Neuroscience
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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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The appropriate level of microtubule stability is fundamental in neurons to assure correct polarity, migration, vesicles transport and to prevent axonal degeneration. In the present study, we have identified Notch pathway as an endogenous microtubule stabilizer. ⋯ However, contrary to Taxol, Jagged1 induced downregulation of the microtubule severing protein Spastin. We suggest that a fine-tuned manipulation of Notch signaling may represent a novel approach to modulate neuronal cytoskeleton plasticity.
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Recent studies have demonstrated nicotinamide (NAM), a soluble B-group vitamin, to be an effective treatment in experimental models of traumatic brain injury (TBI). However, research on this compound has been limited to administration regimens starting shortly after injury. This study was conducted to establish the window of opportunity for NAM administration following controlled cortical impact (CCI) injury to the frontal cortex. ⋯ In the working memory task both the 15-min and 4-h groups also improved working memory compared with saline treatment. The window of opportunity for NAM treatment is task-dependent and extends to 8 h for the sensorimotor tests but only extends to 4 h post-injury in the cognitive tests. These results suggest that a 50 mg/kg treatment regimen starting at the clinically relevant time point of 4 h may result in attenuated injury severity in the human TBI population.
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Mechanisms underlying cold hypersensitivity in neuropathic states are unclear. Recent data indicate both transient receptor potential (TRP) M8 and TRPA1 play a role. In relation to TRPA1, there are reported increases in mRNA. ⋯ In contrast, compared with naive rats, mechanical thresholds of the Adelta-fibers in SNL rats are significantly decreased, the proportion of cold-sensitive and MO-sensitive Adelta-fibers is significantly increased and the response magnitude of Adelta-fibers to MO is significantly increased. MO-induced activity in Adelta-fibers is significantly reduced by Ruthenium Red (TRPA1 receptor antagonist). These results demonstrate that TRPA1 is expressed on peripheral nociceptors, and they are up-regulated on intact Adelta-fibers following nerve injury, contributing to cold hypersensitivity.
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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.