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After traumatic brain injury, the brain extracellular matrix undergoes structural rearrangement due to changes in matrix composition, activation of proteases, and deposition of chondroitin sulfate proteoglycans by reactive astrocytes to produce the glial scar. These changes lead to a softening of the tissue, where the stiffness of the contusion core and peripheral pericontusional regions becomes softer than that of healthy tissue. Pioneering mechanotransduction studies have shown that soft substrates upregulate intermediate filament proteins in reactive astrocytes; however, many other aspects of astrocyte biology remain unclear. Here, we developed a platform for the culture of cortical astrocytes using polyacrylamide (PA) gels of varying stiffness (measured in Pascal; Pa) to mimic injury-related regions in order to investigate the effects of tissue stiffness on astrocyte reactivity and morphology. Our results show that substrate stiffness influences astrocyte phenotype; soft 300 Pa substrates led to increased GFAP immunoreactivity, proliferation, and complexity of processes. Intermediate 800 Pa substrates increased Aggrecan+, Brevican+, and Neurocan+ astrocytes. The stiffest 1 kPa substrates led to astrocytes with basal morphologies, similar to a physiological state. These results advance our understanding of astrocyte mechanotransduction processes and provide evidence of how substrates with engineered stiffness can mimic the injury microenvironment.

Background: Reactive astrogliosis and microgliosis are coordinated responses to CNS insults and are pathological hallmarks of traumatic brain injury (TBI). In these conditions, persistent reactive gliosis can impede tissue repopulation and limit neurogenesis. Thus, modulating this phenomenon has been increasingly recognized as potential therapeutic approach. Methods: In this study, we investigated the potential of the flavonoid agathisflavone to modulate astroglial and microglial injury responses and promote neurogenesis in the subventricular zone (SVZ) neurogenic niche. Agathisflavone, or the vehicle in controls, was administered directly into the lateral ventricles in postnatal day (P)8-10 mice by twice daily intracerebroventricular (ICV) injections for 3 days, and brains were examined at P11. Results: In the controls, ICV injection caused glial reactivity along the needle track, characterised immunohistochemically by increased astrocyte expression of glial fibrillary protein (GFAP) and the number of Iba-1+ microglia at the lesion site. Treatment with agathisflavone decreased GFAP expression, reduced both astrocyte reactivity and the number of Iba-1+ microglia at the core of the lesion site and the penumbra, and induced a 2-fold increase on the ratio of anti-inflammatory CD206+ to pro-inflammatory CD16/32+ microglia. Notably, agathisflavone increased the population of neuroblasts (GFAP+ type B cells) in all SVZ microdomains by up to double, without significantly increasing the number of neuronal progenitors (DCX+). Conclusions: Although future studies should investigate the underlying molecular mechanisms driving agathisflavone effects on microglial polarization and neurogenesis at different timepoints, these data indicate that agathisflavone could be a potential adjuvant treatment for TBI or central nervous system disorders that have reactive gliosis as a common feature. [ABSTRACT FROM AUTHOR]

Schwann cell transplantation is considered one of the most promising cell-based therapy to repair injured spinal cord due to its unique growth-promoting and myelin-forming properties. A the Food and Drug Administration-approved Phase I clinical trial has been conducted to evaluate the safety of transplanted human autologous Schwann cells to treat patients with spinal cord injury. A major challenge for Schwann cell transplantation is that grafted Schwann cells are confined within the lesion cavity, and they do not migrate into the host environment due to the inhibitory barrier formed by injury-induced glial scar, thus limiting axonal reentry into the host spinal cord. Here we introduce a combinatorial strategy by suppressing the inhibitory extracellular environment with injection of lentivirus-mediated transfection of chondroitinase ABC gene at the rostral and caudal borders of the lesion site and simultaneously leveraging the repair capacity of transplanted Schwann cells in adult rats following a mid-thoracic contusive spinal cord injury. We report that when the glial scar was degraded by chondroitinase ABC at the rostral and caudal lesion borders, Schwann cells migrated for considerable distances in both rostral and caudal directions. Such Schwann cell migration led to enhanced axonal regrowth, including the serotonergic and dopaminergic axons originating from supraspinal regions, and promoted recovery of locomotor and urinary bladder functions. Importantly, the Schwann cell survival and axonal regrowth persisted up to 6 months after the injury, even when treatment was delayed for 3 months to mimic chronic spinal cord injury. These findings collectively show promising evidence for a combinatorial strategy with chondroitinase ABC and Schwann cells in promoting remodeling and recovery of function following spinal cord injury.

Traumatic brain injury is a global health crisis, causing significant death and disability worldwide. Neuroinflammation that follows traumatic brain injury has serious consequences for neuronal survival and cognitive impairments, with astrocytes involved in this response. Following traumatic brain injury, astrocytes rapidly become reactive, and astrogliosis propagates from the injury core to distant brain regions. Homeostatic astroglial proteins are downregulated near the traumatic brain injury core, while pro-inflammatory astroglial genes are overexpressed. This altered gene expression is considered a pathological remodeling of astrocytes that produces serious consequences for neuronal survival and cognitive recovery. In addition, glial scar formed by reactive astrocytes is initially necessary to limit immune cell infiltration, but in the long term impedes axonal reconnection and functional recovery. Current therapeutic strategies for traumatic brain injury are focused on preventing acute complications. Statins, cannabinoids, progesterone, beta-blockers, and cerebrolysin demonstrate neuroprotective benefits but most of them have not been studied in the context of astrocytes. In this review, we discuss the cell signaling pathways activated in reactive astrocytes following traumatic brain injury and we discuss some of the potential new strategies aimed to modulate astroglial responses in traumatic brain injury, especially using cell-targeted strategies with miRNAs or lncRNA, viral vectors, and repurposed drugs.

Objective Spinal cord injury (SCI), one of the major disabilities concerning central nervous system injury, results in permanent tissue loss and neurological impairment. The existing therapeutic options for SCI are limited and predominantly consist of chemical compounds. In this study, we delved into the neuroprotective effects of myricetin, a natural flavonoid compound, and the underlying mechanisms, specifically in the context of SCI, utilizing an in vivo model. Previously, our investigations revealed an elevation in the phosphorylated form of Lin-11, Isl-1, and Mec-3 kinase1 (LIMK1) at chronic time points postinjury, coinciding with neuronal loss and scar formation. Our primary objective here was to assess the potential neuroprotective properties of myricetin in SCI and to ascertain if these effects were linked to LIMK inhibition, a hitherto unexamined pathway to date. Methods Computational docking and molecular dynamics simulation studies were performed to assess myricetin’s potential to bind with LIMK. Then, using a rat contusion model, SCI was induced and different molecular techniques (Western blot, Evans Blue assay, quantitative reverse transcription polymerase chain reaction and immunohistochemistry) were performed to determine the effects of myricetin. Results Remarkably, computational docking models identified myricetin as having a better interaction profile with LIMK than standard. Subsequent to myricetin treatment, a significant downregulation in phosphorylated LIMK expression was observed at chronic time points. This reduction correlated with a notable decrease in glial and fibrotic scar formation, and enhanced neuroprotection indicating a positive outcome in vivo. Conclusion In summary, our findings underscore myricetin’s potential as a bioactive compound capable of attenuating SCI-induced injury cascades by targeting the LIMK pathway.

