Plos One
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Triggering receptor expressed on myeloid cells-2 (TREM2) is a microglial surface receptor involved in phagocytosis. Clearance of apoptotic debris after stroke represents an important mechanism to re-attain tissue homeostasis and thereby ensure functional recovery. The role of TREM2 following stroke is currently unclear. ⋯ Although we initially expected an exaggerated pro-inflammatory response following ablation of TREM2, our data support a contradictory scenario that the sub-acute inflammatory reaction after stroke is attenuated in TREM2-KO mice. We therefore conclude that TREM2 appears to sustain a distinct inflammatory response after stroke.
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Somatostatin (Som), one of the most concentrated neuropeptides in the brain, is highly expressed in the olfactory bulb (OB). However, the temporal profile by which OB somatostatin-expressing (Som+) interneurons are produced and the molecular mechanisms controlling this profile are totally unknown. In the present study, we found that all the Som+ interneurons in the mouse external plexiform layer (EPL) and the rat glomerular layer (GL) express the transcription factor Sp8. ⋯ Within the mouse OB, the production of Som+ interneurons is maximal during late embryogenesis and decreases after birth, whereas the generation of Som+ interneurons is low during embryogenesis and increases gradually after birth in the rat OB. Interestingly, genetic ablation of Sp8 by cre/loxP-based recombination severely reduces the number of Som+ interneurons in the EPL of the mouse OB. Taken together, these results suggest that Sp8 is required for the normal production of Som+ interneurons in the EPL of the mouse OB.
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Neurosurgical therapeutic interventions include components that are presumed to be therapeutically inert, such as craniotomy and electrode implantation. Because these procedures may themselves exert neuroactive actions, with anecdotal evidence suggesting that craniotomy and electrode placement may have a particularly significant impact on epileptic seizures, the importance of their inclusion in sham control groups has become more compelling. Here we set out to test the hypothesis that craniotomy alone is sufficient to alter experimental seizures in rats. ⋯ We found that craniotomy significantly decreased the severity of experimental seizures on postoperative days 3, 6, and 10; this effect was dependent on the size of craniotomy. Animals with craniotomies returned to control seizure severity by 20 days post-craniotomy. These data support the hypothesis that damage to the skull is sufficient to cause a significant alteration in seizure susceptibility over an extended postoperative period, and indicate that this damage should not be considered neurologically inert.
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Axonal regeneration is an essential condition to re-establish functional neuronal connections in the injured adult central nervous system (CNS), but efficient regrowth of severed axons has proven to be very difficult to achieve. Although significant progress has been made in identifying the intrinsic and extrinsic mechanisms involved, many aspects remain unresolved. Axonal development in embryonic CNS (hippocampus) requires the obligate activation of the insulin-like growth factor 1 receptor (IGF-1R). ⋯ Blocking experiments using either an antibody which neutralises IGF-1R activation, shRNA designed against the IGF-1R sequence, or the PI3K pathway inhibitor LY294002, all significantly reduced axon regeneration from adult RGC in vitro (∼40% RGC possessed axons in controls vs 2-8% in the different blocking studies). Finally, co-transfection of RGC with shRNA to silence IGF-1R together with a vector containing a constitutively active form of downstream PI3K (p110), fully restored axonal outgrowth in vitro. Hence these data demonstrate that axonal regeneration in adult CNS neurons requires re-expression and activation of IGF-1R, and targeting this system may offer new therapeutic approaches to enhancing axonal regeneration following trauma.
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Hydrogen sulfide (H2S) is the third most common endogenously produced gaseous signaling molecule, but its impact on hepatic ischemia/reperfusion (I/R) injury, especially on mitochondrial function, remains unclear. In this study, rats were randomized into Sham, I/R, ischemia preconditioning (IPC) or sodium hydrosulfide (NaHS, an H2S donor) preconditioning groups. To establish a model of segmental (70%) warm hepatic ischemia, the hepatic artery, left portal vein and median liver lobes were occluded for 60 min and then unclamped to allow reperfusion. ⋯ Mechanistic studies revealed that NaHS preconditioning markedly increased the expression of phosphorylated protein kinase B (p-Akt), phosphorylated glycogen synthase kinase-3 beta (p-GSK-3β) and B-cell lymphoma-2 (Bcl-2) and decreased the release of mitochondrial cytochrome c and cleaved caspase-3/9 levels. Therefore, NaHS administration prior to hepatic I/R ameliorates mitochondrial and hepatocellular damage through the inhibition of MPTP opening and the activation of Akt-GSK-3β signaling. Furthermore, this study provides experimental evidence for the clinical use of H2S to reduce liver damage after perioperative I/R injury.