Impacts of epidural electrical stimulation on Wnt signaling,FAAH, and BDNF following thoracic spinal cord injury in rat

Electrical stimulation (ES) has been shown to improve some of impairments after spinal cord injury (SCI), but the underlying mechanisms remain unclear. The Wnt signaling pathways and the endocannabinoid system appear to be modulated in response to SCI. This study aimed to investigate the effect of ES therapy on the activity of canonical/noncanonical Wnt signaling pathways, brain-derived neurotrophic factor (BDNF), and fatty-acid amide hydrolase (FAAH), which regulate endocannabinoids levels. Forty male Wistar rats were randomly divided into four groups: (a) Sham, (b) laminectomy + epidural subthreshold ES, (c) SCI, and (d) SCI + epidural subthreshold ES. A moderate contusion SCI was performed at the thoracic level (T10). Epidural subthreshold ES was delivered to upper the level of T10 segment every day (1 hr/rat) for 2 weeks. Then, animals were killed and immunoblotting was used to assess spinal cord parameters. Results revealed that ES intervention for 14 days could significantly increase wingless-type3 (Wnt3), Wnt7, β-catenin, Nestin, and cyclin D1 levels, as well as phosphorylation of glycogen synthase kinase 3β and Jun N-terminal kinase. Additionally, SCI reduced BDNF and FAAH levels, and ES increased BDNF and FAAH levels in the injury site. We propose that ES therapy may improve some of impairments after SCI through Wnt signaling pathways. Outcomes also suggest that BDNF and FAAH are important players in the beneficial impacts of ES therapy. However, the precise mechanism of BDNF, FAAH, and Wnt signaling pathways on SCI requires further investigation.     

A food-derived synergist of NGF signaling: identification of protein tyrosine phosphatase 1B as a key regulator of NGF receptor-initiated signal transduction

Neurotrophins, such as the nerve growth factor (NGF), play an essential role in the growth, development, survival and functional maintenance of neurons in the central and peripheral systems. They also prevent neuronal cell death under various stressful conditions, such as ischemia and neurodegenerative disorders. NGF induces cell differentiation and neurite outgrowth by binding with and activating the NGF receptor tyrosine kinase followed by activation of a variety of signaling cascades. We have investigated the NGF-dependent neuritogenesis enhancer potential of a food-derived small molecule contained in Brassica vegetables and identified the protein tyrosine phosphatase (PTP) 1B as a key regulator of the NGF receptor-initiated signal transduction. Based on an extensive screening of Brassica vegetable extracts for the neuritogenic-promoting activity in the rat pheochromocytoma cell line PC12, we found the Japanese horseradish, wasabi (Wasabia japonica, syn. Eutrema wasabi), as the richest source and identified 6-methylsulfinylhexyl isothiocyanate (6-HITC), an analogue of sulforaphane isolated from broccoli, as one of the major neuritogenic enhancers in the wasabi. 6-HITC strongly enhanced the neurite outgrowth and neurofilament expression elicited by a low-concentration of NGF that alone was insufficient to induce neuronal differentiation. 6-HITC also facilitated the sustained-phosphorylation of the extracellular signal-regulated kinase and the autophosphorylation of the NGF receptor TrkA. It was found that PTP1B act as a phosphatase capable of dephosphorylating Tyr-490 of TrkA and was inactivated by 6-HITC in a redox-dependent manner. The identification of PTP1B as a regulator of NGF signaling may provide new clues about the chemoprotective potential of food components, such as isothiocyanates.     

Collagen scaffolds modified with collagen-binding bFGF promotes the neural regeneration in a rat hemisected spinal cord injury model

Nerve conduit is one of strategies for spine cord injury(SCI)treatment.Recently,studies showed that biomaterials could guide the neurite growth and promote axon regeneration at the injury site.However,the scaffold by itself was difficult to meet the need of SCI functional recovery.The basic fibroblast growth factor(bFGF)administration significantly promotes functional recovery after organ injuries.Here,using a rat model of T9 hemisected SCI,we aimed at assessing the repair capacity of implantation of collagen scaffold(CS)modified by collagen binding bFGF(CBD-bFGF).The results showed that CS combined with CBD-bFGF treatment improved survival rates after the lateral hemisection SCI.The CS/CBD-bFGF group showed more significant improvements in motor than the simply CS-implanted and untreated control group,when evaluated by the 21-point Basso-Beattie-Bresnahan(BBB)score and footprint analysis.Both hematoxylin and eosin(H&E)and immunohistochemical staining of neurofilament(NF)and glial fibrillary acidic protein(GFAP)demonstrated that fibers were guided to grow through the implants.These findings indicated that administration of CS modified with CBD-bFGF could promote spinal cord regeneration and functional recovery.     

