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Spinal cord injury (SCI) is defined as damage to the spinal cord that temporarily or permanently changes its function. There is no definite treatment established for neurological complete injury patients. This study investigated the effect of ginseng extract and ginsenosides on neurological recovery and antioxidant efficacies in rat models following SCI and explore the appropriate dosage. Searches were done on PubMed, Embase, and Chinese databases, and animal studies matches the inclusion criteria were selected. Pair-wise meta-analysis and subgroup analysis were performed. Ten studies were included, and the overall methodological qualities were low quality. The result showed ginseng extract and ginsenosides significantly improve neurological function, through the Basso, Beattie, and Bresnahan (BBB) locomotor rating scale (pooled MD = 4.40; 95% CI = 3.92 to 4.88; p, Graphical abstract Image 1

Chronic spinal cord compression (CSCC) is induced by disc herniation and other reasons, leading to movement and sensation dysfunction, with a serious impact on quality of life. Spontaneous disc herniation rarely occurs in rodents, and therefore establishing a chronic spinal cord compression (CSCC) animal model is of crucial importance to explore the pathogenesis and treatment of CSCC. The absence of secreted protein, acidic, and rich in cysteine (SPARC) leads to spontaneous intervertebral disc degeneration in mice, which resembles human disc degeneration. In this study, we evaluated whether SPARC-null mice may serve as an animal model for CSCC. We performed rod rotation test, pain threshold test, gait analysis, and Basso Mouse Scale score. Our results showed that the motor function of SPARC-null mice was weakened, and magnetic resonance images revealed compression at different spinal cord levels, particularly in the lumbar segments. Immunofluorescence staining and western blot assay showed that the absence of SPARC induced apoptosis of neurons and oligodendrocytes, activation of microglia/macrophages with M1/M2 phenotype and astrocytes with A1/A2 phenotype; it also activated the expression of the NOD-like receptor protein 3 inflammasome and inhibited brain-derived neurotrophic factor/tyrosine kinase B signaling pathway. Notably, these findings are characteristics of CSCC. Therefore, we propose that SPARC-null mice may be an animal model for studying CSCC caused by disc herniation.

Cervical spondylotic myelopathy (CSM) is a common cause of disability with few treatments. Aberrant mitochondrial dynamics play a crucial role in the pathogenesis of various neurodegenerative diseases. Thus, regulation of mitochondrial dynamics may offer therapeutic benefit for the treatment of CSM. Muscone, the active ingredient of an odoriferous animal product, exhibits anti-inflammatory and neuroprotective effects for which the underlying mechanisms remain obscure. We hypothesized that muscone might ameliorate inflammatory responses and neuronal damage by regulating mitochondrial dynamics. To this end, the effects of muscone on a rat model of chronic cervical cord compression, as well as activated BV2 cells and injured neurons, were assessed. The results showed that muscone intervention improved motor function compared with vehicle-treated rats. Indeed, muscone attenuated pro-inflammatory cytokine expression, neuronal-apoptosis indicators in the lesion area, and activation of the nod-like receptor family pyrin domain-containing 3 inflammasome, nuclear transcription factor-κB, and dynamin-related protein 1 in Iba1- and βIII-tubulin-labeled cells. Compared with vehicle-treated rats, compression sites of muscone-treated animals exhibited elongated mitochondrial morphologies in individual cell types and reduced reactive oxygen species. In vitro results indicated that muscone suppressed microglial activation and neuronal damage by regulating related-inflammatory or apoptotic molecules. Moreover, muscone inhibited dynamin-related protein 1 activation in activated BV2 cells and injured neurons, whereby it rescued mitochondrial fragmentation and reactive oxygen species production, which regulate a wide range of inflammatory and apoptotic molecules. Our findings reveal that muscone attenuates neuroinflammation and neuronal damage in rats with chronic cervical cord compression by regulating mitochondrial fission events, suggesting its promise for CSM therapy.

