Tlr4 Deletion Modulates Cytokine and Extracellular Matrix Expression in Chronic Spinal Cord Injury, Leading to Improved Secondary Damage and Functional Recovery.

Toll-like receptors (TLRs) play an important role in the innate immune response after CNS injury. Although TLR4 is one of the best characterized, its role in chronic stages after spinal cord injury (SCI) is not well understood. We examined the role of TLR4 signaling in injury-induced responses at 1 d, 7 d, and 8 weeks after spinal cord contusion injury in adult female TLR4 null and wild-type mice. Analyses include secondary damage, a range of transcriptome and protein analyses of inflammatory, cell death, and extracellular matrix (ECM) molecules, as well as immune cell infiltration and changes in axonal sprouting and locomotor recovery. Lack of TLR4 signaling results in reduced neuronal and myelin loss, reduced activation of NFκB, and decreased expression of inflammatory cytokines and necroptotic cell death pathway at a late time point (8 weeks) after injury. TLR4 null mice also showed reduction of scar-related ECM molecules at 8 weeks after SCI, accompanied by increase in ECM molecules associated with perineuronal nets, increased sprouting of serotonergic fibers, and improved locomotor recovery. These findings reveal novel effects of TLR4 signaling in chronic SCI. We show that TLR4 influences inflammation, cell death, and ECM deposition at late-stage post-injury when secondary injury processes are normally considered to be over. This highlights the potential for late-stage targeting of TLR4 as a potential therapy for chronic SCI.

Early-Stage Application of Agomir-137 Promotes Locomotor Recovery in a Mouse Model of Motor Cortex Injury.

Traumatic brain injury (TBI) is a significant risk factor for neurodegenerative disorders, and patients often experience varying degrees of motor impairment. MiR-137, a broadly conserved and brain-enriched miRNA, is a key regulator in neural development and in various neurological diseases. Following TBI, the expression of miR-137 is dramatically downregulated. However, whether miR-137 is a therapeutic target for TBI still remains unknown. Here, for the first time, we demonstrate that intranasal administration of miR-137 agomir (a mimic) in the early stage (0-7 days) of TBI effectively inhibits glial scar formation and improves neuronal survival, while early-stage administration of miR-137 antagomir (an inhibitor) deteriorates motor impairment. This study elucidates the therapeutic potential of miR-137 mimics in improving locomotor recovery following motor cortex injury.

Perforin affects regeneration in a mouse spinal cord injury model.

MATERIALS AND METHODS: Locomotor outcomes in perforin-deficient (Pfp-/-) mice and wild-type littermate controls were measured after severe compression injury of the lower thoracic spinal cord up to six weeks after injury. RESULTS: According to both the Basso mouse scale score and single frame motion analysis, motor recovery of Pfp-/- mice was similar to wild-type controls. Interestingly, immunohistochemical analysis of cell types at six weeks after injury showed enhanced cholinergic reinnervation of spinal motor neurons caudal to the lesion site and neurofilament-positive structures at the injury site in Pfp-/- mice, whereas numbers of microglia/macrophages and astrocytes were decreased compared with controls. CONCLUSIONS: We conclude that, although, loss of perforin does not change the locomotor outcome after injury, it beneficially affects diverse cellular features, such as number of axons, cholinergic synapses, astrocytes and microglia/macrophages at or caudal to the lesion site. Perforin's ability to contribute to Rag2's influence on locomotion was observed in mice doubly deficient in perforin and Rag2 which recovered better than Rag2-/- or Pfp-/- mice, suggesting that natural killer cells can cooperate with T- and B-cells in spinal cord injury.

Anti-Inflammatory Nanotherapeutics by Targeting Matrix Metalloproteinases for Immunotherapy of Spinal Cord Injury.

