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

Abstract

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 to prevent the progression of PD. However, this putative mechanism has so far not been validated. In our previous post-mortem study, we found that mRNA expression of H4R was upregulated in the basal ganglia of PD patients. In the present study, we found indeed an upregulation of microglia associated inflammation markers from microarray data of the substantia nigra pars compacta (SNpc) of PD patients. We validated the mechanism underlying our human PD results using the rotenone-induced PD rat model, in which the expression of H4R and microglial markers mRNA were significantly increased in the SNpc. Inhibition of H4R in rotenone-induced rats by infusion of the specific H4R antagonist JNJ7777120 into the left lateral ventricle blocked microglial activation, reduced apomorphine-induced rotational behaviour, and prevented 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 3 PD rat model, and provides a lead for a promising therapeutic strategy aimed at modifying H4R activation to clinically tackle microglial activation and thereby the progression of PD.

Microglial histamine H4R in the pathophysiology of Parkinson’s disease—a new actor on the stage?

“…The authors also demonstrate that rotenone treatment causes upregulation of histamine H 4 R mRNA in the ventral mesencephalon of the animals. Thus, the rat model used by Zhou et al (2019) reflects the findings previously obtained in postmortem studies with PD patients (Shan et al 2012). Upregulation of histamine H 4 R in the rotenone-lesioned rats was almost completely inhibited by JNJ7777120 (Zhou et al 2019).…”

“…H 4 R mRNA was significantly increased in the caudate nucleus and the putamen of PD patients, and a strong inverse relationship was observed between histamine methyltransferase mRNA in the substantia nigra and PD duration (Shan et al 2012). Now, the same research group is involved in the publication of an in vivo study in a rat model of rotenone-induced PD, suggesting a direct link between microglial H 4 R activation and the occurrence of M1-activated microglia (Zhou et al 2019). The authors used male Sprague-Dawley rats at 4 months of age.…”

“…In a stereotactic surgery, 12 μg (6 μg/μl) of rotenone ((2R,6aS,12aS)-1,2,6,6a,12,12a-hexahydro-2isopropenyl-8,9-dimethoxychromeno [3,4-b]furo(2,3-h)chromen-6-one) was infused into the right SNpc to induce PDlike pathology. Control animals underwent the same procedure with administration of solvent (50% DMSO/50% PEG4000) (Zhou et al 2019). Every animal also received a permanent fixed cannula in the left lateral ventricle.…”

“…This was, however, at least partially compensated by the fact that rotenone was only infused into the right SNpc, while JNJ7777120 was administered into the left lateral ventricle. Thus, in the animals receiving rotenone plus JNJ7777120, the left non-lesioned side could serve as a control for endogenous JNJ7777120 effects (Zhou et al 2019).…”

Src Inhibition Attenuates Neuroinflammation and Protects Dopaminergic Neurons in Parkinson’s Disease Models

“…Through all the above substances, uncontrolled overactivation of microglial cells could cause neuronal damage and death (Thameem Dheen et al, 2007); thus, many studies have focused on anti-inflammatory agents because they might help inhibit the progression of this disease. Zhou et al (2019) found that inhibiting proinflammatory microglia could prevent the progression of Parkinson-like pathology and behavior in a rat model.…”