Objective: Studies have shown that docosahexaenoic acid (DHA) has a beneficial effect in the treatment of spinal cord injury. A meta-analysis was used to study the effect of DHA on the neurological recovery in the rat spinal cord injury model, and the relationship between the recovery of motor function after spinal cord injury and the time and method of administration and the dose of DHA. Data source: Published studies on the effect of DHA on spinal cord injury animal models from seven databases were searched from their inception to January 2019, including PubMed, MEDLINE, EMBASE, the China National Knowledge Infrastructure, Wanfang, VIP, and SinoMed databases. The search terms included “spinal cord injury” “docosahexaenoic acid”, and “rats”. Data selection: Studies that evaluated the influence of DHA in rat models of spinal cord injury for locomotor functional recovery were included. The intervention group included any form of DHA treatment and the control group included treatment with normal saline, vehicle solution or no treatment. The Systematic Review Centre for Laboratory animal Experimentation’s risk of bias assessment tool was used for the quality assessment of the included studies. Literature inclusion, quality evaluation and data extraction were performed by two researchers. Meta-analysis was then conducted on all studies that met the inclusion criteria. Statistical analysis was performed on the data using RevMan 5.1.2. software. Outcome measures: The primary outcome measure was the score on the Basso, Beattie, and Bresnahan scale. Secondary outcome measures were the sloping plate test, balance beam test, stair test and grid exploration test. Results: A total of 12 related studies were included, 3 of which were of higher quality and the remaining 9 were of lower quality. The highest mean Basso, Beattie, and Bresnahan scale score occurred at 42 days after DHA treatment in spinal cord injury rats. At 21 days after treatment, the mean difference in Basso, Beattie, Bresnahan scores between the DHA group and the control group was the most significant (pooled MD = 4.14; 95% CI = 3.58–4.70; P < 0.00001). In the subgroup analysis, improvement in the Basso, Beattie, and Bresnahan scale score was more significant in rats administered DHA intravenously (pooled MD = 2.74; 95% CI = 1.41–4.07; P < 0.0001) and subcutaneously (pooled MD = 2.99; 95% CI = 2.29–3.69; P < 0.00001) than in the groups administered DHA orally (pooled MD = 3.04; 95% CI = –1.01 to 7.09; P = 0.14). Intravenous injection of DHA at 250 nmol/kg (pooled MD = 2.94; 95% CI = 2.47–3.41; P < 0.00001] and 1000 nmol/kg [pooled MD = 3.60; 95% CI = 2.66–4.54; P < 0.00001) significantly improved the Basso, Beattie, and Bresnahan scale score in rats and promoted the recovery of motor function. Conclusion: DHA can promote motor functional recovery after spinal cord injury in rats. The administration of DHA by intravenous or subcutaneous injection is more effective than oral administration of DHA. Intravenous injection of DHA at doses of 250 nmol/kg or 1000 nmol/kg is beneficial. Because of the small number and the low quality of the included studies, more high-quality research is needed in future to substantiate the results.

Spinal cord injury (SCI) is a devastating condition that has few treatment options. Riluzole, a sodium channel blocker used to treat amyotrophic lateral sclerosis, has been initially trialed in human SCI. We performed a systematic review to critically assess the efficacy of riluzole in locomotor recovery and damage extension in SCI rat models, and the potential for clinical translation. PubMed, Embase, Cochrane Library, and Chinese databases were searched from their inception date to March 2018. Two reviewers independently selected animal studies that evaluated neurological recovery and lesion area following riluzole treatment in SCI rat models, extracted data and assessed methodological quality. Pairwise meta-analysis, subgroup analysis, and network meta-analysis were performed to assess the effects of riluzole on SCI. Ten eligible studies were included. Two studies had high methodological quality. Overall, the Basso, Beattie, and Bresnahan scores were increased in riluzole-treated animals versus controls, and effect sizes showed a gradual increase from the 1st (five studies, n = 104, mean difference = 1.24, 95% CI = 0.11 to 2.37, p = 0.03) to 6th week after treatment (five studies, n = 120, mean difference = 2.34, 95% CI = 1.26 to 3.42, p < 0.0001). Riluzole was associated with improved outcomes in the inclined plane test and the tissue preservation area. Subgroup analyses suggested an association of locomotor recovery with riluzole dose. Network meta-analysis showed that 5 mg/kg riluzole exhibited greater protection than 2.5 and 8 mg/kg riluzole. Collectively, this review suggests that riluzole has a protective effect on SCI, with good safety and a clear mechanism of action and may be suitable for future clinical trials or applications. However, animal results should be interpreted with caution given the known limitations in animal experimental design and methodological quality.