Reactive astrogliosis and inflammation are pathologic hallmarks of spinal cord injury. After injury, dysfunction of glial cells (astrocytes) results in glial scar formation, which limits neuronal regeneration. The blood–spinal cord barrier maintains the structural and functional integrity of the spinal cord and does not allow blood vessel components to leak into the spinal cord microenvironment. After the injury, disruption in the spinal cord barrier causes an imbalance of the immunological microenvironment. This triggers the process of neuroinflammation, facilitated by the actions of microglia, neutrophils, glial cells, and cytokines production. Recent work has revealed two phenotypes of astrocytes, A1 and A2, where A2 has a protective type, and A1 releases neurotoxins, further promoting glial scar formation. Here, we first describe the current understanding of the spinal cord microenvironment, both pre-, and post-injury, and the role of different glial cells in the context of spinal cord injury, which forms the essential update on the cellular and molecular events following injury. We aim to explore in-depth signaling pathways and molecular mediators that trigger astrocyte activation and glial scar formation. This review will discuss the activated signaling pathways in astrocytes and other glial cells and their collaborative role in the development of gliosis through inflammatory responses. [ABSTRACT FROM AUTHOR]

Glial scar formation is a major obstacle to nerve regeneration following spinal cord injury (SCI). Pin1 and the PI3K/AKT/CDK2 signaling pathway play crucial roles in neuronal regulation, but research on their involvement in glial scarring remains limited. In this study, we have for the first time observed that Pin1, PI3K, AKT, and CDK2 are upregulated and interact with each other following SCI. Further experiments revealed that Pin1 contributes to the development of glial scars by promoting astrocyte proliferation, inhibiting apoptosis, and activating the PI3K/AKT/CDK2 pathway. Additionally, all‐trans retinoic acid (ATRA), a specific chemical inhibitor of Pin1, effectively suppresses Pin1 expression. However, its clinical application is limited by its short half‐life and susceptibility to inactivation. To address these issues, we have developed a thermosensitive sodium beta‐glycerophosphate (β‐GP)/chitosan (CS) hydrogel loaded with ATRA (β‐GP/CS@ATRA). This hydrogel exhibits favorable morphology and biocompatibility. Compared to free ATRA, the β‐GP/CS@ATRA hydrogel significantly enhances functional motor recovery after SCI and protects spinal cord tissue, thereby inhibiting glial scar formation. Mechanistically, ATRA administration blocks the development of glial scars and the activation of the PI3K/AKT/CDK2 pathway by inhibiting Pin1 expression. This study suggests that combining ATRA with a hydrogel to target Pin1 expression may be a promising strategy for treating glial scar formation following SCI. [ABSTRACT FROM AUTHOR]

Regeneration, the complex process of restoring damaged or absent cells, tissues, and organs, varies considerably between species. The zebrafish is a remarkable model organism for its impressive regenerative abilities, particularly in organs such as the heart, fin, retina, spinal cord, and brain. Unlike mammals, zebrafish can regenerate with limited or absent scarring, a phenomenon closely linked to the activation of stem cells and immune cells. This review examines the unique roles played by the immune response and inflammation in zebrafish and mouse during regeneration, highlighting the cellular and molecular mechanisms behind their divergent regenerative capacities. By focusing on zebrafish telencephalic regeneration and comparing it to that of the rodents, this review highlights the importance of a well‐controlled, acute, and non‐persistent immune response in zebrafish, which promotes an environment conducive to regeneration. The knowledge gained from understanding the mechanisms of zebrafish regeneration holds great promises for the treatment of human neurodegenerative diseases and brain damage (stroke and traumatic brain injuries), as well as for the advancement of regenerative medicine approaches. [ABSTRACT FROM AUTHOR]

Spinal cord injury (SCI) is a complex neurodegenerative pathology that consistently harbours a poor prognostic outcome. At present, there are few therapeutic strategies that can halt neuronal cell death and facilitate functional motor recovery. However, recent studies have highlighted the Wnt pathway as a key promoter of axon regeneration following central nervous system (CNS) injuries. Emerging evidence also suggests that the temporal dysregulation of Wnt may drive cell death post-SCI. A major challenge in SCI treatment resides in developing therapeutics that can effectively target inflammation and facilitate glial scar repair. Before Wnt signalling is exploited for SCI therapy, further research is needed to clarify the implications of Wnt on neuroinflammation during chronic stages of injury. In this review, an attempt is made to dissect the impact of canonical and non-canonical Wnt pathways in relation to individual aspects of glial and fibrotic scar formation. Furthermore, it is also highlighted how modulating Wnt activity at chronic time points may aid in limiting lesion expansion and promoting axonal repair. [ABSTRACT FROM AUTHOR]

The role of glial scars in the pathophysiology of spinal cord injury (SCI) is widely recognized, as they pose physical barriers against axonal regeneration and persistent chronic inflammation by releasing cytotoxic agents, thereby impeding nerve repair. Consequently, preventing glial scarring has emerged as an important therapeutic objective in SCI management. Following SCI, astrocytes undergo a phenotypic transition into scar‐forming astrocytes, which critically depends on the activation of inflammatory responses and the integrin‐N‐cadherin pathway. To explore improved SCI treatment, a nano‐antagonist hydrogel (Nano‐ant Gel), comprising N‐cadherin nano‐antagonists and a polyphenol hydrogel designed to inhibit glial scarring by mitigating inflammatory response and modulating astrocyte behavior, thereby facilitating spinal cord‐injury repair, is developed and characterized. The hydrogel exhibits notable anti‐inflammatory properties, specific calcium ion‐adsorption capabilities, and antagonistic effects against N‐cadherin, effectively impeding the formation and aggregation of scar‐forming astrocytes. Its efficacy is comprehensively assessed using a model of contusive SCI, with which it effectively inhibits glial scar formation and promotes axonal regeneration. Notably, the Nano‐ant Gel significantly improves the locomotor functions of mice with SCI, suggesting that it represents a promising approach for treating the condition. [ABSTRACT FROM AUTHOR]

BACKGROUND: The alteration of miR-146a-3p level is a common event in the pathogenesis of most neurological diseases, and the specific mechanism of miR146a-3p regulation of astrocytes has not been studied. OBJECTIVE: To verify that miR-146a-3p regulates astrocyte proliferation, migration and apoptosis through insulin-like growth factor 1. METHODS: 12 SD rats were divided into a sham operation group and a spinal cord injury group, with six rats in each group. RNA sequencing analysis was performed on the spinal cord tissues of all groups 2 weeks after surgery to screen out the differential genes (log2FC > 2), and to select spinal cord injury-related genes (Score > 20) in the Genecards database, and then to predict the target genes of miR-146a-3p by Targetscan. The intersection of three gene sets was obtained to screen out insulin-like growth factor 1 as one of the important target genes. qPCR, western blot assay and immunohistochemistry were performed to analyze the expression level of insulin-like growth factor 1 in spinal cord tissues. The primary astrocytes were divided into NC group, NC-mimics group and miR-146a-3p mimics group. Annexin-V/PI staining was used to detect cell apoptosis. CCK-8 assay was used to detect cell proliferation. Transwell assay was used to detect cell migration ability. RESULTS AND CONCLUSION: The expression of miR-146a-3p in the spinal cord tissue of the spinal cord injury group was lower than that of the sham operation group (P < 0.05). The expression of insulin-like growth factor 1 in the spinal cord tissue of the spinal cord injury group was higher than that of the sham operation group (P < 0.05). Compared with the NC group and NC-mimics group, the apoptotic rate of astrocytes was increased (P < 0.01); the proliferation of astrocytes was decreased (P < 0.01) and the number of migration was decreased (P < 0.01) in the miR-146a-3p mimics group. To conclude, the expression of miR-146a-3p decreased and the expression of insulin-like growth factor 1 increased in spinal cord tissue after spinal cord injury. miR -146a-3p targeted regulation of insulin-like growth factor 1 in astrocytes, inhibited the proliferation and migration of astrocytes and promoted their apoptosis. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) is a chronic condition that causes permanent disability, particularly cognitive impairment resulting from glial scar formation. Minocycline treatment inhibits glial scar formation through the Ciliary Neurotropic Factor (CNTF) pathway in multiple sclerosis. We hypothesized that minocycline could also inhibit CNTF, which would play a role in the inhibition of glial scar formation in TBI. The objective was to evaluate the role of minocycline in inhibiting glial scar formation through the CNTF signaling pathway and ameliorating cognitive impairment in TBI model rats. Male Sprague Dawley rats (n = 16) were divided into 4 groups (n = 4/group). TBI through the weight drop model is performed on day 0, followed by minocycline treatment of 25 mg/kg (MNO1 group), 50 mg/kg (MNO2 group) and 100 mg/kg (MNO3 group) given for 14 days. The NOR test is performed on day 15, followed by immunofluorescence double staining on day 16. Minocycline plays a role in inhibiting glial scar formation in TBI model rats. Minocycline inhibits the formation of CNTF with an effect proportion of 66.3 %, which plays a role in inhibiting glial scar in the perilesional area in TBI model rats. Inhibition of glial scar improves cognitive function impairment in TBI model rats. Administration of minocycline improves cognitive function in TBI model rats with an effect proportion of 46.7 %. It can be concluded that minocycline inhibits glial scar through the inhibition of CNTF expression and ameliorates cognitive impairment in a rat model of TBI. [ABSTRACT FROM AUTHOR]