自噬通过BDNF/TrkB信号通路对脊髓损伤的保护作用

脊髓型颈椎病(cervical spondylotic myelopathy, CSM)是临床常见病、多发病,由该病引起的脊髓受损而产生的脊髓功能障碍是其最常见的临床特征。在脊髓损伤中,多种因素能通过自噬相关信号通路而激活自噬,适度的自噬可以对脊髓损伤起到神经保护作用,而增加细胞存活率、恢复和增加自噬通量可以改善损伤后的脊髓功能的恢复;在CSM脊髓损伤中,脑源性神经营养因子(brain derived neurotrophic factor, BDNF)与其受体原肌球蛋白受体激酶B(tropomyosin receptor kinase B, TrkB)及其相关通路是参与保护神经细胞的重要途径之一,细胞自噬在这一过程中起到了重要的调节作用。本文通过阐释自噬与BDNF/TrkB信号通路在CSM过程中的作用及其对脊髓损伤的保护机制,以期对基础研究及临床研究提供理论支持。     

Altered distribution of interstitial cells and innervation in the rat urinary bladder following spinal cord injury

Changes in the distribution of interstitial cells (IC) are reportedly associated with dysfunctional bladder. This study investigated whether spinal cord injury (SCI) resulted in changes to IC subpopulations (vimentin-positive with the ultrastructural profile of IC), smooth muscle and nerves within the bladder wall and correlated cellular remodelling with functional properties. Bladders from SCI (T8/9 transection) and sham-operated rats 5 weeks post-injury were used for ex vivo pressure-volume experiments or processed for morphological analysis with transmission electron microscopy (TEM) and light/confocal microscopy. Pressure-volume relationships revealed low-pressure, hypercompliance in SCI bladders indicative of decompensation. Extensive networks of vimentin-positive IC were typical in sham lamina propria and detrusor but were markedly reduced post-SCI; semi-quantitative analysis showed significant reduction. Nerves labelled with anti-neurofilament and anti-vAChT were notably decreased post-SCI. TEM revealed lamina propria IC and detrusor IC which formed close synaptic-like contacts with vesicle-containing nerve varicosities in shams. Lamina propria and detrusor IC were ultrastructurally damaged post-SCI with retracted/lost cell processes and were adjacent to areas of cellular debris and neuronal degradation. Smooth muscle hypertrophy was common to SCI tissues. In conclusion, IC populations in bladder wall were decreased 5 weeks post-SCI, accompanied with reduced innervation, smooth muscle hypertrophy and increased compliance. These novel findings indicate that bladder wall remodelling post-SCI affects the integrity of interactions between smooth muscle, nerves and IC, with compromised IC populations. Correlation between IC reduction and a hypercompliant phenotype suggests that disruption to bladder IC contribute to pathophysiological processes underpinning the dysfunctional SCI bladder.     

夹脊电针疗法联合重复经颅磁刺激对不完全性脊髓损伤后神经病理性疼痛患者心理状态、血清炎性因子和疼痛介质的影响

摘要 目的：观察夹脊电针疗法联合重复经颅磁刺激（rTMS）对不完全性脊髓损伤（ISCI）后神经病理性疼痛（NP）患者心理状态、血清炎性因子和疼痛介质的影响。方法：选择ISCI后并发NP患者113例,根据随机数字表法分为对照组（n=56,rTMS治疗）和研究组（n=57,对照组基础上结合夹脊电针疗法）,连续治疗4周后观察两组疼痛改善、心理状态、血清炎性因子和疼痛介质水平的变化。结果：研究组的临床总有效率高于对照组（P<0.05）。研究组治疗4周后的疼痛评级指数（PRI）、现实疼痛指数（PPI）、视觉模拟评分（VAS）评分低于对照组（P<0.05）。研究组治疗4周后的焦虑自评量表（SAS）、抑郁自评量表（SDS）评分低于对照组（P<0.05）。研究组治疗4周后的肿瘤坏死因子-α（TNF-α）、降钙素原（PCT）低于对照组,白细胞介素-10（IL-10）则高于对照组（P<0.05）。研究组治疗4周后的前列腺素E₂（PGE₂）、5-羟色胺（5-HT）低于对照组,β-内啡肽（β-EP）则高于对照组（P<0.05）。结论：夹脊电针疗法联合rTMS治疗ISCI后NP患者,可有效减轻疼痛症状,改善其心理状态、血清炎性因子和疼痛介质水平。     