Neuroinflammation is critically involved in the repair of spinal cord injury (SCI), and macrophages associated with inflammation propel the degeneration or recovery in the pathological process. Currently, efforts have been focused on obtaining efficient therapeutic anti-inflammatory drugs to treat SCI. However, these drugs are still unable to penetrate the blood spinal cord barrier and lack the ability to target lesion areas, resulting in unsatisfactory clinical efficacy. Herein, a polymer-based nanodrug delivery system is constructed to enhance the targeting ability. Because of increased expression of matrix metalloproteinases (MMPs) in injured site after SCI, MMP-responsive molecule, activated cell-penetrating peptides (ACPP), is introduced into the biocompatible polymer PLGA-PEI-mPEG (PPP) to endow the nanoparticles with the ability for diseased tissue-targeting. Meanwhile, etanercept (ET), a clinical anti-inflammation treatment medicine, is loaded on the polymer to regulate the polarization of macrophages, and promote locomotor recovery. The results show that PPP-ACPP nanoparticles possess satisfactory lesion targeting effects. Through inhibited consequential production of proinflammation cytokines and promoted anti-inflammation cytokines, ET@PPP-ACPP could decrease the percentage of M1 macrophages and increase M2 macrophages. As expected, ET@PPP-ACPP accumulates in lesion area and achieves effective treatment of SCI; this confirmed the potential of nano-drug loading systems in SCI immunotherapy.

Time-to-treatment window and cross-sex potential of ß2-adrenergic receptor-induced mitochondrial biogenesis-mediated recovery after spinal cord injury.

Mitochondrial dysfunction is a well-characterized consequence of spinal cord injury (SCI). We previously reported that treatment with the FDA-approved ß2-adrenergic receptor agonist formoterol beginning 8 h post-SCI induces mitochondrial biogenesis (MB) and improves body composition and locomotor recovery in female mice. To determine the time-to-treatment window of formoterol, female mice were subjected to 80 kdyn contusion SCI and daily administration of vehicle or formoterol (0.3 mg/kg) beginning 24 h after injury. This delayed treatment paradigm improved body composition in female mice by 21 DPI, returning body weight to pre-surgery weight and restoring gastrocnemius mass to sham levels; however, there was no effect on locomotor recovery, as measured by the Basso-Mouse Scale (BMS), or lesion volume. To assess the cross-sex potential of formoterol, injured male mice were treated with vehicle or formoterol (0.3 or 1.0 mg/kg) beginning 8 h after SCI. Formoterol also improved body composition post-SCI in male mice, restoring body weight and muscle mass regardless of dose. Interestingly, however, improved BMS scores and decreased lesion volume was observed only in male mice treated with 0.3 mg/kg. Additionally, 0.3 mg/kg formoterol induced MB in the gastrocnemius and injured spinal cord, as evidenced by increased MB protein expression and mitochondrial number. These data indicate that formoterol treatment improves recovery post-SCI in both male and female mice in a dose- and initiation time-dependent manner. Furthermore, formoterol-induced functional recovery post-SCI is not directly associated with peripheral effects, such as muscle mass and body weight.

CRID3, a blocker of apoptosis associated speck like protein containing a card, ameliorates murine spinal cord injury by improving local immune microenvironment.

BACKGROUND: After spinal cord injury (SCI), destructive immune cell subsets are dominant in the local microenvironment, which are the important mechanism of injury. Studies have shown that inflammasomes play an important role in the inflammation following SCI, and apoptosis-associated speck-like protein containing a card (ASC) is the adaptor protein shared by inflammasomes. Therefore, we speculated that inhibiting ASC may improve the local microenvironment of injured spinal cord. Here, CRID3, a blocker of ASC oligomerization, was used to study its effect on the local microenvironment and the possible role in neuroprotection following SCI. METHODS: Murine SCI model was created using an Infinite Horizon impactor at T9 vertebral level with a force of 50 kdynes and CRID3 (50 mg/kg) was intraperitoneally injected following injury. ASC and its downstream molecules in inflammasome signaling pathway were measured by western blot. The immune cell subsets were detected by immunohistofluorescence (IHF) and flow cytometry (FCM). The spinal cord fibrosis area, neuron survival, myelin preservation, and functional recovery were assessed. RESULTS: Following SCI, CRID3 administration inhibited inflammasome-related ASC and caspase-1, IL-1ß, and IL-18 activation, which consequently suppressed M1 microglia, Th1 and Th1Th17 differentiation, and increased M2 microglia and Th2 differentiation. Accordingly, the improved histology and behavior have also been found. CONCLUSIONS: CRID3 may ameliorate murine SCI by inhibiting inflammasome activation, reducing proinflammatory factor production, restoring immune cell subset balance, and improving local immune microenvironment, and early administration may be a promising therapeutic strategy for SCI.

