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

Abstract

Parkinson’s disease (PD), the second most-common neurodegenerative disease after Alzheimer’s disease, is a devastating condition which is caused by degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) (Kalia and Lang 2015). In addition, PD patients typically develop Lewy pathology, an accumulation of protein aggregates (“Lewy bodies”) in the central nervous system (CNS) that primarily consist of misfolded α-synuclein (Kalia and Lang 2015). The clinical features of PD comprise severe motor disturbances like bradykinesia, rest tremor, or muscle rigidity as well as non-motor symptoms, e.g., cognitive decline or sleep problems (Kalia and Lang 2015). Pharmacotherapy tries to compensate for the deficit of dopaminergic signaling by inhibiting dopamine metabolism (MAO-B inhibitors), by substituting dopamine (levodopa) or by directly stimulating dopaminergic receptors with agonists (Zeuner et al. 2019). Curing the disease or at least stopping its progression, however, is a yet unachieved goal. A very important and long-neglected factor in the pathophysiology of PD and of other neurodegenerative diseases is neuroinflammation with involvement of activated microglia (Liddelow et al. 2017). Specifically, the pro-inflammatory (in analogy to macrophage activation) “classically activated” M1 type of microglia, releasing pro-inflammatory cytokines like IL1-β and TNF-α, is of specific relevance (Moehle and West 2015). Consequently, molecules that inhibit M1 microglia activation could provide a promising approach to stop the pathophysiological processes underlying initiation and progression of PD. Literature from the recent years suggests that the histamine H4R might be an emerging molecular target on the way to this goal. Microglial expression of functional H4R has been demonstrated in the murine N9 microglial cell line, in murine organotypic slice cultures, and in cortical explants (Ferreira et al. 2012) as well as in primary rat microglia cells (Dong et al. 2014). Recently, in vivo data were published, showing that H4R mRNA is present in the striatum of wild-type mice and that the H4R agonist VUF8430 (2-[(aminoiminomethyl)amino] ethyl carbamimidothioic acid ester) as well as histamine itself cause microglial activation (Frick et al. 2016). The effect of histamine was inhibited by the H4R antagonist JNJ-10191584 (= VUF-6002; 1-[(5-chloro-1H-benzimidazol-2-yl)carbonyl]-4methylpiperazine) (Frick et al. 2016). A first association between H4R and PD was found in a postmortem study by Shan et al. (2012). H4R 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 H4R 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. Through this cannula, one of the following agents was administered for 3 weeks and at a dose of 5 μg/day: (i) the histamine H4Rselective antagonist JNJ7777120 (1-[(5-chloro-1H-indol-2yl)carbonyl]-4-methylpiperazine); (ii) the acetylcholine esterase inhibitor donepezil hydrochloride (2,3-dihydro-5,6dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1Hinden-1-one hydrochloride), which also suppresses microglial activation; (iii) the highly selective histamine H3R antagonist * Erich H. Schneider [email protected]