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.
Cerebral ischemia-reperfusion (I-R) transiently increased autophagy by producing excessively reactive oxygen species (ROS); on the other hand, activated autophagy would remove ROS-damaged mitochondria and proteins, which led to cell survival. However, the regulation mechanism of autophagy activity during cerebral I-R is still unclear. In this study, we found that deficiency of the TRPM2 channel which is a ROS sensor significantly decreased I-R-induced neuronal damage. I-R transiently increased autophagy activity both in vitro and in vivo. More importantly, TRPM2 deficiency decreased I-R-induced neurological deficit score and infarct volume. Interestingly, our results indicated that TRPM2 deficiency could further activate AMPK rather than Beclin1 activity, suggesting that TRPM2 inhibits autophagy by regulating the AMPK/mTOR pathway in I-R. In conclusion, our study reveals that ROS-activated TRPM2 inhibits autophagy by downregulating the AMPK/mTOR pathway, which results in neuronal death induced by cerebral I-R, further supporting that TRPM2 might be a potential drug target for cerebral ischemic injury therapy.
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