Experimental evolution of response to anoxia in Drosophilamelanogaster: recovery of locomotion following CO2 or N2 exposure.

Many insects enter coma upon exposure to anoxia, a feature routinely exploited by experimentalists to handle them. But the genetic and physiological bases of anoxic coma induction and recovery are only partially understood, as are the long-term consequences for the animal's performance. We examined three populations of Drosophila melanogaster (designated B) that have been inadvertently under selection for rapid recovery from CO2 exposure for nearly 40 years (around 1000 generations) resulting from routine maintenance practices. We contrasted CO2 and N2 (presumed a less reactive gas) knockdown and recovery times of these B flies with six populations of common ancestry (A and C populations) that were not exposed to CO2 over the same period. We found that B populations showed faster and more consistent locomotor recovery than A or C populations after CO2 knockdown, a result also observed with N2 knockdown. A and C populations showed much higher variance in recovery time after CO2 exposure than after N2 exposure, suggesting gas-specific effects on pathways associated with locomotor recovery. Although these selection treatments result in considerable variation in life history attributes and body size, with the characteristic intermediacy of B populations, their superiority in resistance to gas exposure and locomotor recovery suggests that this is a direct consequence of prior repeated exposure to anoxia, broadly, and CO2, specifically. Hence we describe a powerful new evolutionary model for the genetic and physiological investigation of anoxic coma in insects.

Induced Pluripotent Stem Cell Transplantation Improves Locomotor Recovery in Rat Models of Spinal Cord Injury: a Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND/AIMS: Spinal cord injury (SCI) has long been a subject of great interest in a wide range of scientific fields. Several attempts have been made to demonstrate motor function improvement in rats with SCI after transplantation of induced pluripotent stem cells (iPSC). This systematic review and meta-analysis was designed to summarize the effects of iPSC on locomotor recovery in rat models of SCI. METHODS: We searched the publications in the PubMed, Medline, Science Citation Index, Cochrane Library, CNKI, and Wan-fang databases and the China Biology Medicine disc. Results were analyzed by Review Manager 5.3.0. The quality of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. RESULTS: Six randomized controlled preclinical trials covering eight comparisons and including 212 rats were selected. The subgroup analyses were based on the following items: different SCI models, cell counts, iPSC sources, iPSC differentiations and transplantation methods. The pooled results indicated that iPSC transplantation significantly improved locomotor recovery of rats after SCI by sustaining beneficial effects, especially in the subgroups of contusion, moderate cell counts (5×105), source of human fetal lung fibroblasts, iPSC-neural precursors and intraspinal injection. CONCLUSION: Our meta-analysis of the effects of iPSC transplantation on locomotor function in SCI models is, to our knowledge, the first meta-analysis in this field. We conclude that iPSC transplantation improves locomotor recovery in rats with SCI, implicating this strategy as an effective therapy. However, more studies are required to validate our conclusions.

Impact of neural cell adhesion molecule deletion on regeneration after mouse spinal cord injury.

The neural cell adhesion molecule (NCAM) plays important functional roles in development of the nervous system. We investigated the influence of a constitutive ablation of NCAM on the outcome of spinal cord injury. Transgenic mice lacking NCAM (NCAM-/-) were subjected to severe compression injury of the lower thoracic spinal cord using wild-type (NCAM+/+) littermates as controls. According to the single-frame motion analysis, the NCAM-/- mice showed reduced locomotor recovery in comparison to control mice at 3 and 6 weeks after injury, indicating an overall positive impact of NCAM on recovery after injury. Also the Basso Mouse Scale score was lower in NCAM-/- mice at 3 weeks after injury, whereas at 6 weeks after injury the difference between genotypes was not statistically significant. Worse locomotor function was associated with decreased monoaminergic and cholinergic innervation of the spinal cord caudal to the injury site and decreased axonal regrowth/sprouting at the site of injury. Astrocytic scar formation at the injury site, as assessed by immunohistology for glial fibrillary acidic protein at and around the lesion site was increased in NCAM-/- compared with NCAM+/+ mice. Migration of cultured monolayer astrocytes from NCAM-/- mice was reduced as assayed by scratch wounding. Numbers of Iba-1 immunopositive microglia were not different between genotypes. We conclude that constitutive NCAM deletion in young adult mice reduces recovery after spinal cord injury, validating the hypothesized beneficial role of this molecule in recovery after injury.