As a severe progressive degenerative disease, cervical spondylotic myelopathy (CSM) has a poor prognosis and is associated with physical pain, stiffness, motor or sensory dysfunction, and a high risk of spinal cord injury and acroparalysis. Thus, therapeutic strategies that promote efficient spinal cord regeneration in this chronic and progressive disease are urgently needed. Effective and reproducible animal spinal cord compression models are required to understand the complex biological mechanism underlying CSM. Most spinal cord injury models reflect acute and structural destructive conditions, whereas animal models of CSM present a chronic compression in the spinal cord. This paper presents a protocol to generate a rat spinal cord compression model, which was further evaluated by assessing the behavioral score and observing the compressed spinal cord region. The behavioral assessments showed decreased monitor motor disability, including joint movements, stepping ability, coordination, trunk stability, and limb muscle strength. Hematoxylin and eosin (H&E) staining and immunostaining revealed considerable neuronal apoptosis in the compressed region of the spinal cord.

Cervical spondylotic myelopathy (CSM) is the most prevalent type of non-traumatic spinal cord injury. The pathological process of CSM is relatively complicated. Most of the chronic cervical cord compression animal models established using hydrophilic expanding polymer are single-segment compression, which was deviated from clinical practice with double-segment or multi-segment compression. This study aims to better mimic the actual clinical compression by using a new type of hydrophilic expanding polymer to establish an animal model of double-level cervical cord compression.Progressive cord compression was done with implantation of polyvinyl alcohol-polyacrylamide hydrogel in the spinal canal at the C3-4 and C5-6 levels. Sprague-Dawley rats (n = 32) were divided into three groups: sham (no compression, n = 12) and screw compression group (n = 8), and hydrogel compression group (n = 12). Functional deficits were characterized using motor function scores, forelimb grip strength, hindlimb pain threshold, and gait analysis, while compression was imaged with magnetic resonance imaging. The apoptosis, inflammation, and demyelination were assessed by hematoxylin and eosin staining, Luxol fast blue staining, TUNEL assay, immunofluorescence staining, and Western blot analysis.Motor function scores for rats with cervical cord hydrogel compression were significantly decline in motor function scores, an increase in allodynia, neurons and oligodendrocytes apoptosis related to B cell lymphoma-2 (Bcl-2)/Bcl-2 associated X (Bax)/cleaved caspase-3, and impaired axonal conduction, as well as neuroinflammation zone related to microglia or macrophages aggregation related to the nucleotide-binding domain, leucine-rich-repeat-containing family, pyrin domain-containing 3 (NLRP3) inflammasome activation, and activation of astrocytes, as well as oxidative stress were observed.We believe that this model utilizing compression on double-level cervical cord will allow researchers to investigate of translationally relevant therapeutic methods for CSM.

Cervical spondylotic myelopathy (CSM) is a clinically symptomatic entity arising from the spinal cord compression by degenerative diseases. Although endoplasmic reticulum (ER) stress has been commonly observed in several neurodegenerative diseases, the relationship between ER stress and CSM remains unknown. Shikonin is known to protect PC12 by inhibiting apoptosis in vitro. This study hypothesised that ER stress was vital in neuronal apoptosis in CSM. Shikonin might inhibit such responses by regulating ER stress through the protein kinase-like ER kinase-eukaryotic translation initiation factor 2 α-subunit-C/EBP homologous protein (PERK-eIF2α-CHOP) signalling pathway. Thus, the aim of this study was evaluating the neuroprotective effect of shikonin in rats with double-level chronic cervical cord compression, as well as primary rat cortical neurons with glutamate-induced neurotoxicity. The result showed that ER stress-related upregulation of PERK-eIF2α-CHOP resulted in rat neuronal apoptosis after chronic cervical cord compression; then, shikonin promoted motor recovery and inhibited neuronal apoptosis by attenuating PERK-eIF2α-CHOP and prevented Bax translocation from cytoplasm to mitochondrion induced by CHOP of neurons in rats with chronic compression. Also, it was found that shikonin could protect rat primary cortical neuron against glutamate toxicity by regulating ER stress through the PERK-eIF2α-CHOP pathway in vitro. In conclusion, shikonin might inhibit neuronal apoptosis by regulating ER stress through attenuating the activation of PERK-eIF2α-CHOP.

