Neuroscience
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Aquaporin-4 (AQP4) regulates retinal water homeostasis and participates in retinal oedema pathophysiology. β-dystroglycan (β-DG) is responsible for AQP4 polarization and can be cleaved by matrix metalloproteinase-9 (MMP9). Retinal oedema induced by ischemia-reperfusion (I/R) injury is an early complication. Bumetanide (BU) has potential efficacy against cytotoxic oedema. ⋯ BU suppressed glial responses and mitochondria-mediated apoptotic protein expression, including that of Caspase-3 and Cyto C, raised the Bcl-2/Bax ratio, and lowered the number of apoptotic cells in the retina. Both BU and U0126 downregulated p-ERK and MMP9 expression. Thus, BU treatment suppressed β-DG cleavage, recovered AQP4 polarization partially via inhibiting ERK/MMP9 signaling pathway, and possess potential neuroprotective efficacy in the rat retinal ischemia-reperfusion injury model.
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Noisy galvanic vestibular stimulation has been shown to improve vestibular perception in healthy subjects. Here, we sought to obtain similar results using more natural stimuli consisting of small-amplitude motion perturbations of the whole body. Thirty participants were asked to report the perceived direction of antero-posterior sinusoidal motion on a MOOG platform. ⋯ At the individual level, the threshold was lower with at least one noise level than the threshold without noise in 87% of participants. Thus, small, stochastic oscillations of the whole body can increase the probability of recognizing the direction of motion from low, normally subthreshold vestibular signals, possibly due to stochastic resonance mechanisms. We suggest that, just as the external noise of the present experiments, also the spontaneous random oscillations of the head and body associated with standing posture are beneficial by enhancing vestibular thresholds with a mechanism similar to stochastic resonance.
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Gastrin-releasing peptide (GRP) in the spinal dorsal horn acts on the GRP receptor, and this signalling mechanism has been strongly implicated in itch. However, the source of GRP in the dorsal horn is not fully understood. For example, the BAC transgenic mouse line GRP::GFP only captures around 25% of GRP-expressing cells, and Grp mRNA is found in several types of excitatory interneuron. ⋯ Cell bodies and axons of all GRP-GFP cells were labelled, confirming reliability of the antibodies. Among the other populations, we found the highest degree of co-expression (>50%) in axons of NPFF-expressing cells, while this was somewhat lower (10-20%) in cells that expressed substance P and NKB, and much lower (<10%) in other classes. Our findings show that these antibodies reliably detect GRP-expressing neurons and axons, and that in addition to the GRP-GFP cells, excitatory interneurons expressing NPFF or substance P are likely to be the main source of GRP in the spinal dorsal horn.
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Cofilin 1 is an actin depolymerizing protein playing a fundamental role in the turnover of actin filaments specifically in dendritic spines, where it has been associated with structural and functional plasticity processes. Using a differential proteomic approach, we recently identified cofilin 1 as a potential candidate for controlling plasticity levels in the mouse visual cortex. Here, we focus on analyzing the expression of cofilin 1 and of its serine-3 phosphorylated inactive form in the mouse visual cortex during postnatal development and its modulation by visual input. ⋯ By immunohistochemistry, we identified that the phospho-cofilin 1 immunopositive signal is homogeneously expressed along the different layers of the mouse visual cortex and that it increases during postnatal development. Furthermore, monocular deprivation increases the phospho-cofilin 1 signal in the contralateral cortex to the deprived eye during the critical period but not in the adult stage. Altogether, these results suggest that cofilin 1 and its modification by phosphorylation are relevant players in the processes controlling experience-dependent plasticity in the mouse visual cortex.
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PR-957 [low molecular mass polypeptide (LMP)-7 selective inhibitor] regulates T helper (Th) cell differentiation and inflammatory response in multiple neurological diseases. Hence, this study aimed to explore the effect of PR-957 on Th1/Th2/Th17 cell differentiation, therapeutic efficacy and its potential mechanisms in Alzheimer's disease (AD). The LMP7 expressions in peripheral blood mononuclear cells from 30 AD patients and 30 healthy controls (HC) were detected. ⋯ SC79 addition upregulated pAKT/AKT expression, Th1 cells, and Th17 cells, while downregulated Th2 cells; also SC79 could alleviate the effect of PR-957 on regulating PI3K/AKT pathway and Th1, Th2, and Th17 cell differentiation in AD CD4+ T cells. Furthermore, PR-957 attenuated cognitive impairment and neurofibrillary tangle; also it inhibited Th17 cell differentiation and PI3K/AKT pathway in the brain and spleen of AD mice. In conclusion, PR-957 suppresses Th1 and Th17 cell differentiation, attenuates neural injury and improves cognitive function via inactivating PI3K/AKT pathway in AD.