Interleukin-25 is detrimental for recovery after spinal cord injury in mice.

BACKGROUND: The cytokine, interleukin (IL)-25, is thought to be critically involved in inducing a type 2 immune response which may contribute to regeneration after central nervous system (CNS) trauma. We investigated whether applying recombinant IL-25, locally or systemically, in a mouse model of spinal cord injury (SCI) improves functional and histological recovery. FINDINGS: Repeated systemic administration of IL-25 did not influence functional recovery following SCI. In contrast, a single local administration of IL-25 significantly worsened locomotor outcome, which was evident from a decreased Basso mouse scale (BMS) score compared with phosphate-buffered saline (PBS)-treated controls. This was accompanied by a significant increase in lesion size, demyelination, and T helper cell infiltration. CONCLUSIONS: These data show for the first time that IL-25 is either ineffective when applied systemically or detrimental to spinal cord recovery when applied locally. Our findings question the potential neuroprotective role of IL-25 following CNS trauma.

Adoptive transfer of M2 macrophages promotes locomotor recovery in adult rats after spinal cord injury.

Classically activated pro-inflammatory (M1) and alternatively activated anti-inflammatory (M2) macrophages populate the local microenvironment after spinal cord injury (SCI). The former type is neurotoxic while the latter has positive effects on neuroregeneration and is less toxic. In addition, while the M1 macrophage response is rapidly induced and sustained, M2 induction is transient. A promising strategy for the repair of SCI is to increase the fraction of M2 cells and prolong their residence time. This study investigated the effect of M2 macrophages induced from bone marrow-derived macrophages on the local microenvironment and their possible role in neuroprotection after SCI. M2 macrophages produced anti-inflammatory cytokines such as interleukin (IL)-10 and transforming growth factor ß and infiltrated into the injured spinal cord, stimulated M2 and helper T (Th)2 cells, and produced high levels of IL-10 and -13 at the site of injury. M2 cell transfer decreased spinal cord lesion volume and resulted in increased myelination of axons and preservation of neurons. This was accompanied by significant locomotor improvement as revealed by Basso, Beattie and Bresnahan locomotor rating scale, grid walk and footprint analyses. These results indicate that M2 adoptive transfer has beneficial effects for the injured spinal cord, in which the increased number of M2 macrophages causes a shift in the immunological response from Th1- to Th2-dominated through the production of anti-inflammatory cytokines, which in turn induces the polarization of local microglia and/or macrophages to the M2 subtype, and creates a local microenvironment that is conducive to the rescue of residual myelin and neurons and preservation of neuronal function.

Mesenchymal stem cells improve locomotor recovery in traumatic spinal cord injury: systematic review with meta-analyses of rat models.

Traumatic spinal cord injury (SCI) is a devastating event with huge personal and societal costs. A limited number of treatments exist to ameliorate the progressive secondary damage that rapidly follows the primary mechanical impact. Mesenchymal stem or stromal cells (MSCs) have anti-inflammatory and neuroprotective effects and may thus reduce secondary damage after administration. We performed a systematic review with quantitative syntheses to assess the evidence of MSCs versus controls for locomotor recovery in rat models of traumatic SCI, and identified 83 eligible controlled studies comprising a total of 1,568 rats. Between-study heterogeneity was large. Fifty-three studies (64%) were reported as randomised, but only four reported adequate methodologies for randomisation. Forty-eight studies (58%) reported the use of a blinded outcome assessment. A random-effects meta-analysis yielded a difference in behavioural Basso-Beattie-Bresnahan (BBB) locomotor score means of 3.9 (95% confidence interval [CI] 3.2 to 4.7; P<0.001) in favour of MSCs. Trial sequential analysis confirmed the findings of the meta-analyses with the upper monitoring boundary for benefit being crossed by the cumulative Z-curve before reaching the diversity-adjusted required information size. Only time from intervention to last follow-up remained statistically significant after adjustment using multivariate random-effects meta-regression modelling. Lack of other demonstrable explanatory variables could be due to insufficient meta-analytic study power. MSCs would seem to demonstrate a substantial beneficial effect on locomotor recovery in a widely-used animal model of traumatic SCI. However, the animal results should be interpreted with caution concerning the internal and external validity of the studies in relation to the design of future clinical trials.

