Corrigendum: Deferoxamine promotes recovery of traumatic spinal cord injury by inhibiting ferroptosis

<正>The original version of the article titled"Deferoxamine promotes recovery of traumatic spinal cord injury by inhibiting ferroptosis"contained typographical errors in Graphical Abstract and Abstract section. In Graphical Abstract, cystine was incorrectly written as cysteine (Additional file 1). In Abstract section,"A rat model of spinal cord injury at thoracic10 segment..."was incorrectly written as UA rat model of Deferoxamine at thoracic 10 segment...","Simultaneously,the sham and spinal cord injury     

Sodium selenite promotes neurological function recovery after spinal cord injury by inhibiting ferroptosis

Ferroptosis is a recently discovered form of iron-dependent cell death,which occurs during the pathological process of various central nervous system diseases o...     

Lithium promotes recovery after spinal cord injury

Lithium is associated with oxidative stress and apoptosis,but the mechanism by which lithium protects against spinal cord injury remains poorly understood.In this study,we found that intraperitoneal administration of lithium chloride(LiCl)in a rat model of spinal cord injury alleviated pathological spinal cord injury and inhibited expression of tumor necrosis factorα,interleukin-6,and interleukin 1β.Lithium inhibited pyroptosis and reduced inflammation by inhibiting Caspase-1 expression,reducing the oxidative stress response,and inhibiting activation of the Nod-like receptor protein 3 inflammasome.We also investigated the neuroprotective effects of lithium intervention on oxygen/glucose-deprived PC12 cells.We found that lithium reduced inflammation,oxidative damage,apoptosis,and necrosis and up-regulated nuclear factor E2-related factor 2(Nrf2)and heme oxygenase-1 in PC12 cells.All-trans retinoic acid,an Nrf2 inhibitor,reversed the effects of lithium.These results suggest that lithium exerts anti-inflammatory,anti-oxidant,and anti-pyroptotic effects through the Nrf2/heme oxygenase-1 pathway to promote recovery after spinal cord injury.This study was approved by the Animal Ethics Committee of Xi’an Jiaotong University(approval No.2018-2053)on October 23,2018.     

Lithium promotes recovery of neurological function after spinal cord injury by inducing autophagy

Lithium promotes autophagy and has a neuroprotective effect on spinal cord injury(SCI); however, the underlying mechanisms remain unclear. Therefore, in this study, we investigated the effects of lithium and the autophagy inhibitor 3-methyladenine(3-MA) in a rat model of SCI. The rats were randomly assigned to the SCI, lithium, 3-MA and sham groups. In the 3-MA group, rats were intraperitoneally injected with 3-MA(3 mg/kg) 2 hours before SCI. In the lithium and 3-MA groups, rats were intraperitoneally injected with lithium(LiCl; 30 mg/kg) 6 hours after SCI and thereafter once daily until sacrifice. At 2, 3 and 4 weeks after SCI, neurological function and diffusion tensor imaging indicators were remarkably improved in the lithium group compared with the SCI and 3-MA groups. The Basso, Beattie and Bresnahan locomotor rating scale score and fractional anisotropy values were increased, and the apparent diffusion coefficient value was decreased. Immunohistochemical staining showed that immunoreactivities for Beclin-1 and light-chain 3 B peaked 1 day after SCI in the lithium and SCI groups. Immunoreactivities for Beclin-1 and light-chain 3 B were weaker in the 3-MA group than in the SCI group, indicating that 3-MA inhibits lithium-induced autophagy. Furthermore, NeuN+ neurons were more numerous in the lithium group than in the SCI and 3-MA groups, with the fewest in the latter. Our findings show that lithium reduces neuronal damage after acute SCI and promotes neurological recovery by inducing autophagy. The neuroprotective mechanism of action may not be entirely dependent on the enhancement of autophagy, and furthermore, 3-MA might not completely inhibit all autophagy pathways.     