Background. Qi She Pill (QSP) is a traditional prescription for the treatment of neuropathic pain (NP) that is widely used in China. However, no network pharmacology studies of QSP in the treatment of NP have been conducted to date. Objective. To verify the potential pharmacological effects of QSP on NP, its components were analyzed via target docking and network analysis, and network pharmacology methods were used to study the interactions of its components. Materials and Methods. Information on pharmaceutically active compounds in QSP and gene information related to NP were obtained from public databases, and a compound-target network and protein-protein interaction network were constructed to study the mechanism of action of QSP in the treatment of NP. The mechanism of action of QSP in the treatment of NP was analyzed via Gene Ontology (GO) biological process annotation and Kyoto Gene and Genomics Encyclopedia (KEGG) pathway enrichment, and the drug-like component-target-pathway network was constructed. Results. The compound-target network contained 60 compounds and 444 corresponding targets. The key active compounds included quercetin and beta-sitosterol. Key targets included PTGS2 and PTGS1. The protein-protein interaction network of the active ingredients of QSP in the treatment of NP featured 48 proteins, including DRD2, CHRM, β2-adrenergic receptor, HTR2A, and calcitonin gene-related peptide. In total, 53 GO entries, including 35 biological process items, 7 molecular function items, and 11 cell related items, were identified. In addition, eight relevant (KEGG) pathways were identified, including calcium, neuroactive ligand-receptor interaction, and cAMP signaling pathways. Conclusion. Network pharmacology can help clarify the role and mechanism of QSP in the treatment of NP and provide a foundation for further research.

Objective: To evaluate the efficacy and safety of MK-801 and its effect on lesion volume in rat models of acute brain injury. Data Sources: Key terms were “stroke”, “brain diseases”, “brain injuries”, “brain hemorrhage, traumatic”, “acute brain injury”, “dizocilpine maleate”, “dizocilpine”, “MK-801”, “MK801”, “rat”, “rats”, “rattus” and “murine”. PubMed, Cochrane library, EMBASE, the China National Knowledge Infrastructure, WanFang database, the VIP Journal Integration Platform (VJIP) and SinoMed databases were searched from their inception dates to March 2018. Data Selection: Studies were selected if they reported the effects of MK-801 in experimental acute brain injury. Two investigators independently conducted literature screening, data extraction, and methodological quality assessments. Outcome Measures: The primary outcomes included lesion volume and brain edema. The secondary outcomes included behavioral assessments with the Bederson neurological grading system and the water maze test 24 hours after brain injury. Results: A total of 52 studies with 2530 samples were included in the systematic review. Seventeen of these studies had a high methodological quality. Overall, the lesion volume (34 studies, n = 966, MD = −58.31, 95% CI: −66.55 to −50.07; P < 0.00001) and degree of cerebral edema (5 studies, n = 75, MD = −1.21, 95% CI: −1.50 to −0.91; P < 0.00001) were significantly decreased in the MK-801 group compared with the control group. MK-801 improved spatial cognition assessed with the water maze test (2 studies, n = 60, MD = −10.88, 95% CI: −20.75 to −1.00; P = 0.03) and neurological function 24 hours after brain injury (11 studies, n = 335, MD = −1.04, 95% CI: −1.47 to −0.60; P < 0.00001). Subgroup analysis suggested an association of reduction in lesion volume with various injury models (34 studies, n = 966, MD = −58.31, 95% CI: −66.55 to −50.07; P = 0.004). Further network analysis showed that 0–1 mg/kg MK-801 may be the optimal dose for treatment in the middle cerebral artery occlusion animal model. Conclusion: MK-801 effectively reduces brain lesion volume and the degree of cerebral edema in rat models of experimental acute brain injury, providing a good neuroprotective effect. Additionally, MK-801 has a good safety profile, and its mechanism of action is well known. Thus, MK-801 may be suitable for future clinical trials and applications.