Objective: Spinal cord injury (SCI), one of the major disabilities concerning central nervous system injury, results in permanent tissue loss and neurological impairment. The existing therapeutic options for SCI are limited and predominantly consist of chemical compounds. In this study, we delved into the neuroprotective effects of myricetin, a natural flavonoid compound, and the underlying mechanisms, specifically in the context of SCI, utilizing an in vivo model. Previously, our investigations revealed an elevation in the phosphorylated form of Lin-11, Isl-1, and Mec-3 kinase1 (LIMK1) at chronic time points postinjury, coinciding with neuronal loss and scar formation. Our primary objective here was to assess the potential neuroprotective properties of myricetin in SCI and to ascertain if these effects were linked to LIMK inhibition, a hitherto unexamined pathway to date. Methods: Computational docking and molecular dynamics simulation studies were performed to assess myricetin's potential to bind with LIMK. Then, using a rat contusion model, SCI was induced and different molecular techniques (Western blot, Evans Blue assay, quantitative reverse transcription polymerase chain reaction and immunohistochemistry) were performed to determine the effects of myricetin. Results: Remarkably, computational docking models identified myricetin as having a better interaction profile with LIMK than standard. Subsequent to myricetin treatment, a significant downregulation in phosphorylated LIMK expression was observed at chronic time points. This reduction correlated with a notable decrease in glial and fibrotic scar formation, and enhanced neuroprotection indicating a positive outcome in vivo. Conclusion: In summary, our findings underscore myricetin's potential as a bioactive compound capable of attenuating SCI-induced injury cascades by targeting the LIMK pathway. [ABSTRACT FROM AUTHOR]

BACKGROUND: Spinal cord injury not only causes serious physical and psychological injuries to patients but also brings a heavy economic burden to society. Spinal cord injury is initially triggered by mechanical trauma, followed by secondary injuries, and as the disease progresses, a glial scar develops. OBJECTIVE: To summarize the pathological process of spinal cord injury and strategies for stem cell transplantation to repair spinal cord injury, aiming to provide the best protocol for treating spinal cord injury. METHODS: Computer search was used to search PubMed and CNKI databases. Chinese search terms were “stem cell transplantation, spinal cord injury”. English search terms were “stem cell, spinal cord injury, spinal cord, mesenchymal stem cells, neural stem cells, pathophysiology, clinical trial, primary injury, secondary injury”. The literature was screened according to the inclusion and exclusion criteria. Finally, 91 articles were included for review analysis. RESULTS AND CONCLUSION: (1) The strategies for repairing spinal cord injury through stem cell transplantation can be divided into exogenous stem cell transplantation and endogenous stem cell transplantation. The exogenous stem cell transplantation strategy for the treatment of spinal cord injury is divided into four kinds: injecting stem cells into the site of injury; transplantation of biomaterials loaded with stem cells; fetal tissue transplantation; transplantation of engineered neural network tissue or spinal cord-like tissue. (2) Compared with a single treatment method, combination therapy can more effectively promote nerve regeneration and spinal cord function recovery. (3) Microenvironment regulating the injury site, magnetic stimulation, electrical stimulation, epidural oscillating electric field stimulation, transcription factor overexpression and rehabilitation therapy can be combined with stem cell transplantation for combination therapy, thereby promoting the recovery of spinal cord function. [ABSTRACT FROM AUTHOR]

Unsuccessful axonal regeneration in transected spinal cord injury (SCI) is mainly attributed to shortage of growth factors, inhibitory glial scar, and low intrinsic regenerating capacity of severely injured neurons. Previously, we constructed an axonal growth permissive pathway in a thoracic hemisected injury by transplantation of Schwann cells overexpressing glial-cell-derived neurotrophic factor (SCs-GDNF) into the lesion gap as well as the caudal cord and proved that this novel permissive bridge promoted the regeneration of descending propriospinal tract (dPST) axons across and beyond the lesion. In the current study, we subjected rats to complete thoracic (T11) spinal cord transections and examined whether these combinatorial treatments can support dPST axons' regeneration beyond the transected injury. The results indicated that GDNF significantly improved graft–host interface by promoting integration between SCs and astrocytes, especially the migration of reactive astrocyte into SCs-GDNF territory. The glial response in the caudal graft area has been significantly attenuated. The astrocytes inside the grafted area were morphologically characterized by elongated and slim process and bipolar orientation accompanied by dramatically reduced expression of glial fibrillary acidic protein. Tremendous dPST axons have been found to regenerate across the lesion and back to the caudal spinal cord which were otherwise difficult to see in control groups. The caudal synaptic connections were formed, and regenerated axons were remyelinated. The hindlimb locomotor function has been improved. [ABSTRACT FROM AUTHOR]

This editorial titled "Restoring neural circuits after spinal cord injury" discusses the challenges and potential approaches to restoring neural circuits after spinal cord injury. It emphasizes the need for effective pharmaceutical, cellular, and tissue engineering methods to achieve functional recovery. The editorial explores various techniques, including stem cell therapies, growth factors, biomaterials, microRNAs, and traditional herbal medicine, that show promise in promoting axon regeneration and restoring neural circuitry. It also highlights the importance of rehabilitation exercises and psychological support in the formation and remodeling of functional neural circuits. However, despite progress in various research fields, there are currently no effective treatments to completely regenerate axons and rebuild neural circuits after spinal cord injury. The editorial concludes by highlighting the potential of electrical stimulation and digital bridging utilizing cortical implants in reconstructing neural pathways and restoring functional recovery in individuals with spinal cord injury. [Extracted from the article]

Combinations of different biomaterials with their own advantages as well as functionalization with other components have long been implemented in tissue engineering to improve the performance of the overall material. Biomaterials, particularly hydrogel platforms, have shown great potential for delivering compounds such as drugs, growth factors, and neurotrophic factors, as well as cells, in neural tissue engineering applications. In central the nervous system, astrocyte reactivity and glial scar formation are significant and complex challenges to tackle for neural and functional recovery. GelMA hydrogel‐based tissue constructs have been developed in this study and combined with two different formulations of phosphate glass fibers (PGFs) (with Fe3+ or Ti2+ oxide) to impose physical and mechanical cues for modulating astrocyte cell behavior. This study was also aimed at investigating the effects of lithium‐loaded GelMA‐PGFs hydrogels in alleviating astrocyte reactivity and glial scar formation offering novel perspectives for neural tissue engineering applications. The rationale behind introducing lithium is driven by its long‐proven therapeutic benefits in mental disorders, and neuroprotective and pronounced anti‐inflammatory properties. The optimal concentrations of lithium and LPS were determined in vitro on primary rat astrocytes. Furthermore, qPCR was conducted for gene expression analysis of GFAP and IL‐6 markers on primary astrocytes cultured 3D into GelMA and GelMA‐PGFs hydrogels with and without lithium and in vitro stimulated with LPS for astrocyte reactivity. The results suggest that the combination of bioactive phosphate‐based glass fibers and lithium loading into GelMA structures may impact GFAP expression and early IL‐6 expression. Furthermore, GelMA‐PGFs (Fe) constructs have shown improved performance in modulating glial scarring over GFAP regulation. [ABSTRACT FROM AUTHOR]