Potential Roles of Specific Subclasses of Premotor Interneurons in Spinal Cord Function Recovery after Traumatic Spinal Cord Injury in Adults.

The differential expression of transcription factors during embryonic development has been selected as the main feature to define the specific subclasses of spinal interneurons. However, recent studies based on single-cell RNA sequencing and transcriptomic experiments suggest that this approach might not be appropriate in the adult spinal cord, where interneurons show overlapping expression profiles, especially in the ventral region. This constitutes a major challenge for the identification and direct targeting of specific populations that could be involved in locomotor recovery after a traumatic spinal cord injury in adults. Current experimental therapies, including electrical stimulation, training, pharmacological treatments, or cell implantation, that have resulted in improvements in locomotor behavior rely on the modulation of the activity and connectivity of interneurons located in the surroundings of the lesion core for the formation of detour circuits. However, very few publications clarify the specific identity of these cells. In this work, we review the studies where premotor interneurons were able to create new intraspinal circuits after different kinds of traumatic spinal cord injury, highlighting the difficulties encountered by researchers, to classify these populations.

Spinal cord injury-induced metabolic impairment and steatohepatitis develops in non-obese rats and is exacerbated by premorbid obesity.

Impaired sensorimotor functions are prominent complications of spinal cord injury (SCI). A clinically important but less obvious consequence is development of metabolic syndrome (MetS), including increased adiposity, hyperglycemia/insulin resistance, and hyperlipidemia. MetS predisposes SCI individuals to earlier and more severe diabetes and cardiovascular disease compared to the general population, which trigger life-threatening complications (e.g., stroke, myocardial infarcts). Although each comorbidity is known to be a risk factor for diabetes and other health problems in obese individuals, their relative contribution or perceived importance in propagating systemic pathology after SCI has received less attention. This could be explained by an incomplete understanding of MetS promoted by SCI compared with that from the canonical trigger diet-induced obesity (DIO). Thus, here we compared metabolic-related outcomes after SCI in lean rats to those of uninjured rats with DIO. Surprisingly, SCI-induced MetS features were equal to or greater than those in obese uninjured rats, including insulin resistance, endotoxemia, hyperlipidemia, liver inflammation and steatosis. Considering the endemic nature of obesity, we also evaluated the effect of premorbid obesity in rats receiving SCI; the combination of DIO + SCI exacerbated MetS and liver pathology compared to either alone, suggesting that obese individuals that sustain a SCI are especially vulnerable to metabolic dysfunction. Notably, premorbid obesity also exacerbated intraspinal lesion pathology and worsened locomotor recovery after SCI. Overall, these results highlight that normal metabolic function requires intact spinal circuitry and that SCI is not just a sensory-motor disorder, but also has significant metabolic consequences.

Restoring endoplasmic reticulum homeostasis improves functional recovery after spinal cord injury.

The endoplasmic reticulum (ER) stress response (ERSR) is activated to maintain protein homeostasis or induce apoptosis in the ER in response to distinct cellular insults including hypoxia, inflammation, and oxidative damage. Recently, we showed ERSR activation in a mouse model of a contusive spinal cord injury (SCI) and an improved hindlimb locomotor function following SCI when the pro-apoptotic arm of ERSR was genetically inhibited. The objective of the current study was to explore if the pharmacological enhancement of the homeostatic arm of the ERSR pathway can improve the functional outcome after SCI. Salubrinal enhances the homeostatic arm of the ERSR by increasing phosphorylation of eIF2α. Salubrinal significantly enhanced the levels of phosphorylated eIF2α protein and modulated the downstream ERSR effectors assessed at the lesion epicenter 6h post-SCI. Hindlimb locomotion showed significant improvement in animals treated with salubrinal. Treadmill-based-gait assessment showed a significant increase in maximum speed of coordinated walking and a decrease in rear stance time and stride length in salubrinal-treated animals. This improved functional recovery corresponded with increased white matter sparing and decreased oligodendrocyte apoptosis. In addition, salubrinal protected cultured mouse oligodendrocyte progenitor cells against the ER stress-inducing toxin tunicamycin. These data suggest that boosting the homeostatic arm of the ERSR reduces oligodendrocyte loss after traumatic SCI and support the contention that pharmacological targeting of the ERSR after CNS trauma is a therapeutically viable approach.

