Neuroscience
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In the present study, the effect of medroxyprogesterone (MPA) is evaluated for its effect on pentylenetetrazole (PTZ) kindling model of epileptogenesis in mice followed by evaluation on kindling-induced changes in cognitive and motor functions. To explore whether the effects are mediated via progesterone receptors, a selective antagonist of progesterone (mifepristone, MIF) was also taken. Kindling was induced by once every 2 days treatment with PTZ (25 mg/kg, i.p.) for 5 weeks. ⋯ On grip strength test (GST) and spontaneous alternation behavior (SAB), a significant decline in GST and % alternation was observed in kindled mice which was reversed by pre-treatment with MPA. MIF, however, could reverse only the reduced % alternation and not grip strength (GS) in PTZ-kindled animals. The study shows that MPA has antiepileptogenic effects against development of PTZ-induced kindling in mice that may not be mediated via progesterone receptors.
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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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Comparative Study
Agonist of 5-HT1A/7 receptors but not that of 5-HT2 receptors disinhibits tracheobronchial-projecting airway vagal preganglionic neurons of rats.
The vagus nerves supply the major cholinergic tone to airway smooth muscles physiologically and play critical roles in the genesis of airway hyperreactivity under some pathological conditions. Postganglionic airway cholinergic tone relies largely on the ongoing activity of medullary airway vagal preganglionic neurons (AVPNs), of which the tracheobronchial-projecting ones are primarily located in the external formation of the nucleus ambiguus (eNA). AVPNs are regulated by 5-HT, and 5-HT(1A/7) and 5-HT(2) receptors have been indicated to be involved. ⋯ The 8-OH-DPAT inhibition of the GABAergic and glycinergic sIPSCs was prevented by 5-HT(1A/7) receptor antagonist N-[2-[4-(2-Methoxyphenyl)-1-piperazinyl] ethyl]-N-2-pyridinylcyclohexanecarboxamide maleate salt (WAY-100635) (1 μmol L(-1)). 8-OH-DPAT had no effect on the glutamatergic spontaneous excitatory postsynaptic currents (sEPSCs) and caused no alterations in the baseline current and input resistance of T-AVPNs. DOI had no effect on any types of the synaptic inputs of T-AVPNs. These results suggest that 5-HT(1A/7) receptor agonist causes "disinhibition" of T-AVPNs, which might, in part, account for the reflex increase of airway resistance.
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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.