Metabolic disorders are risk factors for stroke exacerbating subsequent complications. Rapidly after brain injury, a glial scar forms, preventing excessive inflammation and limiting axonal regeneration. Despite the growing interest in wound healing following brain injury, the formation of a glial scar in the context of metabolic disorders is poorly documented. In this study, we used db/db mice to investigate the impact of metabolic perturbations on brain repair mechanisms, with a focus on glial scarring. First, we confirmed the development of obesity, poor glucose regulation, hyperglycaemia and liver steatosis in these mice. Then, we observed that 3 days after a 30‐min middle cerebral artery occlusion (MCAO), db/db mice had larger infarct area compared with their control counterparts. We next investigated reactive gliosis and glial scar formation in db/+ and db/db mice. We demonstrated that astrogliosis and microgliosis were exacerbated 3 days after stroke in db/db mice. Furthermore, we also showed that the synthesis of extracellular matrix (ECM) proteins (i.e., chondroitin sulphate proteoglycan, collagen IV and tenascin C) was increased in db/db mice. Consequently, we demonstrated for the first time that metabolic disorders impair reactive gliosis post‐stroke and increase ECM deposition. Given that the damage size is known to influence glial scar, this study now raises the question of the direct impact of hyperglycaemia/obesity on reactive gliosis and glia scar. It paves the way to promote the development of new therapies targeting glial scar formation to improve functional recovery after stroke in the context of metabolic disorders. [ABSTRACT FROM AUTHOR]

This study investigated the mechanism of neurotrophin-3 (NT-3) in promoting spinal cord injury repair through the transforming growth factor-beta (TGF-β) signaling pathway. A mouse model of spinal cord injury was established. Forty C57BL/6J mice were randomized into model, NT-3, NT-3 + TGF-β1 and NT-3 + LY364947 groups. The Basso–Beattie–Bresnahan (BBB) scores of the NT-3 and NT-3 + LY364947 groups were significantly higher than the model group. The BBB score of the NT-3 + TGF-β1 group was significantly lower than NT-3 group. Hematoxylin-eosin staining and transmission electron microscopy showed reduction in myelin sheath injury, more myelinated nerve fibers in the middle section of the catheter, and relatively higher density and more neatly arranged regenerated axons in the NT-3 and NT-3 + LY364947 groups compared with the model and NT-3 + TGF-β1 groups. Immunofluorescence, TUNEL and Western blot analysis showed that compared with model group, the NEUN expression increased, and the apoptosis and Col IV, LN, CSPG, tenascin-C, Sema 3 A, EphB2 and Smad2/3 protein expression decreased significantly in the NT-3 and NT-3 + LY364947 groups; the condition was reversed in the NT-3 + TGF-β1 group compared with the NT-3 group. NT-3 combined with TGF-β signaling pathway promotes astrocyte differentiation, reduces axon regeneration inhibitory molecules, apoptosis and glial scar formation, promotes axon regeneration, and improves spinal cord injury. [ABSTRACT FROM AUTHOR]

Abstract Background Spinal cord injury (SCI) is a debilitating illness in humans that causes permanent loss of movement or sensation. To treat SCI, exosomes, with their unique benefits, can circumvent limitations through direct stem cell transplantation. Therefore, we utilized Gelfoam encapsulated with exosomes derived from human umbilical cord mesenchymal stem cells (HucMSC-EX) in a rat SCI model. Methods SCI model was established through hemisection surgery in T9 spinal cord of female Sprague-Dawley rats. Exosome-loaded Gelfoam was implanted into the lesion site. An in vivo uptake assay using labeled exosomes was conducted on day 3 post-implantation. Locomotor functions and gait analyses were assessed using Basso-Beattie-Bresnahan (BBB) locomotor rating scale and DigiGait Imaging System from weeks 1 to 8. Nociceptive responses were evaluated through von Frey filament and noxious radiant heat tests. The therapeutic effects and potential mechanisms were analyzed using Western blotting and immunofluorescence staining at week 8 post-SCI. Results For the in vivo exosome uptake assay, we observed the uptake of labeled exosomes by NeuN+, Iba1+, GFAP+, and OLIG2+ cells around the injured area. Exosome treatment consistently increased the BBB score from 1 to 8 weeks compared with the Gelfoam-saline and SCI control groups. Additionally, exosome treatment significantly improved gait abnormalities including right-to-left hind paw contact area ratio, stance/stride, stride length, stride frequency, and swing duration, validating motor function recovery. Immunostaining and Western blotting revealed high expression of NF200, MBP, GAP43, synaptophysin, and PSD95 in exosome treatment group, indicating the promotion of nerve regeneration, remyelination, and synapse formation. Interestingly, exosome treatment reduced SCI-induced upregulation of GFAP and CSPG. Furthermore, levels of Bax, p75NTR, Iba1, and iNOS were reduced around the injured area, suggesting anti-inflammatory and anti-apoptotic effects. Moreover, exosome treatment alleviated SCI-induced pain behaviors and reduced pain-associated proteins (BDNF, TRPV1, and Cav3.2). Exosomal miRNA analysis revealed several promising therapeutic miRNAs. The cell culture study also confirmed the neurotrophic effect of HucMSCs-EX. Conclusion Implantation of HucMSCs-EX-encapsulated Gelfoam improves SCI-induced motor dysfunction and neuropathic pain, possibly through its capabilities in nerve regeneration, remyelination, anti-inflammation, and anti-apoptosis. Overall, exosomes could serve as a promising therapeutic alternative for SCI treatment.

Background: Spinal cord injury (SCI) is a debilitating illness in humans that causes permanent loss of movement or sensation. To treat SCI, exosomes, with their unique benefits, can circumvent limitations through direct stem cell transplantation. Therefore, we utilized Gelfoam encapsulated with exosomes derived from human umbilical cord mesenchymal stem cells (HucMSC-EX) in a rat SCI model. Methods: SCI model was established through hemisection surgery in T9 spinal cord of female Sprague-Dawley rats. Exosome-loaded Gelfoam was implanted into the lesion site. An in vivo uptake assay using labeled exosomes was conducted on day 3 post-implantation. Locomotor functions and gait analyses were assessed using Basso-Beattie-Bresnahan (BBB) locomotor rating scale and DigiGait Imaging System from weeks 1 to 8. Nociceptive responses were evaluated through von Frey filament and noxious radiant heat tests. The therapeutic effects and potential mechanisms were analyzed using Western blotting and immunofluorescence staining at week 8 post-SCI. Results: For the in vivo exosome uptake assay, we observed the uptake of labeled exosomes by NeuN+, Iba1+, GFAP+, and OLIG2+ cells around the injured area. Exosome treatment consistently increased the BBB score from 1 to 8 weeks compared with the Gelfoam-saline and SCI control groups. Additionally, exosome treatment significantly improved gait abnormalities including right-to-left hind paw contact area ratio, stance/stride, stride length, stride frequency, and swing duration, validating motor function recovery. Immunostaining and Western blotting revealed high expression of NF200, MBP, GAP43, synaptophysin, and PSD95 in exosome treatment group, indicating the promotion of nerve regeneration, remyelination, and synapse formation. Interestingly, exosome treatment reduced SCI-induced upregulation of GFAP and CSPG. Furthermore, levels of Bax, p75NTR, Iba1, and iNOS were reduced around the injured area, suggesting anti-inflammatory and anti-apoptotic effects. Moreover, exosome treatment alleviated SCI-induced pain behaviors and reduced pain-associated proteins (BDNF, TRPV1, and Cav3.2). Exosomal miRNA analysis revealed several promising therapeutic miRNAs. The cell culture study also confirmed the neurotrophic effect of HucMSCs-EX. Conclusion: Implantation of HucMSCs-EX-encapsulated Gelfoam improves SCI-induced motor dysfunction and neuropathic pain, possibly through its capabilities in nerve regeneration, remyelination, anti-inflammation, and anti-apoptosis. Overall, exosomes could serve as a promising therapeutic alternative for SCI treatment. [ABSTRACT FROM AUTHOR]

