Neuroscience
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Humanin (HN) has been identified as an endogenous peptide that inhibited AD-relevant neuronal cell death. HNG, a variant of HN in which the 14th amino acid serine was replaced with glycine, can reduce infarct volume and improve neurological deficits after ischemia/reperfusion injury. In this study, we aimed to examine the neuroprotective effect of HNG on traumatic brain injury (TBI) in mice and explored whether the protective effect was associated with regulating apoptosis and autophagy. ⋯ Reduced lesion volume (day 14, P<0.05) was also observed even when HNG was administered intraperitoneally (i.p.) at 1h and 2h post TBI, and minor amelioration in motor and Morris water maze test deficits was also observed. Immunoblotting results showed that HNG pretreatment (i.c.v.) reversed TBI-induced cleavage of cysteinyl aspartate-specific protease-3 and poly ADPribose-polymerase and decline of Bcl-2, suppressed LC3II, Beclin-1 and vacuolar sorting protein 34 activation and maintained p62 levels in the injured cortex and hippocampus post TBI (compared with vehicle). In conclusion, HNG treatment improved morphological and functional outcomes after TBI in mice and the protective effect of HNG against TBI may be associated with down-regulating apoptosis and autophagy.
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Vascular dementia (VD), defined as a loss of memory and cognitive function resulting from vascular lesions in the brain, is the second-most-common cause of dementia in the elderly, after Alzheimer's disease. In recent years, research has focused on the pathogenesis of VD, and mitochondrial bioenergetic deficits have been suggested to contribute to VD onset. To further investigate the role of mitochondria in VD, we used a rat model of VD, which involved permanent bilateral occlusion of the common carotid arteries (with a 1-week interval between artery occlusion to avoid an abrupt reduction in cerebral blood flow) leading to chronic cerebral hypoperfusion. ⋯ The ischemia group mitochondria also exhibited decreased respiration coupled to decreased expression and activity of the electron transport chain complex IV (cytochrome c oxidase). These results indicate that the mitochondrial oxidative metabolism is inhibited in the hippocampi of rats following chronic ischemia-induced VD. As the mitochondrial oxidative metabolism deficits, namely mitochondrial bioenergetic deficits directly affect the functions of neurons, it may contribute to VD onset.
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Pretreatment with estrogen has been shown to increase subventricular zone (SVZ) neurogenesis and improve neurological outcome after cerebral ischemia reperfusion injury in mice. However, the potential of post-stroke estrogen administration to enhance neurogenesis is largely unknown. In this study, we explored whether post-stroke estradiol administration had any effect on SVZ neurogenesis in a rat model of permanent focal cerebral ischemia and elucidated the potential mechanism of its effects. ⋯ Post-stroke estradiol administration increased BrdU-labeled cells, nestin-positive cells, doublecortin (DCX)-positive cells and BrdU+/DCX+ cells in the ischemic ipsilateral SVZ at all time points (P<0.05). Treatment with estradiol also increased HIF-1α and VEGF protein levels in the ischemic ipsilateral SVZ at all time points examined (P<0.05). These findings indicate that post-stroke estradiol administration promotes SVZ neurogenesis in rats, probably by increasing HIF-1α and VEGF protein expression.
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Angiotensins (Angs) modulate blood pressure, hydro-electrolyte composition, and antinociception. Although Ang (5-8) has generally been considered to be inactive, we show here that Ang (5-8) was the smallest Ang to elicit dose-dependent responses and receptor-mediated antinociception in the rat ventrolateral periaqueductal gray matter (vlPAG). Ang (5-8) antinociception seems to be selective, because it did not alter blood pressure or act on vascular or intestinal smooth muscle cells. ⋯ Endopeptidase EP 24.11 and amastatin-sensitive aminopeptidase from the vlPAG catalyzed the synthesis (from Ang II or Ang III) and inactivation of Ang (5-8), respectively. Selective inhibitors of neuronal-nitric oxide (NO) synthase, soluble guanylyl cyclase (sGC) and a non-selective opioid receptor (opioid-R) inhibitor blocked Ang (5-8)-induced antinociception. In conclusion, Ang (5-8) is a new member of the Ang family that selectively and strongly modulates antinociception via NO-sGC and endogenous opioid in the vlPAG.
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As a widely used intravenous short-acting anesthetic, propofol is recently indicated by clinical and animal studies for its abuse potential, but the mechanism underlying propofol abuse is largely unknown. This study examined the contribution of dopamine receptor subtype (D1 and D2 receptors) and neuroanatomical locus (i.e. nuclear accumbens) in the maintenance of propofol self-administration in rats. ⋯ We demonstrated (i) systemic administration of SCH23390 (10, 30, 100 μg/kg, i.p.) dose-dependently decreased the rate of propofol-maintained self-administration, suggesting a critical role of the D1 receptor in mediating propofol self-administration; (ii) the blockade of the propofol self-administration by SCH23390 was specific since spiperone and eticlopride did not affect propofol self-administration and SCH23390 at these doses did not affect food-maintained responding under an FR5 schedule; (iii) intra-accumbenal injection of SCH23390 (2.5 μg/site) but not eticopride (3.0 μg/site) attenuated the propofol self-administration, localizing nuclear accumbal D1 receptors as a critical locus in the reinforcement of propofol. Together, these findings provide the first direct evidence that D1 receptors in nuclear accumbens play an important role in the maintenance of propofol self-administration.