spectrum Disorder. Pharmaceuticals. 2024; 17(7):831. https://doi.org/10.3390/ph17070831

Chicago/Turabian Style

Thomas, Shilu Deepa, Sabna Abdalla, Nermin Eissa, Amal Akour, Niraj Kumar Jha, Shreesh Ojha, and Bassem Sadek. 2024. "Targeting Microglia in Neuroinflammation: H3 Receptor Antagonists as a Novel Therapeutic Approach for Alzheimer’s Disease, Parkinson’s Disease, and Autism Spectrum Disorder" Pharmaceuticals 17, no. 7: 831. https://doi.org/10.3390/ph17070831

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