Histamine-4 receptor antagonist JNJ7777120 inhibits pro-inflammatory microglia and prevents the progression of Parkinson-like pathology and behaviour in a rat model.

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 (HR), 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 HR 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 HR-, and microglial markers were significantly increased in the ventral midbrain. Inhibition of HR in rotenone-induced PD rat model by infusion of the specific HR antagonist JNJ7777120 into the lateral ventricle resulted in blockade of microglial activation. In addition, pharmacological targeting of HR 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 HR antagonist in a commonly used PD rat model, and proposes the HR as a promising target to clinically tackle microglial activation and thereby the progression of PD.