Triptolide promotes spinal cord repair by inhibiting astrogliosis and inflammation

Spinal cord injury (SCI) is a cause of major neurological disability, and no satisfactory treatment is currently available. Traumatic SCI directly damages the cell bodies and/or processes of neurons and triggers a series of endogenous processes, including neuroinflammatory response and reactive astrogliosis. In this study, we found that triptolide, one of the major active components of the traditional Chinese herb Tripterygium wilfordii Hook F, inhibited astrogliosis and inflammation and promoted spinal cord repair. Triptolide was shown to prevent astrocytes from reactive activation by blocking the JAK2/STAT3 pathway in vitro and in vivo. Furthermore, astrocytic gliosis and glial scar were greatly reduced in injured spinal cord treated with triptolide. Triptolide treatment was also shown to decrease the ED‐1 or CD11b‐positive inflammatory cells at the lesion site. Using neurofilament staining and anterograde tracing, a significantly greater number of regenerative axons were observed in the triptolide‐treated rats. Importantly, behavioral tests revealed that injured rats receiving triptolide had improved functional recovery as assessed by the Basso, Beattie, and Bresnahan open‐field scoring, grid‐walk, and foot‐print analysis. These results suggested that triptolide promoted axon regeneration and locomotor recovery by attenuating glial scaring and inflammation, and shed light on the potential therapeutic benefit for SCI. © 2010 Wiley‐Liss, Inc.     

Transplantation of olfactory mucosa following spinal cord injury promotes recovery in rats

Several recent studies have demonstrated the potential therapeutic role of olfactory ensheathing cells in spinal cord injury. The aim of this study was to elucidate whether grafts of nasal olfactory mucosa containing olfactory ensheathing cells can repair the injured rat spinal cord as compared with the nasal respiratory mucosa containing no olfactory ensheathing cells. These grafts were then transplanted into the partially removed rat spinal cord. Compared with the respiratory mucosa-transplanted rats, the olfactory mucosa-transplanted rats partially recovered the movement of their hindlimbs and joints. Corticospinal tracing indicated that olfactory mucosa transplantation restored the severed tract. Therefore, olfactory mucosa has potential value in the repair of spinal cord injury.     

移植人羊膜间充质干细胞促进脊髓损伤大鼠神经功能恢复

目的研究移植人羊膜间充质干细胞（hAMSCs）是否促进脊髓损伤大鼠神经功能恢复,探索其可能作用机制。 方法60只雌性SD大鼠按照随机数字表法分为磷酸盐缓冲液（PBS）治疗组（30只）和hAMSCs治疗组（30只）。脊髓损伤采用脊髓撞击损伤模型,hAMSCs或PBS立刻移植到离脊髓损伤中心2 mm的头尾两端。免疫荧光检测细胞分化,血管再生和轴突再生。酶联免疫吸附剂测定试剂盒检测脑源性神经营养因子（BDNF）和血管内皮生长因子（VEGF）含量,BBB运动功能评分检测行为学。 结果在脊髓损伤后14 d、21 d和28 d,hAMSCs治疗组BBB评分分别为（8.75±0.701）、（10.375±0.532）和（12.125±0.350）,高于PBS组（6.0±0.463）、（7.25±0.412）和（9.125±0.440）,差异具有统计学意义（P<0.05）。在第7天和第14天,hAMSCs治疗组BDNF表达水平分别为（75.138±4.367）pg/mg和（66.483±4.099）pg/mg,高于PBS组（43.901±3.607）pg/mg和（41.108±3.848）pg/mg,差异具有统计学意义（P<0.05）。在第7天,第14天和第28天,hAMSCs治疗组VEGF表达水平分别为（23.328±2.463）pg/mg,（22.301±2.223）pg/mg和（14.855±1.282）pg/mg,高于PBS组（9.978±1.572）pg/mg,（9.271±1.496）pg/mg和（7.113±1.123）pg/mg,差异具有统计学意义（P<0.05）。hAMSCs治疗组血管数目（17.5±2.102）高于PBS组（6.25±1.750）,差异具有统计学意义（P<0.05）。hAMSCs治疗组小鼠抗5羟色胺阳性神经纤维面积（3486±203.643）和GAP43阳性神经纤维面积（4568.25±253.881）高于PBS组（2070.25±156.344）和（2455.725±314.475）,差异具有统计学意义（P<0.05）。 结论移植hAMSCs能促进脊髓损伤大鼠神经功能恢复,其作用机制可能是通过增加神经营养因子表达,促进血管再生和轴突再生。因此hAMSCs移植是治疗脊髓损伤的理想方法。     