Cannabinoids inhibit ethanol-induced activation of liver toxicity in rats through JNK/ERK/MAPK signaling pathways

Cannabinoids (CBs) are psychoactive compounds, with reported anticancer, anti-inflammatory, and anti-neoplastic properties. The study was aimed at assessing the hepatoprotective effects of CB against ethanol (EtOH)-induced liver toxicity in rats. The animals were divided into seven groups: control (Group I) and Group II were treated with 50% ethanol (EtOH 5 mg/kg). Groups III, IV, and VI were treated with (EtOH + CB 10 mg/kg), (EtOH + CB 20 mg/kg), and (EtOH + CB 30 mg/kg), respectively. Groups V and VII consisted of animals treated with 20 and 30 mg/kg, of CB, respectively. Biochemical analysis revealed that Group IV (EtOH + CB 20 mg/kg) had reduced levels of ALT—alanine transferase, AST—aspartate aminotransferase, ALP—alanine peroxidase, MDA—malondialdehyde and increased levels of GSH-reduced glutathione. Histopathological analysis of liver and kidney tissues showed that EtOH + CB (20 and 30 mg/kg) treated animal groups exhibited normal tissue architecture similar to that of the control group. ELISA revealed that the inflammatory markers were reduced in the animal groups that were treated with EtOH + CB 20 mg/kg, in comparison to the animals treated only with EtOH. The mRNA expression levels of COX-2, CD-14, and MIP-2 showed a remarkable decrease in EtOH + CB treated animal groups to control groups. Western blot analysis revealed that CB downregulated p38/JNK/ERK thereby exhibiting its hepatoprotective property by inhibiting mitogen-activated protein kinase pathways. Thus, our findings suggest that CB is a potential candidate for the treatment of alcohol-induced hepatotoxicity.     

Fibroblast growth factors in the management of spinal cord injury

Spinal cord injury (SCI) possesses a significant health and economic burden worldwide. Traumatic SCI is a devastating condition that evolves through two successive stages. Throughout each of these stages, disturbances in ionic homeostasis, local oedema, ischaemia, focal haemorrhage, free radicals stress and inflammatory response were observed. Although there are no fully restorative cures available for SCI patients, various molecular, cellular and rehabilitative therapies, such as limiting local inflammation, preventing secondary cell death and enhancing the plasticity of local circuits in the spinal cord, were described. Current preclinical studies have showed that fibroblast growth factors (FGFs) alone or combination therapies utilizing cell transplantation and biomaterial scaffolds are proven effective for treating SCI in animal models. More importantly, some studies further demonstrated a paucity of clinical transfer usage to promote functional recovery of numerous patients with SCI. In this review, we focus on the therapeutic capacity and pitfalls of the FGF family and its clinical application for treating SCI, including the signalling component of the FGF pathway and the role in the central nervous system, the pathophysiology of SCI and the targets for FGF treatment. We also discuss the challenges and potential for the clinical translation of FGF‐based approaches into treatments for SCI.     

miR-22-3p enhances the intrinsic regenerative abilities of primary sensory neurons via the CBL/p-EGFR/p-STAT3/GAP43/p-GAP43 axis

Spinal cord injury (SCI) is a devastating disease. Strategies that enhance the intrinsic regenerative ability are very important for the recovery of SCI to radically prevent the occurrence of sensory disorders. Epidermal growth factor (EGF) showed a limited effect on the growth of primary sensory neuron neurites due to the degradation of phosphorylated-epidermal growth factor receptor (p-EGFR) in a manner dependent on Casitas B-lineage lymphoma (CBL) (an E3 ubiquitin-protein ligase). MiR-22-3p predicted from four databases could target CBL to inhibit the expression of CBL, increase p-EGFR levels and neurites length via STAT3/GAP43 pathway rather than Erk1/2 axis. EGF, EGFR, and miR-22-3p were downregulated sharply after injury. In vivo miR-22-3p Agomir application could regulate CBL/p-EGFR/p-STAT3/GAP43/p-GAP43 axis, and restore spinal cord sensory conductive function. This study clarified the mechanism of the limited promotion effect of EGF on adult primary sensory neuron neurite and targeting miR-22-3p could be a novel strategy to treat sensory dysfunction after SCI.     

