A Western diet impairs CNS energy homeostasis and recovery after spinal cord injury: Link to astrocyte metabolism.
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ABSTRACT:
SUBMITTER: Kim HN
PROVIDER: S-EPMC7982964 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The trillions of microbes that exist in the gastrointestinal tract have emerged as pivotal regulators of mammalian development and physiology. Disruption of this gut microbiome, a process known as dysbiosis, causes or exacerbates various diseases, but whether gut dysbiosis affects recovery of neurological function or lesion pathology after traumatic spinal cord injury (SCI) is unknown. Data in this study show that SCI increases intestinal permeability and bacterial translocation from the gut. These changes are associated with immune cell activation in gut-associated lymphoid tissues (GALTs) and significant changes in the composition of both major and minor gut bacterial taxa. Postinjury changes in gut microbiota persist for at least one month and predict the magnitude of locomotor impairment. Experimental induction of gut dysbiosis in naive mice before SCI (e.g., via oral delivery of broad-spectrum antibiotics) exacerbates neurological impairment and spinal cord pathology after SCI. Conversely, feeding SCI mice commercial probiotics (VSL#3) enriched with lactic acid-producing bacteria triggers a protective immune response in GALTs and confers neuroprotection with improved locomotor recovery. Our data reveal a previously unknown role for the gut microbiota in influencing recovery of neurological function and neuropathology after SCI.
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Project description:Spinal cord injury (SCI) causes severe disability, and the current inability to restore function to the damaged spinal cord leads to lasting detrimental consequences to patients. One strategy to reduce SCI morbidity involves limiting the spread of secondary damage after injury. Previous studies have shown that connexin 43 (Cx43), a gap junction protein richly expressed in spinal cord astrocytes, is a potential mediator of secondary damage. Here, we developed a specific inhibitory antibody, mouse-human chimeric MHC1 antibody (MHC1), that inhibited Cx43 hemichannels, but not gap junctions, and reduced secondary damage in 2 incomplete SCI mouse models. MHC1 inhibited the activation of Cx43 hemichannels in both primary spinal astrocytes and astrocytes in situ. In both SCI mouse models, administration of MHC1 after SCI significantly improved hind limb locomotion function. Remarkably, a single administration of MHC1 30 minutes after injury improved the recovery up to 8 weeks post-SCI. Moreover, MHC1 treatment decreased gliosis and lesion sizes, increased white and gray matter sparing, and improved neuronal survival. Together, these results suggest that inhibition of Cx43 hemichannel function after traumatic SCI reduces secondary damage, limits perilesional gliosis, and improves functional recovery. By targeting hemichannels specifically with an antibody, this study provides a potentially new, innovative therapeutic approach in treating SCI.
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Project description:More than 90% of spinal cord injuries are caused by traumatic accidents and are often associated with other tissue damage (polytrauma) that can provide a source of continued pain input during recovery. In a clinically relevant spinal cord contusion injury model, prior work has shown that noxious stimulation at an intensity that engages pain (C) fibers soon after injury augments secondary injury and impairs functional recovery. Noxious input increases the expression of pro-inflammatory cytokines (interleukin 1β and 18), cellular signals associated with cell death (caspase 3 and 8), and physiological signs of hemorrhage. Here, it is shown that reducing neural excitability after spinal cord injury (SCI) with the local anesthetic lidocaine (micro-injected by means of a lumbar puncture) blocks these adverse cellular effects. In contrast, treatment with an analgesic dose of morphine had no effect. Contused rats that received nociceptive stimulation soon after injury exhibited poor locomotor recovery, less weight gain, and greater tissue loss at the site of injury. Prophylactic application of lidocaine blocked the adverse effect of nociceptive stimulation on behavioral recovery and reduced tissue loss from secondary injury. The results suggest that quieting neural excitability using lidocaine can reduce the adverse effect of pain input (from polytrauma or surgery) after SCI.
