Histamine-4 receptor antagonist JNJ7777120 inhibits pro-inflammatory microglia and prevents the progression of Parkinson-like pathology and behaviour in a rat model |
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| Affiliation: | 1. College of Medical Laboratory, Dalian Medical University, Dalian, Liaoning 116044, China;2. Netherlands Institute for Neuroscience, an Institute of the Royal Netherlands Academy of Arts and Sciences, Amsterdam, the Netherlands;3. Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands;4. Department of Clinical Laboratory, The First College of Clinical Medical Science, China Three Gorges University, Yichang, Hubei 443003, China;5. Department of Clinical Laboratory, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China;1. Department of Pathophysiology, Medical College of Nantong University, 19 Qixiu Street, Nantong 226001, Jiangsu Province, China;2. Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Medical College of Nantong University, 19 Qixiu Street, Nantong 226001, Jiangsu Province, China;1. Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia;2. Department of Pharmacology and Toxicology, College of Pharmacy, Al-Azhar University, Cairo, Egypt;1. Biomaterials and Advanced Drug Delivery Laboratory, School of Medicine, Stanford University, Palo Alto, CA, USA;2. Department of Psychiatry, Child Study Center, and Interdepartmental Neuroscience Program, Yale University, New Haven, CT, USA;3. Graduate School of Engineering, Applied Quantum Medical Engineering, Tohoku University, Sendai, Miyagi, Japan;4. Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco;1. Klinik für Dermatologie, Allergologie und Venerologie, Medizinische Hochschule Hannover, Hannover, Germany;2. ParamStat, Ash, United Kingdom;3. Ziarco Pharma, Discovery Park, Sandwich, United Kingdom;4. Ostermed, Birmingham Business Park, Birmingham, United Kingdom;5. MAC Clinical Research, Leeds, United Kingdom;6. MAC Clinical Research, Manchester, United Kingdom;7. Department of Dermatology, University Hospital Muenster, Muenster, Germany;1. Department of Pharmacology, JSS College of Pharmacy, Ooty, India;2. Department of Neurochemistry, National Institute of Mental Health & Neuro Sciences, Bangalore, India;3. Department of Entomology and Nematology, and Comprehensive Cancer Research Center, University of California, Davis, United States |
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| Abstract: | The activation of microglial cells is presumed to play a key role in the pathogenesis of Parkinson's disease (PD). The activity of microglia is regulated by the histamine-4 receptor (H4R), thus providing a novel target that may prevent the progression of PD. However, this putative mechanism has so far not been validated. In our previous study, we found that mRNA expression of H4R was upregulated in PD patients. In the present study, we validated this possible mechanism using the rotenone-induced PD rat model, in which mRNA expression levels of H4R-, and microglial markers were significantly increased in the ventral midbrain. Inhibition of H4R in rotenone-induced PD rat model by infusion of the specific H4R antagonist JNJ7777120 into the lateral ventricle resulted in blockade of microglial activation. In addition, pharmacological targeting of H4R in rotenone-lesioned rats resulted in reduced apomorphine-induced rotational behaviour, prevention of dopaminergic neuron degeneration and associated decreases in striatal dopamine levels. These changes were accompanied by a reduction of Lewy body-like neuropathology. Our results provide first proof of the efficacy of an H4R antagonist in a commonly used PD rat model, and proposes the H4R as a promising target to clinically tackle microglial activation and thereby the progression of PD. |
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| Keywords: | Parkinson’s disease Rotenone Histamine 4 receptor antagonist Microglia α-Synuclein |
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