Cannabinoid receptor-2 attenuates neuroinflammation by promoting autophagy-mediated degradation of the NLRP3 inflammasome post spinal cord injury

Frontiers in Immunology, Journal Year: 2022, Volume and Issue: 13

Published: Sept. 26, 2022

Neuroinflammation following spinal cord injury (SCI) results in prolonged neurological damage and locomotor dysfunction. Polarization of microglia is vital to regulation neuroinflammation, although the underlying mechanisms have not yet been elucidated. Endocannabinoid receptor subtype 2 (CB2R) reported ameliorate neurodegeneration via immunomodulation activities. However, machinery context SCI remains unclear.A lipopolysaccharide-induced inflammation model a mouse were employed investigate regulatory role CB2R polarization response excess neuroinflammation. Markers autophagy measured by Western blot analysis, immunofluorescence, flow cytometry, enzyme-linked immunosorbent assays. Histological staining with hematoxylin eosin, Nissl, Luxol® fast blue was conducted using commercial kits. The function hindlimbs experimental mice evaluated Basso Mouse Scale, Louisville Swim footprint assay.The showed that promoted M2 differentiation, increased interleukin (IL)-10 expression, inhibited M1 differentiation decreased expression IL-1β IL-6. activation also ubiquitination NLRP3 inflammasome interacted autophagy-related proteins p62 microtubule-associated 1B light chain 3. Treatment activator JWH-133 reduced loss myelin, apoptosis neurons, glial scarring, leading improved functional recovery hindlimbs, while antagonist AM630 produced opposite results.Taken together, these suggested attenuated neuroinflammation targeting microglial promoting clearance, thereby facilitating post-SCI.

Language: Английский

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Targeted transplantation of engineered mitochondrial compound promotes functional recovery after spinal cord injury by enhancing macrophage phagocytosis

Bioactive Materials, Journal Year: 2023, Volume and Issue: 32, P. 427 - 444

Published: Oct. 27, 2023

Mitochondria are crucial in sustaining and orchestrating cellular functions. Capitalizing on this, we explored mitochondrial transplantation as an innovative therapeutic strategy for acute spinal cord injury (SCI). In our study, developed engineered compound tailored to target macrophages within the SCI region. Sourced from IL-10-induced Mertkhi bone marrow-derived macrophages, conjugated a peptide sequence, cations-cysteine-alanine-glutamine-lysine (CAQK), with mitochondria, optimizing its targeting affinity site. Our data demonstrated that these compounds significantly enhanced macrophage phagocytosis of myelin debris, curtailed lipid buildup, ameliorated dysfunction, attenuated pro-inflammatory profiles both vitro vivo. The intravenously delivered targeted epicenter, being primary recipients. Critically, they promoted tissue regeneration bolstered functional recovery mice. This study heralds transformative approach SCI, spotlighting modulation activity, phagocytosis, phenotype.

Language: Английский

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Zinc ions regulate mitochondrial quality control in neurons under oxidative stress and reduce PANoptosis in spinal cord injury models via the Lgals3-Bax pathway

Free Radical Biology and Medicine, Journal Year: 2024, Volume and Issue: 221, P. 169 - 180

Published: May 21, 2024

Language: Английский

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Repair spinal cord injury with a versatile anti-oxidant and neural regenerative nanoplatform

Journal of Nanobiotechnology, Journal Year: 2024, Volume and Issue: 22(1)

Published: June 20, 2024

Abstract Spinal cord injury (SCI) often results in motor and sensory deficits, or even paralysis. Due to the role of cascade reaction, effect excessive reactive oxygen species (ROS) early middle stages SCI severely damage neurons, most antioxidants cannot consistently eliminate ROS at non-toxic doses, which leads a huge compromise antioxidant treatment SCI. Selenium nanoparticles (SeNPs) have excellent scavenging bioactivity, but toxicity control problem limits therapeutic window. Here, we propose synergistic strategy SeNPs encapsulated by ZIF-8 (SeNPs@ZIF-8) obtain activity. Three different spatial structures SeNPs@ZIF-8 were synthesized coated with ferrostatin-1, ferroptosis inhibitor (FSZ NPs), achieve enhanced anti-oxidant anti-ferroptosis activity without toxicity. FSZ NPs promoted maintenance mitochondrial homeostasis, thereby regulating expression inflammatory factors promoting polarization macrophages into M2 phenotype. In addition, presented strong abilities promote neuronal maturation axon growth through activating WNT4-dependent pathways, while prevented glial scar formation. The current study demonstrates powerful versatile bioactive functions for offers inspiration other neural diseases.