Spinal cord injury (SCI) leads to significant functional impairments below the level of the injury, and astrocytes play a crucial role in the pathophysiology of SCI. Astrocytes undergo changes and form a glial scar after SCI, which has traditionally been viewed as a barrier to axonal regeneration and functional recovery. Astrocytes activate intracellular signaling pathways, including nuclear factor κB (NF-κB) and Janus kinase-signal transducers and activators of transcription (JAK/STAT), in response to external stimuli. NF-κB and STAT3 are transcription factors that play a pivotal role in initiating gene expression related to astrogliosis. The JAK/STAT signaling pathway is essential for managing secondary damage and facilitating recovery processes post-SCI: inflammation, glial scar formation, and astrocyte survival. NF-κB activation in astrocytes leads to the production of pro-inflammatory factors by astrocytes. NF-κB and STAT3 signaling pathways are interconnected: NF-κB activation in astrocytes leads to the release of interleukin-6 (IL-6), which interacts with the IL-6 receptor and initiates STAT3 activation. By modulating astrocyte responses, these pathways offer promising avenues for enhancing recovery outcomes, illustrating the crucial need for further investigation into their mechanisms and therapeutic applications in SCI treatment. [ABSTRACT FROM AUTHOR]

Abstract Objective Traumatic brain injury (TBI) is a chronic, progressive condition associated with permanent disabilities, particularly cognitive impairments. Glial scar formation following TBI is considered a contributing factor to these persistent disabilities. Currently, limited research exists on pharmacological interventions targeting glial scar prevention that require a standard weight drop TBI model for glial scar formation. Since there is no established standard TBI model for glial scar formation, this study aims to validate and modify the height of the weight drop model to identify glial scar formation and cognitive impairments. Methods Fifteen male Sprague Dawley rats were randomly divided into sham, WD1, and WD2 groups. The weight drop model with a 10 g load was applied to the right exposed brain of the rats from a height of 5 cm (WD1) and 10 cm (WD2) using a modified Feeney’s weight drop device. Cognitive impairments were confirmed using the novel object recognition (NOR) test with ethovision software on day 15. Subsequently, the rats were decapitated on day 16, and GFAP immunohistochemical staining was performed to confirm the presence of glial scarring. Results The WD1 and WD2 groups exhibited a significant increase in glial scar formation compared to the sham group, with the WD2 group resulting in even more pronounced glial scar formation. Only the WD2 model caused statistically significant cognitive damage. The negative correlation coefficient indicates that an increase in GFAP + cells will decrease the cognitive function. Conclusion Modification of the height of the weight drop model, by dropping a weight of 10 g from a height of 10 cm (WD2 group) onto the right brain exposed of the rat has been proven to induce the formation of a glial scar and cognitive impairment.

Abstract Traumatic brain injury (TBI), particularly when moderate-to-severe and repetitive, is a strong environmental risk factor for several progressive neurodegenerative disorders. Mislocalization and deposition of transactive response DNA binding protein 43 (TDP-43) has been reported in both TBI and TBI-associated neurodegenerative diseases. It has been hypothesized that axonal pathology, an early event after TBI, may promote TDP-43 dysregulation and serve as a trigger for neurodegenerative processes. We sought to determine whether blocking the prodegenerative Sarm1 (sterile alpha and TIR motif containing 1) axon death pathway attenuates TDP-43 pathology after TBI. We subjected 111 male Sarm1 wild type, hemizygous, and knockout mice to moderate-to-severe repetitive TBI (rTBI) using a previously established injury paradigm. We conducted serial neurological assessments followed by histological analyses (NeuN, MBP, Iba-1, GFAP, pTDP-43, and AT8) at 1 month after rTBI. Genetic ablation of the Sarm1 gene attenuated the expression and mislocalization of phosphorylated TDP-43 (pTDP-43) and accumulation of pTau. In addition, Sarm1 knockout mice had significantly improved cortical neuronal and axonal integrity, functional deficits, and improved overall survival after rTBI. In contrast, removal of one Sarm1 allele delayed, but did not prevent, neurological deficits and neuroaxonal loss. Nevertheless, Sarm1 haploinsufficient mice showed significantly less microgliosis, pTDP-43 pathology, and pTau accumulation when compared to wild type mice. These data indicate that the Sarm1-mediated prodegenerative pathway contributes to pathogenesis in rTBI including the pathological accumulation of pTDP-43. This suggests that anti-Sarm1 therapeutics are a viable approach for preserving neurological function after moderate-to-severe rTBI.

BACKGROUND: Cerebral ischemic stroke is one of the main fatal and disabling diseases in the clinic, but only a few patients benefit from vascular recanalization in time, so it is urgent to explore new and effective therapy. As one of the critical pathological changes of ischemic stroke, the glial scar formed mainly by astrocytes is one major cause that hinders axonal regeneration and neurological recovery at the late stage of stroke. OBJECTIVE: To elucidate the pathological process and crucial signal regulatory mechanism of astrocytes in the formation of glial scar after ischemic stroke, as well as the potential therapeutic targets, to provide a theoretical reference for intervening astrocytic scar formation against ischemic stroke effectively, and novel strategies for promoting post-stroke rehabilitation. METHODS: The relevant articles published in CNKI, PubMed and Web of Science databases from 2010 to 2022 were retrieved. The search terms were “Ischemic stroke, Brain ischemi*, Cerebral ischemi*, Astrocyt*, Astroglia*, Glial scar, Gliosis, Astrogliosis” in Chinese and English. Finally, 78 articles were included after screening and summarized. RESULTS AND CONCLUSION: (1) Astrocytes play an important role in the maintenance of central nervous system homeostasis. After ischemic stroke, astrocytes change from a resting state to an active state. According to the different severities of cerebral ischemic injury, astrocyte activation changes dynamically from swelling and proliferation to glial scar formation. (2) Mature astrocytes are stimulated to restart the cell cycle, then proliferate and migrate to lesions, which is the main source of the glial scar. Neural stem cells in the subventricular zone, neuron-glial antigen 2 precursor cells and ependymal precursor cells in the brain parenchyma can also differentiate into astrocytes. Endothelin-1, aquaporin 4, ciliary neurotrophic factor and connexins are involved in this process. In addition, chondroitin sulfate proteoglycan, as the main component of the extracellular matrix, forms the dense glial scar barrier with proliferated astrocytes, which hinders the polarization and extension of axons. (3) Activation or inhibition of crucial signal molecules involved in astrocyte activation, proliferation, migration and pro-inflammation functions regulate the glial scar formation. Transforming growth factor beta 1/Smad and Janus kinase/signal transducer and activator of transcription 3 are classical pathways related to astrogliosis, while receptor-interacting protein 1 kinase and glycogen synthase kinase 3β are significant molecules regulating the inflammatory response. However, there are relatively few studies on Smad ubiquitination regulatory factor 2 and Interleukin-17 and their downstream signaling pathways in glial scar formation, which are worthy of further exploration. (4) Drugs targeting astrogliosis-related signaling pathways, cell proliferation regulatory proteins and inflammatory factors effectively inhibit the formation of glial scar after cerebral ischemic stroke. Among them, the role of commonly used clinical drugs such as melatonin and valproic acid in regulating glial scar formation has been verified, which makes it possible to use drugs that inhibit glial scar formation to promote the recovery of neurological function in patients with stroke. (5) Considering the protective effects of glial scar in the acute phase, how to choose the appropriate intervention chance of drugs to maintain the protective effect of the glial scar while promoting nerve regeneration and repair in the local microenvironment is the direction of future efforts. [ABSTRACT FROM AUTHOR]