Depression following traumatic spinal cord injury

OBJECTIVES: To describe the epidemiology of depression following traumatic spinal cord injury (SCI) and identify risk factors associated with depression. METHODS: This population-based cohort study followed individuals from date of SCI to 6 years after injury. Administrative data from a Canadian province with a universal publicly funded health care system and centralized databases were used. A Cox proportional hazards model was developed to identify risk factors. RESULTS: Of 201 patients with SCI, 58 (28.9%) were treated for depression. Individuals at highest risk were those with a pre-injury history of depression [hazard rate ratio (HRR) 1.6; 95% CI: 1.1-2.3], a history of substance abuse (HRR 1.6; 95% CI: 1.2-2.3) or permanent neurological deficit (HRR 1.6; 95% CI: 1.2-2.1). CONCLUSION: Depression occurs commonly and early in persons who sustain an SCI. Both patient and injury factors are associated with the development of depression. These should be used to target patients for mental health assessment and services during initial hospitalization and following discharge into the community.     

Modulation of autophagy for neuroprotection and functional recovery in traumatic spinal cord injury

Spinal cord injury(SCI) is a serious central nervous system trauma that leads to loss of motor and sensory functions in the SCI patients. One of the cell death mechanisms is autophagy, which is ‘self-eating' of the damaged and misfolded proteins and nucleic acids, damaged mitochondria, and other impaired organelles for recycling of cellular building blocks. Autophagy is different from all other cell death mechanisms in one important aspect that it gives the cells an opportunity to survive or demise depending on the circumstances. Autophagy is a therapeutic target for alleviation of pathogenesis in traumatic SCI. However, functions of autophagy in traumatic SCI remain controversial. Spatial and temporal patterns of activation of autophagy after traumatic SCI have been reported to be contradictory. Formation of autophagosomes following therapeutic activation or inhibition of autophagy flux is ambiguous in traumatic SCI studies. Both beneficial and harmful outcomes due to enhancement autophagy have been reported in traumatic SCI studies in preclinical models. Only further studies will make it clear whether therapeutic activation or inhibition of autophagy is beneficial in overall outcomes in preclinical models of traumatic SCI. Therapeutic enhancement of autophagy flux may digest the damaged components of the central nervous system cells for recycling and thereby facilitating functional recovery. Many studies demonstrated activation of autophagy flux and inhibition of apoptosis for neuroprotective effects in traumatic SCI. Therapeutic induction of autophagy in traumatic SCI promotes axonal regeneration, supporting another beneficial role of autophagy in traumatic SCI. In contrast, some other studies demonstrated that disruption of autophagy flux in traumatic SCI strongly correlated with neuronal death at remote location and impaired functional recovery. This article describes our current understanding of roles of autophagy in acute and chronic traumatic SCI, crosstalk between autophagy and apoptosis, therapeutic activation or inhibition of autophagy for promoting functional recovery, and future of autophagy in traumatic SCI.     

Oral administration of inosine promotes recovery after experimental spinal cord injury in rat

Inosine, a purine nucleoside, is one of the novel substances, which can preserve the neuronal and glial viability and stimulate intact neurons to extend axons. We, herein, evaluated the effect of oral inosine treatment on spinal cord injury (SCI) recovery by means of locomotor and bladder function, quantification of neurons and spinal cord tissue sparing. Rats after compression SCI were divided into groups—SCI-Aqua and SCI-Inosine (daily application of aqua for injection or inosine)—locomotion of hind limbs (BBB score) and urinary bladder function were evaluated from day 1 to 28 after SCI. The neuronal profile was determined by immunohistochemistry with NeuN antibodies and tissue sparing by Luxol fast blue staining method. SCI affected the functional movement of hind limbs in both groups with gradual improvement (increased BBB score) during survival. However, we found a significant difference in BBB score and recovery of bladder function between SCI-Aqua and SCI-Inosine groups during the second week of survival following SCI. In addition, the number of NeuN positive cells and percentage of tissue sparing was also significantly higher in SCI-Inosine group when compared with the SCI-Aqua group. Daily oral administration of inosine after SCI throughout the survival was beneficial for locomotion and micturition, neuronal survival and tissue sparing. This indicates that inosine may represent one of the co-stimulatory factors for treatment strategies to promote neuronal plasticity after SCI.     