Language: Английский

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Neurotrauma—From Injury to Repair: Clinical Perspectives, Cellular Mechanisms and Promoting Regeneration of the Injured Brain and Spinal Cord

Biomedicines, Journal Year: 2024, Volume and Issue: 12(3), P. 643 - 643

Published: March 13, 2024

Traumatic injury to the brain and spinal cord (neurotrauma) is a common event across populations often causes profound irreversible disability. Pathophysiological responses trauma exacerbate damage of an index injury, propagating loss function that central nervous system (CNS) cannot repair after initial resolved. The way in which lost consequence complex array mechanisms continue chronic phase post-injury prevent effective neural repair. This review summarises events traumatic (TBI) (SCI), comprising description current clinical management strategies, summary known cellular molecular secondary their role prevention A discussion emerging approaches promote neuroregeneration CNS presented. barriers promoting neurotrauma are pathways cell types occur on level. presents challenge traditional pharmacological targeting single pathways. It suggested novel multiple or using combinatorial therapies may yield sought-after recovery for future patients.

Language: Английский

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Molecular Mechanisms and Clinical Application of Multipotent Stem Cells for Spinal Cord Injury

Cells, Journal Year: 2022, Volume and Issue: 12(1), P. 120 - 120

Published: Dec. 28, 2022

Spinal Cord Injury (SCI) is a common neurological disorder with devastating psychical and psychosocial sequelae. The majority of patients after SCI suffer from permanent disability caused by motor dysfunction, impaired sensation, neuropathic pain, spasticity as well urinary complications, small number experience complete recovery. Current standard treatment modalities the aim to prevent secondary injury provide limited recovery lost functions. Stem Cell Therapy (SCT) represents an emerging approach using differentiation, paracrine, self-renewal capabilities stem cells regenerate injured spinal cord. To date, multipotent including mesenchymal (MSCs), neural (NSCs), hematopoietic (HSCs) represent most investigated types for in preclinical clinical studies. microenvironment has significant impact on survival, proliferation, differentiation transplanted cells. Therefore, deep understanding pathophysiology molecular mechanisms through which act may help improve efficacy SCT find new therapeutic approaches such stem-cell-derived exosomes, gene-modified cells, scaffolds, nanomaterials. In this literature review, pathogenesis action MSCs, NSCs, HSCs are comprehensively described. Moreover, treatment, optimal protocol cell administration, recent based or combined also discussed.

Language: Английский

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Mitochondrial dysfunction as a target in spinal cord injury: intimate correlation between pathological processes and therapeutic approaches

Neural Regeneration Research, Journal Year: 2023, Volume and Issue: 18(10), P. 2161 - 2161

Published: Jan. 1, 2023

Traumatic spinal cord injuries interrupt the connection of all axonal projections with their neuronal targets below and above lesion site. This interruption results in either temporary or permanent alterations locomotor, sensory, autonomic functions. Damage tissue prevents re-growth severed axons across reconnection targets. Therefore, absence spontaneous repair leads to sustained impairment voluntary control movement injury. For decades, regeneration have been considered opitome injury goal being damaged long motor sensory tracts a complex process that involves: (1) resealing injured axons; (2) reconstructing cytoskeletal structure inside (3) re-establishing healthy growth cones; (4) assembling cargos. These biological processes require an efficient production adenosine triphosphate, which is affected by mitochondrial dysfunction after From pathological standpoint, during secondary stage injury, homeostasis disrupted, mainly distal segments axons. result reduction triphosphate levels subsequent inactivation triphosphate-dependent ion pumps required for regulation concentrations reuptake neurotransmitters, such as glutamate. The consequences are calcium overload, reactive oxygen species formation, excitotoxicity. events intimately related activation necrotic apoptotic cell death programs, further exacerbate hallmark why restoring function early could represent potentially effective therapeutic intervention overcome failure produced review discusses most recent evidence linking context It also covers future mitochondria-targeted therapeutical approaches, antioxidant molecules, removing anchor proteins, increasing energetic metabolism through creatine treatment. approaches intended enhance functional recovery promoting regeneration-reconnection

