Eccentric contraction (EC) is known to elicit inflammation and damage in skeletal muscle. Proinflammatory cytokine TNF-alpha plays an important role in this pathogenesis, but the time course of its response to EC and the regulatory mechanisms involved are not clear. The purpose of the study is twofold: 1) to investigate the gene expression of TNF-alpha in rat muscle during and after an acute bout of downhill running and the associated oxidoreductive (redox) changes; and 2) to examine whether EC activates muscle ubiquitin-proteolytic pathway resulting in necrosis and oxidative damage. Female Sprague-Dawley rats (age 3 mo) were randomly divided into five groups (n = 6) that ran on treadmill at 25 m/min at -10% grade for 1 h (group 1) or 2 h (group 2) and were killed immediately; ran for 2 h and killed at 6 h after exercise (group 3), ran for 2 h and killed at 24 h after exercise (group 4); and killed at rest as controls (group 5). TNF-alpha mRNA and protein content showed progressive increases in the deep portion of vastus lateralis (DVL) and gastrocnemius muscles during and after EC. These changes were accompanied by a progressive decrease of mitochondrial aconitase activity and NF-kappaB activation. After 2 h of exercise, elevated levels of serum TNF-alpha, endotoxin, creatine kinase, and lipid peroxidation marker were evident and persisted through 24 h postexercise. At 24 h, there were marked increases in H(2)O(2) concentration, myleoperoxidase activity, and endotoxin level, along with nuclear accumulation of p65, in both muscles. mRNA level of ubiquitin-conjugating enzymes (E(2))-14k was progressively upregulated during exercise and recovery, whereas the expression of the Toll-like receptor 4 (TLR4) in DVL was downregulated in both muscles. We conclude that prolonged EC induces TNF-alpha expression possibly due to NF-kappaB activation stimulated by increased reactive oxygen species generation and endotoxin release. These inflammatory and prooxidative responses may underlie the processes of muscle proteolysis and oxidative damage.
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.
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