Hyperbaric oxygen therapy combined with Schwann cell transplantation promotes spinal cord injury recovery

Schwann cell transplantation and hyperbaric oxygen therapy each promote recovery from spinal cord injury, but it remains unclear whether their combination improves therapeutic results more than monotherapy. To investigate this, we used Schwann cell transplantation via the tail vein, hyperbaric oxygen therapy, or their combination, in rat models of spinal cord contusion injury. The combined treatment was more effective in improving hindlimb motor function than either treatment alone; injured spinal tissue showed a greater number of neurite-like structures in the injured spinal tissue, somatosensory and motor evoked potential latencies were notably shorter, and their amplitudes greater, after combination therapy than after monotherapy. These findings indicate that Schwann cell transplantation combined with hyperbaric oxygen therapy is more effective than either treatment alone in promoting the recovery of spinal cord in rats after injury.     

Hepatocyte growth factor promotes endogenous repair and functional recovery after spinal cord injury

Many therapeutic interventions using neurotrophic factors or pharmacological agents have focused on secondary degeneration after spinal cord injury (SCI) to reduce damaged areas and promote axonal regeneration and functional recovery. Hepatocyte growth factor (HGF), which was identified as a potent mitogen for mature hepatocytes and a mediator of inflammatory responses to tissue injury, has recently been highlighted as a potent neurotrophic and angiogenic factor in the central nervous system (CNS). In the present study, we revealed that the extent of endogenous HGF up-regulation was less than that of c-Met, an HGF receptor, during the acute phase of SCI and administered exogenous HGF into injured spinal cord using a replication-incompetent herpes simplex virous-1 (HSV-1) vector to determine whether HGF exerts beneficial effects and promotes functional recovery after SCI. This treatment resulted in the significant promotion of neuron and oligodendrocyte survival, angiogenesis, axonal regrowth, and functional recovery after SCI. These results suggest that HGF gene delivery to the injured spinal cord exerts multiple beneficial effects and enhances endogenous repair after SCI. This is the first study to demonstrate the efficacy of HGF for SCI.     

LINGO-1 antagonist promotes functional recovery and axonal sprouting after spinal cord injury

LINGO-1 is a CNS-specific protein and a functional component of the NgR1/p75/LINGO-1 and NgR1/TAJ(TROY)/LINGO-1 signaling complexes that mediate inhibition of axonal outgrowth. These receptor complexes mediate the axonal growth inhibitory effects of Nogo, myelin-associated glycoprotein (MAG) and oligodendrocyte-myelin glycoprotein (OMgp) via RhoA activation. Soluble LINGO-1 (LINGO-1-Fc), which acts as an antagonist of these pathways by blocking LINGO-1 binding to NgR1, was administered to rats after dorsal or lateral hemisection of the spinal cord. LINGO-1-Fc treatment significantly improved functional recovery, promoted axonal sprouting and decreased RhoA activation and increased oligodendrocyte and neuronal survival after either rubrospinal or corticospinal tract transection. These experiments demonstrate an important role for LINGO-1 in modulating axonal outgrowth in vivo and that treatment with LINGO-1-Fc can significantly enhance recovery after spinal cord injury.     

Oscillating field stimulation promotes axon regeneration and locomotor recovery after spinal cord injury

Oscillating field stimulation(OFS)is a potential method for treating spinal cord injury.Although it has been used in spinal cord injury(SCI)therapy in basic and clinical studies,its underlying mechanism and the correlation between its duration and nerve injury repair remain poorly understood.In this study,we established rat models of spinal cord contusion at T10 and then administered 12 weeks of OFS.The results revealed that effectively promotes the recovery of motor function required continuous OFS for more than 6 weeks.The underlying mechanism may be related to the effects of OFS on promoting axon regeneration,inhibiting astrocyte proliferation,and improving the linear arrangement of astrocytes.This study was approved by the Animal Experiments and Experimental Animal Welfare Committee of Capital Medical University(supplemental approval No.AEEI-2021-204)on July 26,2021.     