Language: Английский

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Advances in molecular therapies for targeting pathophysiology in spinal cord injury

Expert Opinion on Therapeutic Targets, Journal Year: 2023, Volume and Issue: 27(3), P. 171 - 187

Published: March 4, 2023

Introduction Spinal cord injury (SCI) affects 25,000–50,000 people around the world each year and there is no cure for SCI patients currently. The primary damages spinal tissues secondary mechanisms, including ischemia, apoptosis, inflammation, astrogliosis, further exacerbate lesions to cord. Recently, researchers have designed various therapeutic approaches by targeting its major cellular or molecular pathophysiology.Areas covered Some strategies shown promise in repairing injured functional recoveries, such as administering neuroprotective reagents, specific genes promote robust axon regeneration of disconnected fiber tracts, epigenetic factors enhance cell survival neural repair, facilitating neuronal relay pathways neuroplasticity restoration function after SCI. This review focuses on advances preclinical therapies reported recent years.Expert opinion Recent progress developing novel effective encouraging, but many challenges remain future design treatments, highly neuroprotectants early interventions, stimulating with synaptic reconnections among neurons, maximizing recovery lost functions combination strategies, translating most promising into human use.

Language: Английский

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Ligand‐Screened Cerium‐Based MOF Microcapsules Promote Nerve Regeneration via Mitochondrial Energy Supply

Advanced Science, Journal Year: 2023, Volume and Issue: 11(6)

Published: Nov. 30, 2023

Although mitochondria are crucial for recovery after spinal cord injury (SCI), therapeutic strategies to modulate mitochondrial metabolic energy coordinate the immune response and nerve regeneration lacking. Here, a ligand-screened cerium-based metal-organic framework (MOF) with better ROS scavenging drug-loading abilities is encapsulated polydopamine loading creatine obtain microcapsules (Cr/Ce@PDA nanoparticles), which reverse deficits in both macrophages neuronal cells by combining supplementation. It reprogrames inflammatory proregenerative phenotype via succinate/HIF-1α/IL-1β signaling axis. also promotes differentiation of neural activating mTOR pathway paracrine function macrophages. In vivo experiments further confirm effect regulating early ROS-inflammation positive-feedback chain reactions continuously promoting regeneration. This study provides new strategy correcting deficiency following SCI.

Language: Английский

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The RSK2-RPS6 axis promotes axonal regeneration in the peripheral and central nervous systems

PLoS Biology, Journal Year: 2023, Volume and Issue: 21(4), P. e3002044 - e3002044

Published: April 17, 2023

Unlike immature neurons and the ones from peripheral nervous system (PNS), mature central (CNS) cannot regenerate after injury. In past 15 years, tremendous progress has been made to identify molecules pathways necessary for neuroprotection and/or axon regeneration CNS most regenerative models, phosphorylated ribosomal protein S6 (p-RPS6) is up-regulated in neurons, which often associated with an activation of mTOR (mammalian target rapamycin) pathway. However, exact contribution posttranslational modifications this remains elusive. study, we demonstrate that RPS6 phosphorylation essential PNS mice. We show induced during preconditioning effect dorsal root ganglion (DRG) it controlled by p90S6 kinase RSK2. Our results reveal RSK2 controls RSK2-RPS6 axis key process, as well regeneration. Finally, promotes column, spinal cord synaptic plasticity, innervation leading functional recovery. data establish critical role give new insights into mechanisms related growth circuit formation traumatic lesion.

Language: Английский

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