Neuroscience
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GPR37 is an orphan G protein-coupled receptor that is predominantly expressed in the brain and found at particularly high levels in oligodendrocytes. GPR37 has been shown to exert effects on oligodendrocyte differentiation and myelination during development, but the molecular basis of these actions is incompletely understood and moreover nothing is known about the potential role(s) of this receptor under demyelinating conditions. To shed light on the fundamental biology of GPR37, we performed proteomic studies comparing protein expression levels in the brains of mice lacking GPR37 and its close relative GPR37-like 1 (GPR37L1). ⋯ As loss of MAG has previously been shown to result in increased susceptibility to brain insults, we additionally assessed Gpr37-knockout (Gpr37-/-) vs. wild-type mice in the cuprizone model of demyelination. These studies revealed that Gpr37-/- mice exhibit dramatically increased loss of myelin in response to cuprizone, yet do not show any increased loss of oligodendrocyte precursor cells or mature oligodendrocytes. These findings reveal that loss of GPR37 alters oligodendrocyte physiology and increases susceptibility to demyelination, indicating that GPR37 could be a potential drug target for the treatment of demyelinating diseases such as multiple sclerosis.
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Phox2b encodes a paired-like homeodomain-containing transcription factor essential for development of the autonomic nervous system. Phox2b-expressing (Phox2b+) neurons are present in the reticular formation dorsal to the trigeminal motor nucleus (RdV) as well as the nucleus of the solitary tract and parafacial respiratory group. However, the nature of Phox2b+ RdV neurons is still unclear. ⋯ The majority of Phox2b+ (35/46) and half of the Phox2b- neurons (19/40) did not respond to stimulations of the mesencephalic trigeminal nucleus, the trigeminal tract, and the principal sensory trigeminal nucleus. Biocytin labeling revealed that about half of the Phox2b+ (5/12) and Phox2b- RdV neurons (5/10) send their axons to the trigeminal motor nucleus. These results suggest that Phox2b+ RdV neurons have distinct neurotransmitter phenotypes and firing properties from Phox2b- RdV neurons and might play important roles in feeding-related functions including suckling and possibly mastication.
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The cerebrospinal fluid (CSF)-contacting nucleus is implicated in the descending inhibitory pathway in pain processing, whereas the cellular and molecular mechanisms underpinning CSF-contacting nucleus regulating pain signals remains largely elusive. ATP is evidenced to inhibit pain transmission at supraspinal level by the mediation of the receptor P2X, wherein its subtype P2X3 is identified as the most potent. Our present experiment investigated the functionality of P2X3 receptors in CSF-contacting nucleus in the formalin-evoked inflammatory pain. ⋯ ATP (a P2X3 receptor agonist, 100nmol/5µl) by intracerebroventricular (i.c.v.) administration ameliorated pain behaviors and enhanced c-Fos immunoreactivity in the neurons of the periaqueductal gray (PAG), both of which were discounted by pre-administration of A-317491 (a selective P2X3 receptor antagonist, 25nmol/5µl). After the CSF-contacting nucleus was ablated by cholera toxin subunit B-saporin, ATP failed to induce analgesia, with the c-Fos immunoreactivity in the PAG neurons remaining intact. Our results validated that P2X3 receptors in the CSF-contacting nucleus are pivotal in inflammatory pain processing via the activation of PAG neurons.
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Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the progressive loss of memory. The neurodegeneration induced by AD has been linked to oxidative damage. However, little is known about the involvement of NADPH oxidase 2 (Nox2), a multisubunit enzyme that catalyzes the reduction of oxygen to produce reactive oxygen species, in the pathogenesis of AD. ⋯ STZ treatment increased oxidative damage and pro-inflammatory cytokines' release in Wt mice, which was not observed in gp91phox-/- mice. Nox2 deletion had a positive effect on the IL-10 baseline production, suggesting that this cytokine might contribute to the neuroprotection mechanism against STZ-induced neurodegeneration. In summary, our data suggest that the Nox2-dependent reactive oxygen species (ROS) generation contributes to the STZ-induced AD-like state.
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Muscle pain is an important health issue and frequently related to static force exertion. The aim of this study is to evaluate whether peripheral inflammatory mechanisms are involved with static contraction-induced muscle pain in rats. To this end, we developed a model of muscle pain induced by static contraction performed by applying electrical pulses through electrodes inserted into muscle. ⋯ Furthermore, an increased hyperalgesic response was observed when the selective bradykinin B1 agonist des-Arg9-bradykinin was injected into the previously stimulated muscle. Together, these findings demonstrate that static contraction induced mechanical muscle hyperalgesia in gastrocnemius muscle of rats is modulated through peripheral inflammatory mechanisms that are dependent on neutrophil migration, bradykinin, sympathetic amines and prostanoids. Considering the clinical relevance of muscle pain, we propose the present model of static contraction-induced mechanical muscle hyperalgesia as a useful tool for the study of mechanisms underlying static contraction-induced muscle pain.