Neuroscience
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Necrostatin-1 (Nec-1) is an inhibitor of necroptosis, playing an important role in inhibition of pathological death in the central nervous system (CNS). Our earlier study suggests that Nec-1 protects the injured spinal cord. In this study, we found that Nec-1 reduces the elevated Ca(2+) concentration in mitochondria post-injury and preserves the remarkably decreased mitochondrial membrane potential (MMP) level post-spinal cord injury (SCI). ⋯ It also inhibits the up-regulation of mitochondrial fusion genes Mnf1, Mnf2 within 6h post-injury and adjusts the abnormal expression of mitochondrial fission gene Fis1. All these results indicate the improvement of mitochondrial functions in injured spinal cord after the treatment of Nec-1. This research revealed the mechanisms of functional protection of Nec-1 by mitigating mitochondrial dysfunction post-SCI.
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Both central and peripheral sympathetic nervous systems contribute to the cardiovascular effects of dexmedetomidine (DMED), a highly selective and widely used a2-adrenoceptor agonist for sedation, analgesia, and stress management. The central sympatholytic effects are augmented by peripheral inhibition of sympathetic ganglion transmission. The mechanism is not clear. ⋯ In conclusion, DMED dose-dependently inhibits INa and IACh in rat SCG neurons by preferential binding to the inactivated state of the Na(+) channels and the closed state (resting) of nAChR channels respectively. Both inhibitions are a2-adrenoceptor independent. Furthermore, the nAChR channels in rat SCG neurons are much more sensitive to inhibition by DMED than Na(+) channels.
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Early degeneration of pedunculopontine nucleus (PPN) is considered part of changes that characterize premotor stages of Parkinson's disease (PD). In this paper, the effects of unilateral neurotoxic lesion of the PPN in motor execution and in the development of oxidative stress events in striatal and nigral tissues in rats were evaluated. The motor performance was assessed using the beam test (BT) and the cylinder test (CT). ⋯ This significant increase of CAT EA persisted in the nigral tissue (p<0.001) and reached the striatal tissue (p<0.001) seven days after PPN injury. Also at seven days post-injury PPN, increased concentrations of MDA (p<0.01) and a tendency to decrease in the concentrations of NO in both structures (SNpc and striatum) were found. The events associated with the generation of free radicals at nigral and striatal levels, can be part of the physiological mechanisms underlying motor dysfunction in rats with unilateral PPN neurotoxic lesion.
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Serotonin (5-HT) and norepinephrine (NE) have been implicated in the mediation of endogenous analgesic mechanisms via the descending inhibitory pain pathway in the brain, and dysfunction in both the 5-HT and NE systems has been suggested as an etiology of fibromyalgia (FM). Given that 5-HT reuptake inhibition in the brain appears to be associated with pain reduction, this mechanism might exert an analgesic effect also on pain associated with FM. In this case, it would be of interest to investigate the correlation of 5-HT transporter (SERT) occupancy with in vivo analgesic effect on pain associated with FM. ⋯ This finding concerning the precise correlation of SERT occupancy with in vivo analgesic effect on pain associated with FM is reported here for the first time. SERT occupancy level above 70% was necessary for AS1069562 and duloxetine to exert significant analgesic effects on muscular pain. These results suggest that SERT occupancy level is useful in determining appropriate analgesic doses of AS1069562 and duloxetine for treating pain symptoms in FM patients.
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Rats with dopamine depletion caused by 6-hydroxydopamine (6-OHDA) treatment during adulthood and the neonatal period exhibit akinetic motor activity and spontaneous motor hyperactivity during adolescence, respectively, indicating that the behavioral effects of dopamine depletion depend on the period of lesion development. Dopamine depletion during adulthood induces hyperalgesic response to mechanical, thermal, and/or chemical stimuli, whereas the effects of neonatal dopamine depletion on nociceptive response in adolescent rats are yet to be examined. The latter aspect was addressed in this study, and behavioral responses were examined using von-Frey, tail flick, and formalin tests. ⋯ The spinal neuronal response to the formalin injection into the rat hind paw was also examined through immunohistochemical analysis of c-Fos protein. Significantly increased numbers of c-Fos-immunoreactive cells were observed in laminae I-II and V-VI of the ipsilateral spinal cord to the site of the formalin injection in rats with neonatal dopamine depletion compared with vehicle-treated rats. These results suggest that the dopaminergic neural system plays a crucial role in the development of a neural network for tonic pain, including the spinal neural circuit for nociceptive transmission, and that the mechanism underlying hyperalgesia to tonic pain is not always consistent with that of spontaneous motor hyperactivity induced by neonatal dopamine depletion.