In contrast to lipopolysaccharide (LPS)-induced preconditioning, which has repeatedly been examined in the past, the effects of post-ischemic LPS-induced sepsis, although clinically considerably more important, have not systemically been studied. We exposed mice to transient intraluminal middle cerebral artery occlusion (MCAO) and examined the effects of intraperitoneal LPS (0.1 or 1 mg/kg) which was administered 24 h postischemia. Post-ischemic glial reactivity, neuronal survival and neurological outcome were differently modulated by the higher and the lower LPS dose. Although both doses promoted neuronal survival after 72 h, the underlying mechanisms were not similar. Mice receiving 1 mg/kg LPS exhibited transient hypothermia at 1 and 3 hours post sepsis (hps), followed by reduced focal neurological deficits at 24, 48 and 72 hps. The lower dose (0.1 mg/kg) did not induce hypothermia, but reduced microglia/macrophage activation with the appearance of an anti-inflammatory CD206 positive cell phenotype in the brain parenchyma. Together, our results indicate a novel, dose-dependent modulation of microglial cells that is intricately involved in brain protection.
Stroke remains one of leading causes of long-term disability worldwide, and the development of effective restorative therapies is hindered by an incomplete understanding of intrinsic recovery mechanisms in the brain. Here, we explored the involvement of perineuronal nets (PNNs), the facet-like layers of extracellular matrix surrounding fast-spiking interneurons, in brain remodeling and neurological recovery after focal cerebral ischemia in mice with and without induced stroke tolerance. Due to insufficient resolution of conventional microscopy methods, the contribution of ultrastructural changes in PNNs to post stroke brain plasticity remained unknown. Using superresolution stimulated emission depletion (STED) and structured illumination (SR-SIM) microscopy, we revealed that PNN facets become larger and less dense in the post-acute stroke phase. Morphological alterations in PNNs are likely mediated by activated microglia cells, which preferentially enwrap the PNN-coated neurons. The loosening of PNNs is transient and associates with the increased number of GABAergic axonal terminals on inhibitory interneurons in the motor cortical layer 5. The coherent remodeling of PNNs and inhibitory synapses precedes the recovery of motor coordination during the late post-acute stroke phase. In the chronic stroke phase, the initial morphology of PNNs is restored, and the number of GABAergic axonal terminals on motor cortical interneurons is reduced. Our data suggests a novel mechanism of motor cortical plasticity after stroke, and we propose that prolonging PNN loosening during the post-acute period can extend the opening neuroplasticity window into the chronic stroke phase.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.