Cervical spondylotic myelopathy (CSM) is a leading cause of spinal cord dysfunction with few treatment options. Although mitochondrial dynamics are linked to a wide range of pathological changes in neurodegenerative diseases, a connection between aberrant mitochondrial dynamics and CSM remains to be illuminated. In addition, mechanisms underlying the emerging anti-inflammatory and neuroprotective effects of echinacoside (ECH), the main active ingredient of Cistanche salsa, are poorly understood. We hypothesized that excessive mitochondrial fission plays a critical role in regulating inflammatory responses in CSM, and ECH might alleviate such responses by regulating mitochondrial dynamics. To this end, we assessed the effects of ECH and Mdivi-1, a selective inhibitor of dynamin-related protein (Drp1), in a rat model of chronic cervical cord compression and activated BV2 cells. Our results showed that rats with Mdivi-1 intervention had improved motor function compared with vehicle-treated rats. Indeed, Mdivi-1 treatment attenuated pro-inflammatory cytokine expression, as well as activation of the nod-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, nuclear transcription factor-κB (NF-κB), and Drp1 in lesions. Compared with vehicle-treated rats, compression sites of Mdivi-1-treated animals exhibited elongated mitochondrial morphologies and reduced reactive oxygen species (ROS). Similarly, ECH-treated rats exhibited neurological recovery and suppression of inflammatory response or related signals in the lesion area after treatment. Interestingly, ECH treatment partly reversed aberrant mitochondrial fragmentation and oxidative stress within the lesion area. In vitro data suggested that ECH suppressed activated microglia by modulating activation of the NLRP3 inflammasome and NF-κB signaling. Furthermore, we observed that ECH markedly inhibited Drp1 translocation onto mitochondria, whereby it regulated mitochondrial dynamics and ROS production, which act as regulators of NLRP3 inflammasome activation and NF-κB signaling. Thus, our findings reveal that mitochondrial dynamics modulate inflammatory responses during CSM. Moreover, ECH may attenuate neuroinflammation in rats subjected to chronic cervical cord compression by regulating Drp1-dependent mitochondrial fission and activation of downstream signaling.

Background: Knee osteoarthritis (KOA) is a common chronic musculoskeletal disorder that seriously affect quality of life. Patients with KOA frequently develop one or more of the typically following symptoms: joint pain, stiffness, joint friction noise, impaired functionality. Traditional Chinese medicines (TCM) have showed a superior effect and peculiar advantage on the treatment of KOA, among TCMs, the Tong-luo Qu-yu plaster is the convenient and most commonly used method in China to improve symptoms including pain, stiffness and limited mobility in patients with KOA, as it causes few adverse effects. But there is a lack of high quality of clinical evidences to support the therapeutic effect that Chinese adhesive plaster can relieve pain and stiffness. The purpose of this study will be to evaluate the efficacy and safety of Tong-luo Qu-yu plaster in patients with KOA. Methods: This study will be a randomised, double-blind, parallel positive control, multi-center clinical trial. A total of 2000 participants older than 40 years with KOA, will be randomly allocated into a experimental group (n=1500) and a control group (n=500). All participants will receive a conventional conservative treatment lasted for 14 days as two courses, daily 1 time. Tong-luo Qu-yu plaster will be administered externally to participants in the experimental group, while the control group will receive a Qi-zheng Xiao-tong plaster. The outcome of the total Western Ontario and McMaster Universities Arthritis Index scores, TCM syndrome quantitative score, visual analog scale scores will be measured during the assessment visits (baseline and 1-, 2-week follow-up). In addition, adverse events concerning clinical symptoms and signs as well as laboratory tests will be documented during clinical trials. Discussion: This study will be a randomized, double-blind, parallel positive control trial to further evaluate the effectiveness and safety of Tong-luo Qu-yu plaster for patients with KOA in nine medical centers compared with control group, it is expected that the patients with KOA will benefit from this study. Trial Registration: ClinicalTrials.gov, NCT03309501. Registered on 08 November 2017. Keywords: Clinical trials, Knee osteoarthritis, Tong-luo Qu-yu plaster, Randomized, Protocol