Progranulin contributes to endogenous mechanisms of pain defense after nerve injury in mice

Progranulin haploinsufficiency is associated with frontotemporal dementia in humans. Deficiency of progranulin led to exaggerated inflammation and premature aging in mice. The role of progranulin in adaptations to nerve injury and neuropathic pain are still unknown. Here we found that progranulin is up-regulated after injury of the sciatic nerve in the mouse ipsilateral dorsal root ganglia and spinal cord, most prominently in the microglia surrounding injured motor neurons. Progranulin knockdown by continuous intrathecal spinal delivery of small interfering RNA after sciatic nerve injury intensified neuropathic pain-like behaviour and delayed the recovery of motor functions. Compared to wild-type mice, progranulin-deficient mice developed more intense nociceptive hypersensitivity after nerve injury. The differences escalated with aging. Knockdown of progranulin reduced the survival of dissociated primary neurons and neurite outgrowth, whereas addition of recombinant progranulin rescued primary dorsal root ganglia neurons from cell death induced by nerve growth factor withdrawal. Thus, up-regulation of progranulin after neuronal injury may reduce neuropathic pain and help motor function recovery, at least in part, by promoting survival of injured neurons and supporting regrowth. A deficiency in this mechanism may increase the risk for injury-associated chronic pain.     

不同频率功能性磁刺激联合运动想象疗法治疗脊髓损伤后神经源性膀胱尿潴留的疗效对比研究

摘要 目的：观察不同频率功能性磁刺激（FMS）联合运动想象疗法治疗脊髓损伤（SCI）后神经源性膀胱（NB）尿潴留的疗效。方法：将2021年8月至2023年4月期间我院收治的116例SCI后NB尿潴留患者,按随机数字表法分为5Hz组（n=58,5HzFMS联合运动想象疗法治疗）和20Hz组（n=58,20HzFMS联合运动想象疗法治疗）。对比两组排尿情况、尿流动力学指标、肌电图指标、各项量表评分。结果：治疗后,20Hz组日自主排尿次数少于5Hz组,日均单次排尿量、日单次最大尿量多于5Hz组（P<0.05）;20Hz组最大尿流速、最大膀胱容量、充盈期逼尿肌压力、H反射波幅、F波引出率、生活质量综合评定量表-74（GQOL-74）评分高于5Hz组,膀胱残余尿量、H反射潜伏期、F波潜伏期、NB症状评分表（NBSS）、国际下尿路功能症状（LUTS）评分低于5Hz组（P<0.05）。结论：与5Hz频率FMS相比,20Hz频率FMS联合运动想象疗法治疗SCI后NB尿潴留,可缓解临床症状,促进膀胱功能恢复,进一步改善患者的生活质量。     

电针刺激联合局部振动治疗对脊髓损伤并发下肢痉挛患者康复效果及血清BDNF、PDGF的影响

目的:探讨脊髓损伤(SCI)并发下肢痉挛患者经电针刺激联合局部振动治疗后的临床效果。方法:选取本院于2018年1月到2019年6月期间收治的SCI并发下肢痉挛患者90例,根据乱数表法将上述患者分为对照组(n=45)和研究组(n=45),对照组患者给予常规康复系统疗法治疗,研究组在对照组的基础上给予电针刺激联合局部振动治疗,比较两组患者临床疗效、相关量表评分、内收肌角、直腿抬高角以及血清BDNF、PDGF水平。结果:研究组治疗后的临床总有效率为91.11%(41/45),高于对照组的64.44%(29/45)(P0.05)。两组患者治疗后改良Barthel指数、血清BDNF、PDGF水平均升高,且研究组高于对照组(P0.05);改良Ashworth量表、临床痉挛指数评分降低,且研究组低于对照组(P0.05)。两组患者治疗后内收肌角、直腿抬高角均扩大,且研究组大于对照组(P0.05)。结论:电针刺激联合局部振动治疗SCI并发下肢痉挛患者,可有效促进患者康复,改善下肢痉挛,提高生活自理能力,同时还可有效改善血清BDNF、PDGF水平。