Spinal cord injury (SCI) is a severe and disabling injury of the central nervous system, with complex pathological mechanisms leading to sensory and motor dysfunction. Pathological processes, such as oxidative stress, inflammatory response, apoptosis, and glial scarring are important factors that aggravate SCI. Therefore, the inhibition of these pathological processes may contribute to the treatment of SCI. Currently, the pathogenesis of SCI remains under investigation as SCI treatment has not progressed considerably. Resveratrol, a natural polyphenol with anti-inflammatory and antioxidant properties, is considered a potential therapeutic drug for various diseases and plays a beneficial role in nerve damage. Preclinical studies have confirmed that signaling pathways are closely related to the pathological processes in SCI, and resveratrol is believed to exert therapeutic effects in SCI by activating the related signaling pathways. Based on current research on the pathways of resveratrol and its role in SCI, resveratrol may be a potentially effective treatment for SCI. This review summarizes the role of resveratrol in promoting the recovery of nerve function by regulating oxidative stress, inflammation, apoptosis, and glial scar formation in SCI through various mechanisms and pathways, as well as the deficiency of resveratrol in SCI research and the current and anticipated research trends of resveratrol. In addition, this review provides a background for further studies on the molecular mechanisms of SCI and the development of potential therapeutic agents. This information could also help clinicians understand the known mechanisms of action of resveratrol and provide better treatment options for patients with SCI. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI), particularly when moderate-to-severe and repetitive, is a strong environmental risk factor for several progressive neurodegenerative disorders. Mislocalization and deposition of transactive response DNA binding protein 43 (TDP-43) has been reported in both TBI and TBI-associated neurodegenerative diseases. It has been hypothesized that axonal pathology, an early event after TBI, may promote TDP-43 dysregulation and serve as a trigger for neurodegenerative processes. We sought to determine whether blocking the prodegenerative Sarm1 (sterile alpha and TIR motif containing 1) axon death pathway attenuates TDP-43 pathology after TBI. We subjected 111 male Sarm1 wild type, hemizygous, and knockout mice to moderate-to-severe repetitive TBI (rTBI) using a previously established injury paradigm. We conducted serial neurological assessments followed by histological analyses (NeuN, MBP, Iba-1, GFAP, pTDP-43, and AT8) at 1 month after rTBI. Genetic ablation of the Sarm1 gene attenuated the expression and mislocalization of phosphorylated TDP-43 (pTDP-43) and accumulation of pTau. In addition, Sarm1 knockout mice had significantly improved cortical neuronal and axonal integrity, functional deficits, and improved overall survival after rTBI. In contrast, removal of one Sarm1 allele delayed, but did not prevent, neurological deficits and neuroaxonal loss. Nevertheless, Sarm1 haploinsufficient mice showed significantly less microgliosis, pTDP-43 pathology, and pTau accumulation when compared to wild type mice. These data indicate that the Sarm1-mediated prodegenerative pathway contributes to pathogenesis in rTBI including the pathological accumulation of pTDP-43. This suggests that anti-Sarm1 therapeutics are a viable approach for preserving neurological function after moderate-to-severe rTBI. [ABSTRACT FROM AUTHOR]

Objective: Traumatic brain injury (TBI) is a chronic, progressive condition associated with permanent disabilities, particularly cognitive impairments. Glial scar formation following TBI is considered a contributing factor to these persistent disabilities. Currently, limited research exists on pharmacological interventions targeting glial scar prevention that require a standard weight drop TBI model for glial scar formation. Since there is no established standard TBI model for glial scar formation, this study aims to validate and modify the height of the weight drop model to identify glial scar formation and cognitive impairments. Methods: Fifteen male Sprague Dawley rats were randomly divided into sham, WD1, and WD2 groups. The weight drop model with a 10 g load was applied to the right exposed brain of the rats from a height of 5 cm (WD1) and 10 cm (WD2) using a modified Feeney's weight drop device. Cognitive impairments were confirmed using the novel object recognition (NOR) test with ethovision software on day 15. Subsequently, the rats were decapitated on day 16, and GFAP immunohistochemical staining was performed to confirm the presence of glial scarring. Results: The WD1 and WD2 groups exhibited a significant increase in glial scar formation compared to the sham group, with the WD2 group resulting in even more pronounced glial scar formation. Only the WD2 model caused statistically significant cognitive damage. The negative correlation coefficient indicates that an increase in GFAP + cells will decrease the cognitive function. Conclusion: Modification of the height of the weight drop model, by dropping a weight of 10 g from a height of 10 cm (WD2 group) onto the right brain exposed of the rat has been proven to induce the formation of a glial scar and cognitive impairment. [ABSTRACT FROM AUTHOR]

The role of glial scar after intracerebral hemorrhage (ICH) remains unclear. This study aimed to investigate whether microglia-astrocyte interaction affects glial scar formation and explore the specific function of glial scar. We used a pharmacologic approach to induce microglial depletion during different ICH stages and examine how ablating microglia affects astrocytic scar formation. Spatial transcriptomics (ST) analysis was performed to explore the potential ligand-receptor pair in the modulation of microglia-astrocyte interaction and to verify the functional changes of astrocytic scars at different periods. During the early stage, sustained microglial depletion induced disorganized astrocytic scar, enhanced neutrophil infiltration, and impaired tissue repair. ST analysis indicated that microglia-derived insulin like growth factor 1 (IGF1) modulated astrocytic scar formation via mechanistic target of rapamycin (mTOR) signaling activation. Moreover, repopulating microglia (RM) more strongly activated mTOR signaling, facilitating a more protective scar formation. The combination of IGF1 and osteopontin (OPN) was necessary and sufficient for RM function, rather than IGF1 or OPN alone. At the chronic stage of ICH, the overall net effect of astrocytic scar changed from protective to destructive and delayed microglial depletion could partly reverse this. The vital insight gleaned from our data is that sustained microglial depletion may not be a reasonable treatment strategy for early-stage ICH. Inversely, early-stage IGF1/OPN treatment combined with late-stage PLX3397 treatment is a promising therapeutic strategy. This prompts us to consider the complex temporal dynamics and overall net effect of microglia and astrocytes, and develop elaborate treatment strategies at precise time points after ICH.

Seizures are important neurological complications after traumatic brain injury (TBI) and are reported for up to 50% of patients with TBI. Despite several studies, no drug strategy has been able to alter the biological events leading to epileptogenesis. The glial water channel, aquaporin-4 (AQP4), was shown to facilitate cytotoxic cell swelling in ischemia and glial scar formation after stab wound injury. In this study, we examined post-traumatic seizure susceptibility of AQP4-deficient mice (AQP4-/-) after injection of pentylenetetrazole (PTZ) 1 month after controlled cortical impact (CCI) and compared them to wild-type sham injury controls. After PTZ injection, AQP4-/- mice demonstrated dramatically shortened seizure latency (120 ± 40 vs. 300 ± 70 sec; p  0.05) and severity of seizures evoked by PTZ (grade 4.0 ± 0.5 vs. 3.81 ± 0.30; p > 0.05) compared to wild-type counterparts. Immunohistochemical analysis demonstrated decreased immunostaining of microglia to levels comparable to wild-type (12 ± 2 vs. 11 ± 4 cells/hpf, respectively; p > 0.05). Taken together, these results suggest a protective role of AQP4 in post-traumatic seizure susceptibility by promoting astrogliosis, formation of a glial scar, and preventing microgliosis.

