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

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.

Keywords: Histamine 4 receptor antagonist; Microglia; Parkinson’s disease; Rotenone; α-Synuclein.