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Autophagy plays a protective role in motor neuron degeneration following spinal cord ischemia/reperfusion-induced spastic paralysis.

ABSTRACT: Spinal cord ischemia and reperfusion (SCIR) injury can lead to neurologic dysfunction and paraplegia, which are serious complications after shock or thoracoabdominal aortic surgery. Autophagy is a fundamental cellular process in eukaryotes, and homeostasis of autophagic activities in the cytoplasm is critical for the maintenance of neuronal function. To date, no studies have addressed the involvement of autophagy in the regulation of motor neurons in the ventral horn of the spinal cord area following SCIR-induced spastic paralysis or the underlying mechanisms of this process. In this study, we investigated spastic paralysis in rats following SCIR injury. The number of autophagosomes increased 3 h following the injury, and subsequently decreased slowly to near-normal levels in the sham group as indicated by the autophagy markers microtubule-associated protein 1 light chain 3 (LC3), beclin-1, and p62. Furthermore, after treatment with the autophagy inhibitor 3-Methyladenine (3-MA) and autophagy activator rapamycin following SCIR, autophagy in the SCIR-3-MA group decreased significantly, while that in the SCIR-Rap group increased, compared with SCIR-DMSO controls group. Moreover, the assessment of motor neurons function, using Reuter's score and motor evoked potentials (MEP) and somatosensory evoked potentials (SEP), indicated that promoting autophagy reduced scores compared with SCIR controls, while inhibiting autophagy increased the scores, and hence motor neurons function. Autophagy in the SCIR model protected motor neurons function and morphology. These results would provide more evidences for better understanding function of autophagy in motor neurons degeneration and mechanisms underlying spastic paralysis. Autophagy would be a novel target for prevention and therapy in SCIR damage.

SUBMITTER: Wang L

PROVIDER: S-EPMC5622268 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Autophagy plays a protective role in motor neuron degeneration following spinal cord ischemia/reperfusion-induced spastic paralysis.

Wang Li L Feng Dongliang D Liu Yuan Y Li Sen S Jiang Long L Long Zaiyun Z Wu Yamin Y

American journal of translational research 20170915 9

Spinal cord ischemia and reperfusion (SCIR) injury can lead to neurologic dysfunction and paraplegia, which are serious complications after shock or thoracoabdominal aortic surgery. Autophagy is a fundamental cellular process in eukaryotes, and homeostasis of autophagic activities in the cytoplasm is critical for the maintenance of neuronal function. To date, no studies have addressed the involvement of autophagy in the regulation of motor neurons in the ventral horn of the spinal cord area foll ...[more]

PMID: 28979699

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Project description:Summary: We build a model for the molecular and cellular events underlying phenotypic discordance in glycine receptor defects (beta subunit). Some mice progress and die, while their littermates recover and get better, despite the same mutation on an inbred genetic background. We find evidence for glycine neurotransmitter toxicity and loss of glycinergic interneurons early in the disease, but some mice are able to keep things going until they can over-express homomeric alpha1 channels, whereupon they recover. In the mice progressing towards lethality, neurotransmitter toxicity too quickly extends to GABAergic interneurons and motorneurons, and they lose their window of time to upregulate the alpha1 glycine receptor, and they crash and burn. Importantly, human patients with glycine receptor defects typically show a resolution of their phenotype with age, and we propose that the same remodeling events are occuring in human patients. Hypothesis: Our data suggests that functional recovery of GlyRb mutant mice is likely due to expression of homomeric glycine receptors, rescue from excitotoxicity, and subsequent neuronal remodeling. We propose that human patients with hyperekplexia (mutations of glycine receptors) show remodeling similar to that of the recovering spastic mice, as human patients also show a lessening of symptoms as a function of age. Specific Aim: Murine models for human Startle Disease show clinical variability between littermates. Here, we determined the molecular remodeling of spastic GlyRb mutant spinal cord through the course of the disease, and develop a model for clinical disparity between littermates. At young ages, all animals were spastic, showed loss of glycine receptors, increased expression of vesicular glycine/GABA transporter and NMDA receptors, induction of activated caspase3, and preferential loss of glycinergic interneurons consistent with neurotransmitter toxicity model. Those littermates that recovered from symptoms showed strong over-expression of the GlyRa1 subunit, and increased myelination and synaptic plasticity. Littermates that showed a deteriorating clinical course failed to over-express GlyRa1, and also showed relative loss of gephyrin. These molecular changes were associated with preferential loss of GABAergic interneurons, and extensive motorneuron loss. Keywords: other

Project description:Purpose To evaluate whether noninvasive molecular imaging technologies targeting myeloperoxidase (MPO) can reveal early inflammation associated with spinal cord injury after thoracic aortic ischemia-reperfusion (TAR) in mice. Materials and Methods The study was approved by the institutional animal care and use committee. C57BL6 mice that were 8-10 weeks old underwent TAR (n = 55) or sham (n = 26) surgery. Magnetic resonance (MR) imaging (n = 6) or single photon emission computed tomography (SPECT)/computed tomography (CT) (n = 15) studies targeting MPO activity were performed after intravenous injection of MPO sensors (bis-5-hydroxytryptamide-tetraazacyclododecane [HT]-diethyneletriaminepentaacetic acid [DTPA]-gadolinium or indium 111-bis-5-HT-DTPA, respectively). Immunohistochemistry and flow cytometry were used to identify myeloid cells and neuronal loss. Proinflammatory cytokines, keratinocyte chemoattractant (KC), and interleukin 6 (IL-6) were measured with enzyme-linked immunosorbent assay. Statistical analyses were performed by using nonparametric tests and the Pearson correlation coefficient. P < .05 was considered to indicate a significant difference. Results Myeloid cells infiltrated into the injured cord at 6 and 24 hours after TAR. MR imaging confirmed the presence of ischemic lesions associated with mild MPO-mediated enhancement in the thoracolumbar spine at 24 hours compared with the sham procedure. SPECT/CT imaging of MPO activity showed marked MPO-sensor retention at 6 hours (P = .003) that continued to increase at 24 hours after TAR (P = .0001). The number of motor neurons decreased substantially at 24 hours after TAR (P < .01), which correlated inversely with in vivo inflammatory changes detected at molecular imaging (r = 0.64, P = .0099). MPO was primarily secreted by neutrophils, followed by lymphocyte antigen 6 complexhigh monocytes and/or macrophages. There were corresponding increased levels of proinflammatory cytokines KC (P = .0001) and IL-6 (P = .0001) that mirrored changes in MPO activity. Conclusion MPO is a suitable imaging biomarker for identifying and tracking inflammatory damage in the spinal cord after TAR in a mouse model. © RSNA, 2016 Online supplemental material is available for this article.

Dataset Information

Autophagy plays a protective role in motor neuron degeneration following spinal cord ischemia/reperfusion-induced spastic paralysis.

Publications

Autophagy plays a protective role in motor neuron degeneration following spinal cord ischemia/reperfusion-induced spastic paralysis.

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