Combination of methylprednisolone and rosiglitazone promotes recovery of neurological function after spinal cord injury

Methylprednisolone exhibits anti-inflammatory antioxidant properties, and rosiglitazone acts as an anti-inflammatory and antioxidant by activating peroxisome proliferator-activated receptor-γ in the spinal cord. Methylprednisolone and rosiglitazone have been clinically used during the early stages of secondary spinal cord injury. Because of the complexity and diversity of the inflammatory process after spinal cord injury, a single drug cannot completely inhibit inflammation. Therefore, we assumed that a combination of methylprednisolone and rosiglitazone might promote recovery of neurological function after secondary spinal cord injury. In this study, rats were intraperitoneally injected with methylprednisolone(30 mg/kg) and rosiglitazone(2 mg/kg) at 1 hour after injury, and methylprednisolone(15 mg/kg) at 24 and 48 hours after injury. Rosiglitazone was then administered once every 12 hours for 7 consecutive days. Our results demonstrated that a combined treatment with methylprednisolone and rosiglitazone had a more pronounced effect on attenuation of inflammation and cell apoptosis, as well as increased functional recovery, compared with either single treatment alone, indicating that a combination better promoted recovery of neurological function after injury.     

Combination of methylprednisolone and rosiglitazone promotes recovery of neurological function atfer spinal cord injury

Methylprednisolone exhibits anti-inlfammatory antioxidant properties, and rosiglitazone acts as an anti-inlfammatory and antioxidant by activating peroxisome proliferator-activated receptor-γ in the spinal cord. Methylprednisolone and rosiglitazone have been clinically used during the early stages of secondary spinal cord injury. Because of the complexity and diversity of the inlfammatory process atfer spinal cord injury, a single drug cannot completely inhibit inlfammation. hTerefore, we assumed that a combination of methylprednisolone and rosiglitazone might promote recovery of neurological function atfer secondary spinal cord injury. In this study, rats were intraperitoneally injected with methylprednisolone (30 mg/kg) and rosiglitazone (2 mg/kg) at 1 hour atfer injury, and methylprednisolone (15 mg/kg) at 24 and 48 hours atfer injury. Rosiglitazone was then administered once every 12 hours for 7 consecutive days. Our results demonstrated that a combined treatment with methylprednisolone and rosiglitazone had a more pronounced effect on attenuation of inlfammation and cell apoptosis, as well as increased functional recovery, compared with either single treatment alone, indicating that a combination better pro-moted recovery of neurological function atfer injury.     

Structural and functional reorganization of propriospinal connections promotes functional recovery after spinal cord injury

Axonal regeneration and fiber regrowth is limited in the adult central nervous system, but research over the last decades has revealed a high intrinsic capacity of brain and spinal cord circuits to adapt and reorganize after smaller injuries or denervation. Short-distance fiber growth and synaptic rewiring was found in cortex, brain stem and spinal cord and could be associated with restoration of sensorimotor functions that were impaired by the injury. Such processes of structural plasticity were initially observed in the corticospinal system following spinal cord injury or stroke, but recent studies showed an equally high potential for structural and functional reorganization in reticulospinal, rubrospinal or propriospinal projections. Here we review the lesion-induced plastic changes in the propriospinal pathways, and we argue that they represent a key mechanism triggering sensorimotor recovery upon incomplete spinal cord injury. The formation or strengthening of spinal detour pathways bypassing supraspinal commands around the lesion site to the denervated spinal cord were identified as prominent neural substrate inducing substantial motor recovery in different species from mice to primates. Indications for the existence of propriospinal bypasses were also found in humans after cortical stroke. It is mandatory for current research to dissect the biological mechanisms underlying spinal circuit remodeling and to investigate how these processes can be stimulated in an optimal way by therapeutic interventions(e.g., fiber-growth enhancing interventions, rehabilitation). This knowledge will clear the way for the development of novel strategies targeting the remarkable plastic potential of propriospinal circuits to maximize functional recovery after spinal cord injury.