Spinal cord injury (SCI) is a major social problem with a heavy burden on patient physiology and psychology. Glial scar formation and irreversible neuron loss are the two key points during SCI progression. During the acute phase of spinal cord injury, glial scars form, limiting the progression of inflammation. However, in the subacute or chronic phase, glial scarring inhibits axon regeneration. Following spinal cord injury, irreversible loss of neurons leads to further aggravation of spinal cord injury. Several therapies have been developed to improve either glial scar or neuron loss; however, few therapies reach the stage of clinical trials and there are no mainstream therapies for SCI. Exploring the key mechanism of SCI is crucial for finding further treatments. Glycogen synthase kinase-3 (GSK-3) is a widely expressed kinase with important physiological and pathophysiological functions in vivo. Dysfunction of the GSK-3 signaling pathway during SCI has been widely discussed for controlling neurite growth in vitro and in vivo, improving the proliferation and neuronal differentiation of endogenous neural stem cells and functional recovery from spinal cord injury. SCI can decrease the phosphorylated (p)/total (t)-GSK-3β ratio, which leads to an increase in apoptosis, whereas treatment with GSK-3 inhibitors can promote neurogenesis. In addition, several therapies for the treatment of SCI involve signaling pathways associated with GSK-3. Furthermore, signaling pathways associated with GSK-3 also participate in the pathological process of neuropathic pain that remains following SCI. The present review summarized the roles of GSK-3 signaling in SCI to aid in the understanding of GSK-3 signaling during the pathological processes of SCI and to provide evidence for the development of comprehensive treatments. [ABSTRACT FROM AUTHOR]

Traumatic brain injury usually triggers glial scar formation, neuroinflammation, and neurodegeneration. However, the molecular mechanisms underlying these pathological features are largely unknown. Using a mouse model of hippocampal stab injury (HSI), we observed that miR-331, a brain-enriched microRNA, was significantly downregulated in the early stage (0–7 days) of HSI. Intranasal administration of agomir-331, an upgraded product of miR-331 mimics, suppressed reactive gliosis and neuronal apoptosis and improved cognitive function in HSI mice. Finally, we identified IL-1β as a direct downstream target of miR-331, and agomir-331 treatment significantly reduced IL-1β levels in the hippocampus after acute injury. Our findings highlight, for the first time, agomir-331 as a pivotal neuroprotective agent for early rehabilitation of HSI. [ABSTRACT FROM AUTHOR]

BACKGROUND: Improving cerebral infarction micromeningeal circulation and inhibiting scar formation can effectively treat cerebral infarction. Therefore, it is very important to develop safe and effective drugs to improve cerebral microcirculation and scar formation. OBJECTIVE: To investigate the effects of Ratnasampil on pia meningeal microcirculation, Janus kinase 2/signal transducer and activator transcription 3 protein expression and glial scar in rats with cerebral infarction. METHODS: The 15 of 95 male Sprague-Dawley rats were randomly selected as healthy group and the remaining rats used to establish cerebral infarction models. Five rats died accidentally during the modeling process and the remaining rats were successfully modeled. Model rats were divided into model group, low-dose, medium-dose and high-dose groups of Traditional Chinese medicine and nimodipine group with 15 rats in each group. Low-, medium-and highdose groups were given 16.67, 33.34 and 66.68 g/kg Ratnasampil suspension once by intragastric administration respectively at 25 minutes before modeling. The nimodipine group was given 30 mg/kg nimodipine tablet once by intragastric administration at 25 minutes before modeling. MCIP microcirculation image processing system was used to detect cerebral blood flow velocity. Hematoxylin-eosin staining was used to observe brain histopathological morphology. Realtime fluorescence quantitative PCR was used to detect gene levels of Janus kinase 2, signal transducer and activator transcription 3, neurocan and glial fibrillary acidic protein. In situ terminal transferase labeling technique was used to measure cell apoptosis. Western blot was used to detect the protein expression of Janus kinase 2, signal transducer and activator transcription 3, phosphorylated signal transducer and activator transcription 3, neurocan and glial fibrillary acidic protein. RESULTS AND CONCLUSION: Compared with the healthy group, the nimodipine group showed reduced cerebral blood flow velocity, increased expression of Janus kinase 2, signal transducer and activator transcription 3, phosphorylated signal transducer and activator transcription 3, neurocan and glial fibrillary acidic protein, and increased neuronal apoptosis rate at different time points (P < 0.05). Compared with the nimodipine group, the low-dose group showed an increase in cerebral blood flow velocity and a reduction in neuronal apoptosis rate and the expression of Janus kinase 2, signal transducer and activator transcription 3, phosphorylated signal transducer and activator transcription 3, neurocan and glial fibrillary acidic protein (P < 0.05). Compared with the medium-dose group, the high-dose and nimodipine groups showed an increase in cerebral blood flow velocity and a reduction in neuronal apoptosis rate and the expression of Janus kinase 2, signal transducer and activator transcription 3, phosphorylated signal transducer and activator transcription 3, neurocan and glial fibrillary acidic protein (P < 0.05). Compared with the high-dose group, the nimodipine group showed decreased cerebral blood flow velocity, increased neuronal apoptosis rate and elevated expression of Janus kinase 2, signal transducer and activator transcription 3, phosphorylated signal transducer and activator transcription 3, neurocan and glial fibrillary acidic protein at different time points (P < 0.05). The histological structure of the cerebral cortex was normal in the healthy group. In the model group, the number of neurons in the cortex was decreased, some living neurons were pyknotic, and a large number of inflammatory cells were infiltrated. Compared with the model group, these changes were all improved in the low-, medium- and high-dose groups and the nimodipine group, and the high-dose group had a remarkable effect. Overall, these findings suggest that Ratnasampil may affect the formation of glial scar by inhibiting the levels of glial scar marker proteins, including neurocan and glial fibrillary acidic protein, improve the pia meningeal microcirculation, and reduce the apoptosis of brain tissue cells by inhibiting the activation of Janus kinase 2/signal transducer and activator transcription 3 pathway in rats with cerebral infarction, thus playing a role in brain protection. [ABSTRACT FROM AUTHOR]

The development of bioelectronic neural implant technologies has advanced significantly over the past 5 years, particularly in brain–machine interfaces and electronic medicine. However, neuroelectrode‐based therapies require invasive neurosurgery and can subject neural tissues to micromotion‐induced mechanical shear, leading to chronic inflammation, the formation of a peri‐electrode void and the deposition of reactive glial scar tissue. These structures act as physical barriers, hindering electrical signal propagation and reducing neural implant functionality. Although well documented, the mechanisms behind the initiation and progression of these processes are poorly understood. Herein, in silico analysis of micromotion‐induced peri‐electrode void progression and gliosis is described. Subsequently, ventral mesencephalic cells exposed to milliscale fluid shear stress in vitro exhibited increased expression of gliosis‐associated proteins and overexpression of mechanosensitive ion channels PIEZO1 (piezo‐type mechanosensitive ion channel component 1) and TRPA1 (transient receptor potential ankyrin 1), effects further confirmed in vivo in a rat model of peri‐electrode gliosis. Furthermore, in vitro analysis indicates that chemical inhibition/activation of PIEZO1 affects fluid shear stress mediated astrocyte reactivity in a mitochondrial‐dependent manner. Together, the results suggest that mechanosensitive ion channels play a major role in the development of a peri‐electrode void and micromotion‐induced glial scarring at the peri‐electrode region. [ABSTRACT FROM AUTHOR]

Spinal cord injury is one of the leading causes of morbidity and mortality among young adults in many countries including the United States. Difficulty in the regeneration of neurons is one of the main obstacles that leave spinal cord injury patients with permanent paralysis in most instances. Recent research has found that preventing acute and subacute secondary cellular damages to the neurons and supporting glial cells can help slow the progression of spinal cord injury pathogenesis, in part by reactivating endogenous regenerative proteins including Noggin that are normally present during spinal cord development. Noggin is a complex protein and natural inhibitor of the multifunctional bone morphogenetic proteins, and its expression is high during spinal cord development and after induction of spinal cord injury. In this review article, we first discuss the change in expression of Noggin during pathogenesis in spinal cord injury. Second, we discuss the current research knowledge about the neuroprotective role of Noggin in preclinical models of spinal cord injury. Lastly, we explain the gap in the knowledge for the use of Noggin in the treatment of spinal cord injury. The results from extensive in vitro and in vivo research have revealed that the therapeutic efficacy of Noggin treatment remains debatable due to its neuroprotective effects observed only in early phases of spinal cord injury but little to no effect on altering pathogenesis and functional recovery observed in the chronic phase of spinal cord injury. Furthermore, clinical information regarding the role of Noggin in the alleviation of progression of pathogenesis, its therapeutic efficacy, bioavailability, and safety in human spinal cord injury is still lacking and therefore needs further investigation.

