Dick SwaabNeuroscience Symposium
The Neuroscience Symposia are organized weekly by the Netherlands Institute for Neuroscience. The presentations are given by researchers from the institute or by guest speakers. The title and content of the symposium is usually made known in the week prior to the presentation.
Colloquium room – Netherlands Institute for Neuroscience
Ling Shan PhD, group Swaab
4:00 pm – Histamine-4 receptor antagonist inhibits pro-inflammatory microglia and prevents the progression of Parkinson-like pathology: a new therapeutic strategy
4:45 pm – Discussion and drinks
Activation of microglia 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 the basal ganglia of PD patients. In the current study, upregulation of H4RmRNA, stands out by robustness and consistency in an independent genome-wide RNA sequencing study of basal ganglia of PD post-mortem brains. We validated this possible echanism using the rotenone-induced PD rat model, in which mRNA expression levels of H4R-, and microglial markers were significantly increased in the substantia nigra pars compacta (SNpc). 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 and prevention of dopaminergic neuron degeneration and associated decreases in striatal dopamine levels. These changes were accompanied by a reduction of Lewy body-like neuropathology in both SNpc and striatum. Moreover, other neurotransmitters including γ-aminobutyric acid, glutamine, serotonin and the main metabolite of serotonin 5-hydroxyindoleactic acid were relatively stable under the H4R antagonist JNJN7777120 treatment.
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.