Chemogenetic Attenuation of Acute Nociceptive Signaling Enhances Functional Outcomes Following Spinal Cord Injury.

Identifying novel therapeutic approaches to promote recovery of neurological functions following spinal cord injury (SCI) remains a great unmet need. Nociceptive signaling in the acute phase of SCI has been shown to inhibit recovery of locomotor function and promote the development of chronic neuropathic pain. We therefore hypothesized that inhibition of nociceptive signaling in the acute phase of SCI might improve long-term functional outcomes in the chronic phase of injury. To test this hypothesis, we took advantage of a selective strategy utilizing AAV6 to deliver inhibitory (hM4Di) Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) to nociceptors of the L4-L6 dorsal root ganglia to evaluate the effects of transient nociceptor silencing on long-term sensory and motor functional outcomes in a rat thoracic contusion SCI model. Following hM4Di-mediated nociceptor inhibition from 0-14 days post-SCI, we conducted behavioral assessments until 70 days post-SCI, then performed histological assessments of lesion severity and axon plasticity. Our results show highly selective expression of hM4Di within small diameter nociceptors including calcitonin gene-related peptide (CGRP)+ and IB4-binding neurons. Expression of hM4Di in less than 25% of nociceptors was sufficient to increase hindlimb thermal withdrawal latency in naïve rats. Compared with subjects who received AAV-yellow fluorescent protein (YFP; control), subjects who received AAV-hM4Di exhibited attenuated thermal hyperalgesia, greater coordination, and improved hindlimb locomotor function. However, treatment did not impact the development of cold allodynia or mechanical hyperalgesia. Histological assessments of spinal cord tissue suggested trends toward reduced lesion volume, increased neuronal sparing and increased CGRP+ axon sprouting in hM4Di-treated animals. Together, these findings suggest that nociceptor silencing early after SCI may promote beneficial plasticity in the acute phase of injury that can impact long-term functional outcomes, and support previous work highlighting primary nociceptors as possible therapeutic targets for pain management after SCI.

Unintentional Effects from Housing Enhancement Resulting in Functional Improvement in Spinal Cord-Injured Mice.

It is well established that both positive and negative housing conditions of laboratory animals can affect behavioral, biochemical, and physiological responses. Housing enhancements have been shown to have beneficial effects on locomotor outcomes in rodents with spinal cord injury (SCI). Subsequent to an unplanned housing enhancement of the addition of a balcony to home cages by animal care personnel at a research facility, a retrospective analysis of multiple SCI studies was performed to determine whether outcomes differed before (four studies, N = 28) and after (four studies, N = 23) the addition of the balcony. Locomotor and morphological differences were compared after a mild-moderate T9 spinal cord contusion injury in wild-type mice. Post-injury assessments of locomotor function for 6 weeks included Basso Mouse Scale (BMS) and treadmill kinematic assessments (week 6). Balcony-housed mice showed greater improvements not only in basic locomotor functions (weight-supported stepping, balance) compared to those in standard housing, but also surpassed mice in standard housing without the balcony in higher-order locomotor recovery outcomes, including BMS late-stage recovery measures (paw, tail, and trunk indices). Additionally, balcony-housed mice had overall higher BMS scores, consistently attained more BMS subscores, and had better treadmill track width and stride length compared to those with no balcony. The housing enhancement of a balcony led to unforeseen consequences and unexpected higher recovery outcomes compared to mice in standard housing. This retrospective study highlights the importance of housing conditions in the key outcomes of locomotor recovery after incomplete contusive SCIs in mice.

Sitagliptin attenuates neuronal apoptosis via inhibiting the endoplasmic reticulum stress after acute spinal cord injury.