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Project description:BACKGROUND:Spinal cord injury (SCI) is a devastating condition mainly deriving from a traumatic damage of the spinal cord (SC). Immune cells and endogenous SC-neural stem cells (SC-NSCs) play a critical role in wound healing processes, although both are ineffective to completely restore tissue functioning. The role of SC-NSCs in SCI and, in particular, whether such cells can interplay with the immune response are poorly investigated issues, although mechanisms governing such interactions might open new avenues to develop novel therapeutic approaches. METHODS:We used two transgenic mouse lines to trace as well as to kill SC-NSCs in mice receiving SCI. We used Nestin CreERT2 mice to trace SC-NSCs descendants in the spinal cord of mice subjected to SCI. While mice carrying the suicide gene thymidine kinase (TK) along with the GFP reporter, under the control of the Nestin promoter regions (NestinTK mice) were used to label and selectively kill SC-NSCs. RESULTS:We found that SC-NSCs are capable to self-activate after SCI. In addition, a significant worsening of clinical and pathological features of SCI was observed in the NestinTK mice, upon selective ablation of SC-NSCs before the injury induction. Finally, mice lacking in SC-NSCs and receiving SCI displayed reduced levels of different neurotrophic factors in the SC and significantly higher number of M1-like myeloid cells. CONCLUSION:Our data show that SC-NSCs undergo cell proliferation in response to traumatic spinal cord injury. Mice lacking SC-NSCs display overt microglia activation and exaggerate expression of pro-inflammatory cytokines. The absence of SC-NSCs impaired functional recovery as well as neuronal and oligodendrocyte cell survival. Collectively our data indicate that SC-NSCs can interact with microglia/macrophages modulating their activation/responses and that such interaction is importantly involved in mechanisms leading tissue recovery.
| S-EPMC5824446 | biostudies-literature
Project description:Alterations in phospholipids have long been associated with spinal cord injury (SCI). However, their specific roles and signaling cascades in mediating cell death and tissue repair remain unclear. Here we investigated whether alterations of cardiolipin (CL), a family of mitochondrion-specific phospholipids, play a crucial role in mitochondrial dysfunction and neuronal death following SCI. Lipidomic analysis was used to determine the profile of CL alteration in the adult rat spinal cord following a moderate contusive SCI at the 10th thoracic (T10) level. Cellular, molecular, and genetic assessments were performed to determine whether CL alterations mediate mitochondrial dysfunction and neuronal death after SCI, and, if so, whether reversing CL alteration leads to neuroprotection after SCI. Using lipidomic analysis, we uncovered CL alterations at an early stage of SCI. Over 50 distinct CL species were identified, of which 50% showed significantly decreased abundance after SCI. The decreased CL species contained mainly polyunsaturated fatty acids that are highly susceptible to peroxidation. In parallel, 4-HNE, a lipid peroxidation marker, significantly increased after SCI. We found that mitochondrial oxidative stress not only induced CL oxidation, but also resulted in CL loss by activating cPLA2 to hydrolyze CL. CL alterations induced mitochondrial dysfunction and neuronal death. Remarkably, pharmacologic inhibition of CL alterations with XJB-5-131, a novel mitochondria-targeted electron and reactive oxygen species scavenger, reduced cell death, tissue damage and ameliorated motor deficits after SCI in adult rats. These findings suggest that CL alteration could be a novel mechanism that mediates injury-induced neuronal death, and a potential therapeutic target for ameliorating secondary SCI.
| S-EPMC9768173 | biostudies-literature
Project description:Mice with rotarod training showed significant differences in the expression of trophic factors and cytokines, histological repair, and functional recovery when compared with the mice without training. To exlore the potential mechanism, we applied the next-generation sequence to compare the transcriptome profile between two groups. We found that there were 1299 DEGs between two groups with 586 upregulated genes and 713 downregulated genes. GO enrichment analysis revealed that DEGs, especially the downregulated genes, were primarily associated with revascularization biological process like angiogenesis, regulation of vasculature development, regulation of angiogenesis, and cellular component including postsynapse, neuron to neuron synapse, etc. On the other hand, KEGG pathway analysis showed that those significantly altered genes, also downregulated DEGs in particular, were mainly enriched in the PI3K-Akt signaling pathway.
