Neuroscience
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Receptors for the calcium-regulating glycoprotein hormone stanniocalcin-1 (STC-1) have been found within the CNS and whether these receptors exist within the nucleus of the solitary tract (NTS), and their possible role in the regulation of arterial pressure (AP) is unknown. Experiments were done in the rat to: (1) map the distribution of STC-1 receptors throughout NTS using in situ ligand binding that uses a stanniocalcin-alkaline phosphatase (STC-AP) fusion protein; (2) determine whether protein and gene expression for STC-1 exists within NTS using immunohistochemistry, Western blot and real time qPCR; (3) determine the effect of microinjection of STC-1 into NTS on AP and the baroreflex. Cells exhibiting STC-1 binding sites were found mainly within the caudal medial (Sm), gelantinous and commissural subnuclei of NTS. ⋯ Additionally, injection of STC-1 into Sm potentiated the AP responses to electrical stimulation of the ipsilateral aortic depressor nerve. Finally, bilateral injection of STC-1 primary antiserum (1:1000; 100 nl) into Sm elicited a long lasting increase in AP, whereas microinjection of heat inactivated STC-1 antiserum did not alter AP. Taken together these data suggest that endogenous STC-1 signaling in NTS is involved in regulating the excitability of neurons that normally function as components of the baroreceptor reflex controlling AP.
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Yokukansan (YKS), a traditional Japanese medicine, is composed of seven kinds of dried herbs. It is widely prescribed in clinical situation for treating psychiatric disorders such as aggressiveness in patients with dementia. We previously demonstrated that YKS and Uncaria hook (UH), which is a constituent herb of YKS, had a partial agonistic effect to 5-HT(1A) receptors in vitro. ⋯ This in vitro result on GM was further demonstrated in the socially isolated mice. As did YKS and UH, GM ameliorated the isolation-induced increased aggressiveness and decreased sociality, and the effect was counteracted by coadministration of WAY-100635. These lines of results suggest that GM in UH is potent 5-HT(1A) receptor agonist and a candidate for pharmacological effect of YKS on aggressiveness and sociality in socially isolated mice.
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Comparative Study
Turning and unilateral cueing in Parkinson's disease patients with and without freezing of gait.
Freezing of gait (FOG) is one of the most disabling symptoms in Parkinson's disease (PD), and cueing has been reported to improve FOG during straight-line walking. Studies on how cueing affects FOG during turning are lacking. Given the asymmetrical nature of turning and the asymmetrical disease expression, we aimed to gain a new perspective on how unilateral cueing may alleviate FOG. ⋯ The occurrence of FOG is not influenced by turning toward the disease-dominant or nondominant side, which is confirmed by the fact that it does not make a difference at which side unilateral cueing is applied. Cueing reduces FOG during turning, but these effects disappear dramatically after cue removal. This raises further questions as to the influence of training on cue dependency and on the feasibility of either continuous application of cues or using cognitive strategies as an alternative.
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α-synuclein (α-Syn) is a chaperone-like protein that is highly implicated in Parkinson's disease (PD) as well as in dementia with Lewy bodies (DLB). Rare forms of PD occur in individuals with mutations of α-Syn or triplication of wild type α-Syn, and in both PD and DLB the intraneuronal inclusions known as Lewy bodies contain aggregated α-Syn that is highly phosphorylated on serine 129. In neuronal cells and in the brains of α-Syn overexpressing transgenic mice, soluble α-Syn stimulates the activity of protein phosphatase 2A (PP2A), a major serine/threonine phosphatase. ⋯ In cell-free assays, aggregated α-Syn had ∼50% less PP2A stimulatory effects than soluble recombinant α-Syn. Similarly in DLB and α-Syn triplication brains, which contain robust α-Syn aggregation with high levels of serine 129 phosphorylation, PP2A activity was also ∼50% attenuated. As α-Syn normally stimulates PP2A activity, our data suggest that overexpression of α-Syn or sequestration of α-Syn into Lewy bodies has the potential to alter the phosphorylation state of key PP2A substrates; raising the possibility that all forms of synucleinopathy will benefit from treatments aimed at optimizing PP2A activity.
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Cannabinoids have emerged as brain protective agents under neurodegenerative conditions. Many neuroprotective actions of cannabinoids depend on the activation of specific receptors, cannabinoid receptor type 1 (CB1R) and type 2 (CB2R). The aim of the present study was to determine whether the CB2R and CB1R agonist WIN 55,212-2 (WIN) protects neonatal brain against focal cerebral ischemia-reperfusion and whether anti-inflammatory mechanisms play a role in protection. ⋯ MCAO led to increased mRNA expression of CB2R (but not CB1R), chemokine receptors (CCR2 and CX3CR1), and cytokines (IL-1β and TNFα), as well as increased protein expression of chemokines MCP-1 and MIP-1α and microglial activation 24 h after MCAO. WIN administration significantly reduced microglial activation at this point and attenuated infarct volume and microglial accumulation and proliferation in the injured cortex 72 h after MCAO. Cumulatively, our results show that the cannabinoid agonist WIN protects against neonatal focal stroke in part due to inhibitory effects on microglia.