Neuroscience
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Endothelin-1 (ET-1) plays an important role in peripheral pain processing. However, the mechanisms of the nociceptive action of ET-1 have not been fully elucidated. In this study, we investigated the contribution of transient receptor potential vanilloid subfamily 1 (TRPV1) to ET-1-induced thermal hyperalgesia. ⋯ In addition, Western blot analysis was also performed to confirm ET-1-induced phosphorylation of TRPV1. Incubation of ET-1 and intraplantar ET-1 evoked phosphorylation of TRPV1 in HEK293 cells expressing TRPV1 and ET(A) and the skin, respectively. These results suggest that the sensitization of TRPV1 activity through an ET(A)-PKC pathway contributes to ET-1-induced thermal hyperalgesia.
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Activation and injury of microglial cells are involved in a broad range of brain diseases including stroke, brain infection and neurodegenerative diseases. However, there is very little information regarding how to reduce microglial reaction and preserve these cells to provide neuroprotection. Here, we showed that the incubation of C8-B4 mouse microglial cells with lipopolysaccharide (LPS) plus interferon-gamma (IFNgamma) for 24 h decreased the viability of these cells. ⋯ Finally, the isoflurane preconditioning-induced protection was abolished by chelerythrine, a protein kinase C inhibitor. These results suggest that LPS plus IFNgamma activates the iNOS-nitric oxide-glutamate pathway to induce microglial injury and that this activation is attenuated by isoflurane preconditioning. Protein kinase C may be involved in the isoflurane preconditioning effects.
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Individuals engaged in shift- or night-work show disturbed diurnal rhythms, out of phase with temporal signals associated to the light/dark (LD) cycle, resulting in internal desynchronization. The mechanisms underlying internal desynchrony have been mainly investigated in experimental animals with protocols that induce phase shifts of the LD cycle and thus modify the activity of the suprachiasmatic nucleus (SCN). In this study we developed an animal model of night-work in which the light-day cycle remained stable and rats were required to be active in a rotating wheel for 8 h daily during their sleeping phase (W-SP). ⋯ Forced activity during the sleep phase did not modify SCN activity characterized by the temporal patterns of PER1 and PER2 proteins, which remained in phase with the LD cycle. These observations indicate that a working regimen during the sleeping period elicits internal desynchronization in which activity combined with feeding uncouples metabolic functions from the biological clock which remains fixed to the LD cycle. The present data suggest that in the night worker the combination of work and eating during working hours may be the cause of internal desynchronization.
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Statins are increasingly being used for the treatment of a variety of conditions beyond their original indication for cholesterol lowering. We previously reported that simvastatin affected the dopaminergic system in the rat brain. This study aims to investigate regional changes of muscarinic M1/4 receptors in the rat brain after 4-week administration of simvastatin (1 or 10 mg/kg/day). ⋯ Our results also provide strong evidence that chronic simvastatin administration, especially at a low dosage, up-regulates M1/4 receptor binding, which is likely to be independent of its muscarinic agonist-like effect. Alterations in [(3)H]pirenzepine binding in the examined brain areas may represent the specific regions that mediate the clinical effects of simvastatin treatment on cognition and memory via the muscarinic cholinergic system. These findings contribute to a better understanding of the critical roles of simvastatin in treating neurodegenerative disorders, via muscarinic receptors.
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Striatal projection neurons use GABA as their neurotransmitter and express the rate-limiting synthesizing enzyme glutamic acid decarboxylase (GAD) and the vesicular GABA transporter vGAT. The chronic systemic administration of an agonist of dopamine D1/D5-preferring receptors is known to alter GAD mRNA levels in striatonigral neurons in intact and dopamine-depleted rats. In the present study, the effects of a single or subchronic systemic administration of the dopamine D1/D5-preferring receptor agonist SKF-81297 on GAD65, GAD67, PPD and vGAT mRNA levels in the striatum and GABA(A) receptor alpha1 subunit mRNA levels in the substantia nigra, pars reticulata, were measured in rats with a unilateral 6-hydroxydopamine (6-OHDA) lesion. ⋯ Finally, striatal GAD67 mRNA levels were negatively correlated with nigral alpha1 mRNA levels in the dopamine-depleted but not dopamine-intact side. The results suggest that different signaling pathways are involved in the modulation by dopamine D1/D5 receptors of GAD65 and GAD67 mRNA levels in striatonigral neurons. They also suggest that the down-regulation of nigral GABA(A) receptors is linked to the increase in striatal GAD67 mRNA levels in the dopamine-depleted striatum.