2023-07-17 | GSE193806 | GEO
Project description:ObjectiveTo evaluate the impact of using transcutaneous electrical spinal cord stimulation (TSCS) on upper and lower extremity function in individuals with chronic spinal cord injury (SCI).DesignProspective case series.SettingSCI specific rehabilitation hospital.ParticipantsA convenience sample (N = 7) of individuals with tetraplegia who had previously been discharged from outpatient therapy due to a plateau in progress.InterventionsIndividuals participated in 60 min of upper extremity (UE) functional task-specific practice (FTP) in combination with TSCS and 60 min of locomotor training in combination with TSCS 5x/week.Main outcome measuresThe primary outcome for this analysis was the Capabilities of Upper Extremity Test (CUE-T). Secondary outcomes include UE motor score (UEMS), LE motor score (LEMS), sensation (light touch and pin prick), Nine-Hole Peg Test, 10 meter walk test, 6 min walk test, and 5 min stand test.ResultsSeven individuals (four motor complete; three motor incomplete) completed 20-80 sessions UE and LE training augmented with TSCS and without any serious adverse events. Improvements were reported on the CUE-T in all seven individuals. Two individuals improved their ASIA impairment scale (AIS) classification (B to C; C to D) and two individuals improved their neurologic level of injury by one level (C4-C5; C5-C6). Sensation improved in five individuals and all four who started out with motor complete SCIs were able to voluntarily activate their LEs on command in the presence of stimulation.ConclusionIndividuals with chronic SCI who had previously demonstrated a plateau in function after an intensive outpatient therapy program were able to improve in a variety of UE and LE outcomes in response to TSCS without any adverse events. This was a small pilot study and future fully powered studies with comparative interventions need to be completed to assess efficacy.
| S-EPMC9396932 | biostudies-literature
Project description:Spinal cord injury (SCI) is often accompanied by additional tissue damage (polytrauma) that provides a source of pain input. Our studies suggest that this pain input may be detrimental to long-term recovery. In a rodent model, we have shown that engaging pain (nociceptive) fibers caudal to a lower thoracic contusion SCI impairs recovery of locomotor function and increases tissue loss (secondary injury) and hemorrhage at the site of injury. In these studies, nociceptive fibers were activated using intermittent electrical stimulation. The stimulation parameters were derived from earlier studies demonstrating that 6?min of noxious stimulation, at an intensity (1.5?mA) that engages unmyelinated C (pain) fibers, induces a form of maladaptive plasticity within the lumbosacral spinal cord. We hypothesized that both shorter bouts of nociceptive input and lower intensities of stimulation will decrease locomotor function and increase spinal cord hemorrhage when rats have a spinal cord contusion. To test this, the present study exposed rats to electrical stimulation 24 h after a moderate lower thoracic contusion SCI. One group of rats received 1.5?mA stimulation for 0, 14.4, 72, or 180 s. Another group received six minutes of stimulation at 0, 0.17, 0.5, and 1.5?mA. Just 72?s of stimulation induced an acute disruption in motor performance, increased hemorrhage, and undermined the recovery of locomotor function. Likewise, less intense (0.5?mA) stimulation produced an acute disruption in motor performance, fueled hemorrhage, and impaired long-term recovery. The results imply that a brief period of moderate pain input can trigger hemorrhage after SCI and undermine long-term recovery. This highlights the importance of managing nociceptive signals after concurrent peripheral and central nervous system injuries.
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Project description: Not available
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Project description:Lithium is associated with oxidative stress and apoptosis, but the mechanism by which lithium protects against spinal cord injury remains poorly understood. In this study, we found that intraperitoneal administration of lithium chloride (LiCl) in a rat model of spinal cord injury alleviated pathological spinal cord injury and inhibited expression of tumor necrosis factor α, interleukin-6, and interleukin 1 β. Lithium inhibited pyroptosis and reduced inflammation by inhibiting Caspase-1 expression, reducing the oxidative stress response, and inhibiting activation of the Nod-like receptor protein 3 inflammasome. We also investigated the neuroprotective effects of lithium intervention on oxygen/glucose-deprived PC12 cells. We found that lithium reduced inflammation, oxidative damage, apoptosis, and necrosis and up-regulated nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase-1 in PC12 cells. All-trans retinoic acid, an Nrf2 inhibitor, reversed the effects of lithium. These results suggest that lithium exerts anti-inflammatory, anti-oxidant, and anti-pyroptotic effects through the Nrf2/heme oxygenase-1 pathway to promote recovery after spinal cord injury. This study was approved by the Animal Ethics Committee of Xi'an Jiaotong University (approval No. 2018-2053) on October 23, 2018.
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