Regulation of endoplasmic reticulum stress (ER) stress-induced apoptosis and nerve regeneration is a hopeful way for acute spinal cord injury (SCI). Sitagliptin (Sita) is one of dipeptidyl peptidase-4 (DPP-4) inhibitor, which is beneficial neurons damaged diseases. However, its protective mechanisms of avoiding nerve injury remain unclear. In this study, we further investigated the mechanism of the anti-apoptotic and neuroprotective effects of Sita in promoting locomotor recovery from SCI. In vivo results showed that Sita treatment reduced neural apoptosis caused by SCI. Moreover, Sita effectively attenuated the ER tress and associated apoptosis in rats with SCI. A striking feature was the occurrence of nerve fiber regeneration at the lesion site, which eventually led to significant locomotion recovery. In vitro results showed that the PC12 cell injury model induced by Thapsigargin (TG) also showed similar neuroprotective effects. Overall, sitagliptin showed potent neuroprotective effects by targeting the ER stress-induced apoptosis both in vivo and vitro, thus facilitating the regeneration of the injured spinal cord.

The Limited Effects of Estradiol Administration Immediately after Spinal Cord Injury.

OBJECTIVE: We aimed to investigate estradiol (E2) as a therapeutic drug for spinal cord injury (SCI) and elucidate the disagreement in the field about the use of this hormone after an injury. METHODS: Eleven animals underwent surgery (laminectomy at the T9-T10 levels) followed by an intravenous injection (100 µg) of an E2 bolus and the implantation of 0.5cm of Silastic tubing containing 3 mg of E2 (sham E2 + E2 bolus) immediately after the laminectomy. The SCI control animals received a moderate contusion using the Multicenter Animal SCI Study impactor device over the exposed spinal cord followed by an intravenous bolus injection of sesame oil and were implanted with empty Silastic tubing (injury SE + vehicle); treated rats received a bolus of E2 and a Silastic implant with 3 mg of E2 (injury E2 + E2 bolus). Functional locomotor recovery and fine motor coordination were assessed by the Basso, Beattie, and Bresnahan (BBB) open field test and grid-walking tests, respectively, from the acute (7 days post-injury [DPI]) to the chronic stages (35 DPI). Anatomical studies of the cord were performed using Luxol fast blue staining followed by densitometric analysis. RESULTS: As observed in the BBB open field and the grid-walking tests, E2 post-SCI did not improve locomotor function but instead increased spared white matter tissue, in the rostral region. CONCLUSION: Estradiol post-SCI, at the dose and route of administration used in this study, failed to promote locomotor recovery but partially restored spared white matter tissue.

The potential effects of polyunsaturated ω-3 fatty acids on spinal cord injury: A systematic review & meta-analysis of preclinical evidence.

Polyunsaturated fatty acids (PUFAs) have received attention for their anti-inflammatory and antioxidant properties. Preclinical studies have investigated the efficacy of PUFAs in animal models of spinal cord injury (SCI) to determine if these properties can translate to neuroprotection and locomotor recovery. Findings from such studies have been promising, suggesting PUFAs as potential treatments against the neurological dysfunction induced by SCI. This systematic review and meta-analysis sought to investigate the efficacy of PUFAs for promoting locomotor recovery in animal models of SCI. PubMed, Web of Science and Embase (Ovid) were searched for relevant papers and those that examined the restorative effects of PUFAs on locomotor recovery in preclinical SCI models were included in our analysis. A random effects meta-analysis (restricted maximum likelihood estimator) was employed. A total of 28 studies were included and the results showed the claim that PUFAs have a beneficial therapeutic effect for promoting locomotor recovery (SMD = 1.037, 95% CI = 0.809-1.2644, p = <0.001) and cell survival (SMD = 1.101, 95% CI = 0.889-1.313, p = <0.001) in animal models of SCI. No significant differences for the secondary outcomes of neuropathic pain and lesion volume. Moderate asymmetry was observed in the funnel plots for locomotor recovery, cell survival and neuropathic pain measures, suggesting publication bias. Trim-and-fill analysis estimated 13, 3, 0 and 4 missing studies for locomotor recovery, cell survival, neuropathic pain, and lesion volume, respectively. A modified CAMARADES checklist was also used to assess risk of bias, showing that the median score for all included papers was 4 out of a possible 7.