After spinal cord injury (SCI), a fibroblast- and microglia-mediated fibrotic scar is formed in the lesion core, and a glial scar is formed around the fibrotic scar as a result of the activation and proliferation of astrocytes. Simultaneously, a large number of neurons are lost in the injured area. Regulating the dense glial scar and replenishing neurons in the injured area are essential for SCI repair. Polypyrimidine tract binding protein (PTB), known as an RNA-binding protein, plays a key role in neurogenesis. Here, we utilized short hairpin RNAs (shRNAs) and antisense oligonucleotides (ASOs) to knock down PTB expression. We found that reactive spinal astrocytes from mice were directly reprogrammed into motoneuron-like cells by PTB downregulation in vitro. In a mouse model of compression-induced SCI, adeno-associated viral shRNA-mediated PTB knockdown replenished motoneuron-like cells around the injured area. Basso Mouse Scale scores and forced swim, inclined plate, cold allodynia, and hot plate tests showed that PTB knockdown promoted motor function recovery in mice but did not improve sensory perception after SCI. Furthermore, ASO-mediated PTB knockdown improved motor function restoration by not only replenishing motoneuron-like cells around the injured area but also by modestly reducing the density of the glial scar without disrupting its overall structure. Together, these findings suggest that PTB knockdown may be a promising therapeutic strategy to promote motor function recovery during spinal cord repair.

Vimentin is a major type III intermediate filament protein that plays important roles in several basic cellular functions including cell migration, proliferation, and division. Although vimentin is a cytoplasmic protein, it also exists in the extracellular matrix and at the cell surface. Previous studies have shown that vimentin may exert multiple physiological effects in different nervous system injuries and diseases. For example, the studies of vimentin in spinal cord injury and stroke mainly focus on the formation of reactive astrocytes. Reduced glial scar, increased axonal regeneration, and improved motor function have been noted after spinal cord injury in vimentin and glial fibrillary acidic protein knockout (GFAP–/–VIM–/–) mice. However, attenuated glial scar formation in post-stroke in GFAP–/– VIM–/– mice resulted in abnormal neuronal network restoration and worse neurological recovery. These opposite results have been attributed to the multiple roles of glial scar in different temporal and spatial conditions. In addition, extracellular vimentin may be a neurotrophic factor that promotes axonal extension by interaction with the insulin-like growth factor 1 receptor. In the pathogenesis of bacterial meningitis, cell surface vimentin is a meningitis facilitator, acting as a receptor of multiple pathogenic bacteria, including E. coli K1, Listeria monocytogenes, and group B streptococcus. Compared with wild type mice, VIM–/– mice are less susceptible to bacterial infection and exhibit a reduced inflammatory response, suggesting that vimentin is necessary to induce the pathogenesis of meningitis. Recently published literature showed that vimentin serves as a double-edged sword in the nervous system, regulating axonal regrowth, myelination, apoptosis, and neuroinflammation. This review aims to provide an overview of vimentin in spinal cord injury, stroke, bacterial meningitis, gliomas, and peripheral nerve injury and to discuss the potential therapeutic methods involving vimentin manipulation in improving axonal regeneration, alleviating infection, inhibiting brain tumor progression, and enhancing nerve myelination.

The inflammatory response plays an important role in neuroprotection and regeneration after ischemic insult. The use of non-steroidal anti-inflammatory drugs has been a matter of debate as to whether they have beneficial or detrimental effects. In this context, the effects of the anti-inflammatory agent meloxicam have been scarcely documented after stroke, but its ability to inhibit both cyclooxygenase isoforms (1 and 2) could be a promising strategy to modulate post-ischemic inflammation. This study analyzed the effect of meloxicam in a transient focal cerebral ischemia model in rats, measuring its neuroprotective effect after 48 hours and 7 days of reperfusion and the effects of the treatment on the glial scar and regenerative events such as the generation of new progenitors in the subventricular zone and axonal sprouting at the edge of the damaged area. We show that meloxicam’s neuroprotective effects remained after 7 days of reperfusion even if its administration was restricted to the two first days after ischemia. Moreover, meloxicam treatment modulated glial scar reactivity, which matched with an increase in axonal sprouting. However, this treatment decreased the formation of neuronal progenitor cells. This study discusses the dual role of anti-inflammatory treatments after stroke and encourages the careful analysis of both the neuroprotective and the regenerative effects in preclinical studies.

The role of glial scar after intracerebral hemorrhage (ICH) remains unclear. This study aimed to investigate whether microglia-astrocyte interaction affects glial scar formation and explore the specific function of glial scar. We used a pharmacologic approach to induce microglial depletion during different ICH stages and examine how ablating microglia affects astrocytic scar formation. Spatial transcriptomics (ST) analysis was performed to explore the potential ligand-receptor pair in the modulation of microglia-astrocyte interaction and to verify the functional changes of astrocytic scars at different periods. During the early stage, sustained microglial depletion induced disorganized astrocytic scar, enhanced neutrophil infiltration, and impaired tissue repair. ST analysis indicated that microglia-derived insulin like growth factor 1 (IGF1) modulated astrocytic scar formation via mechanistic target of rapamycin (mTOR) signaling activation. Moreover, repopulating microglia (RM) more strongly activated mTOR signaling, facilitating a more protective scar formation. The combination of IGF1 and osteopontin (OPN) was necessary and sufficient for RM function, rather than IGF1 or OPN alone. At the chronic stage of ICH, the overall net effect of astrocytic scar changed from protective to destructive and delayed microglial depletion could partly reverse this. The vital insight gleaned from our data is that sustained microglial depletion may not be a reasonable treatment strategy for early-stage ICH. Inversely, early-stage IGF1/OPN treatment combined with late-stage PLX3397 treatment is a promising therapeutic strategy. This prompts us to consider the complex temporal dynamics and overall net effect of microglia and astrocytes, and develop elaborate treatment strategies at precise time points after ICH. [Display omitted] • Sustained microglial depletion induce disorganized astrocytic scar after ICH. • Microglia-derived IGF1 modulates glial scar formation via mTOR signaling activation. • Repopulating microglia facilitate tissue repair via the combination of IGF1 and OPN. • The glial scar transforms from protection into destruction at chronic stage of ICH. • The elaborate treatment strategies at precise time points should be implemented after ICH. [ABSTRACT FROM AUTHOR]

Spinal cord injury (SCI) is a condition that affects between 8.8 and 246 people in a million and, unlike many other neurological disorders, it affects mostly young people, causing deficits in sensory, motor, and autonomic functions. Promoting the regrowth of axons is one of the most important goals for the neurological recovery of patients after SCI, but it is also one of the most challenging goals. A key event after SCI is the formation of a glial scar around the lesion core, mainly comprised of astrocytes, NG2+-glia, and microglia. Traditionally, the glial scar has been regarded as detrimental to recovery because it may act as a physical barrier to axon regrowth and release various inhibitory factors. However, more and more evidence now suggests that the glial scar is beneficial for the surrounding spared tissue after SCI. Here, we review experimental studies that used genetic and pharmacological approaches to ablate specific populations of glial cells in rodent models of SCI in order to understand their functional role. The studies showed that ablation of either astrocytes, NG2+-glia, or microglia might result in disorganization of the glial scar, increased inflammation, extended tissue degeneration, and impaired recovery after SCI. Hence, glial cells and glial scars appear as important beneficial players after SCI. [ABSTRACT FROM AUTHOR]