Intra-arterial thrombolysis with tenecteplase for the treatment of cervical spinal cord ischemia: Technical case report.

BACKGROUND: In recent years, there have anecdotal reports of intra-arterial thrombolysis (IAT) for the treatment of spinal cord ischemia (SCI) with encouraging results. We describe a patient with acute cervical SCI who underwent IAT with Tenecteplase at our institution. CASE PRESENTATION: A 20-year-old man presented to the emergency department with a 12-hour history of progressive onset upper and lower extremity numbness, weakness, and urinary incontinence after sustaining a fall. MRI of cervical spine demonstrated T2 and STIR hyperintensity in the ventral aspect of the spinal cord spanning the C3, C4, and C5 levels suggestive of SCI. He demonstrated progression of neurologic deficits to C4 ASIA B spinal cord injury with complete loss of motor function, diminished sensation, and absent rectal tone. Emergent angiography was performed with prominent anterior spinal supply via the left ascending cervical artery. A total of 30 mg of Tenecteplase was administered intra-arterially in the bilateral vertebral arteries, bilateral ascending cervical arteries, and bilateral inferior thyroid arteries. Two-week post-intervention neurologic examination demonstrated improvement in injury level and severity. The patient was C6 ASIA C SCI, with 2/5 strength in the distal upper and lower extremities and improved sensation. CONCLUSION: IAT with Tenecteplase may be a feasible option for the treatment of acute spinal cord ischemia in carefully selected patients.

Melatonin Exerts an Anti-Panoptoic Role in Spinal Cord Ischemia-Reperfusion Injured Rats.

Paraplegia is a serious consequence of spinal cord ischemia-reperfusion (SCIR) injury, which leads to neuron death and permanent loss of motor function. However, there is no effective treatment for SCIR. Melatonin exerts a neuroprotective effect in neurodegenerative diseases. However, whether pyroptosis, apoptosis, and necroptosis (PANoptosis) is the primary cause of the massive neural death in SCIR is unknown, and if melatonin exhibits anti-PANoptotic effect in rescuing the disastrous damage is to be decided. This study indicates that melatonin confers neuroprotection in SCIR, attenuating the loss of Nissl body and improving Basso, Beattie & Bresnahan locomotor rating scale scores. Specifically, the apoptotic hallmarks in neurons are increased in SCIR injured spinal cord compared to the sham group. The upregulated trend is reversed by melatonin while the effect of melatonin is abolished by the administration of luzindole, a selective melatonin receptor antagonist. Moreover, similar patterns are found in the necroptotic markers in neurons, the pyroptotic indicators, and the interleukin-1ß staining in microglia. In conclusion, PANoptosis may underlie the mass neural death and paraplegia in SCIR, and melatonin confers neuroprotection to the spinal cord via inhibiting PANoptosis.

SYVN1 attenuates ferroptosis and alleviates spinal cord ischemia-reperfusion injury in rats by regulating the HMGB1/NRF2/HO-1 axis.

BACKGROUND: The ferroptosis of neurons is an important pathological mechanism of spinal cord ischemia reperfusion injury (SCIRI). Previous studies showed that synoviolin 1 (SYVN1) is a good prognostic marker of neurodegenerative diseases, but its mechanism is still unclear. This study aims to explore the role of SYVN1 in the ferroptosis of neurons and to clarify its internal mechanism. METHODS: Rat primary spinal cord neurons were treated with oxygen-glucose deprivation (OGD) for 1, 4 or 8 h, and then cell viability, ROS and MDA levels, glutathione peroxidase (GSH-Px) activity, and the expression of ferroptosis-related proteins GPX4, FTH1 and PTGS2 were detected. OGD/R-induced neurons were transfected with pcDNA-SYVN1 or si-HMGB1, and then cell functions were detected. Transmission electron microscope (TEM) was used to detect cell ferroptosis. The interplay between SYVN1 and high mobility group box 1 (HMGB1) was confirmed with Co-immunoprecipitation (Co-IP) assay. The stability of HMGB1 was measured by ubiquitination assay. Also, cells were treated with pcDNA-SYVN1 or together with ubiquitination inhibitor MG132, as well as treated with pcDNA-SYVN1 and pcDNA-HMGB1 or together with NRF2 activator dimethyl fumarate (DMF), and then Western blotting was used to detect the expression of HMGB1, nuclear NRF2 and HO-1 proteins. In addition, SD rats were occluded left common carotid artery and aortic arch to establish a SCIRI rat model. And rats were injected intrathecal with adenovirus-mediated SYVN1 overexpression vector (Ad-SYVN1, 2 µL, virus titer 5 × 1013 transduction unit [TU]/mL) to overexpress SYVN1. The motion function of rats was quantified using the Basso Rat Scale (BMS) for Locomotion. The ferroptosis and the number of neurons in the spinal cord tissue of rats were detected. RESULTS: SYVN1 overexpression inhibited ferroptosis of SCIRI rats and OGD/R-treated primary spinal cord neurons, and down-regulated the expression of HMGB1. In terms of mechanism, the binding of SYVN1 and HMGB1 promoted the ubiquitination and degradation of HMGB1, and negatively regulated the expression of HMGB1. Moreover, under OGD/R conditions, MG132 treatment or HMGB1 overexpression eliminated the inhibitory effect of SYVN1 overexpression on the ferroptosis of neurons and the activation of the NRF2/HO-1 pathway, and DMF treatment abolished the inhibition of HMGB1 overexpression on the NRF2/HO-1 pathway. Finally, in vivo experiments showed that SYVN1 overexpression could alleviate the spinal cord ischemia-reperfusion injury in rats by down-regulating HMGB1 and promoting the activation of the NRF2/HO-1 pathway. CONCLUSION: SYVN1 regulates ferroptosis through the HMGB1/NRF2/HO-1 axis to prevent spinal cord ischemia-reperfusion injury.

Xenon postconditioning attenuates neuronal injury after spinal cord ischemia/reperfusion injury by targeting endoplasmic reticulum stress-associated apoptosis.

The purpose of the study is to explore the underlying mechanisms of xenon (Xe) which protects against spinal cord ischemia/reperfusion injury (SCIRI). A SCIRI rat model was induced by abdominal artery occlusion for 85 min and reperfusion. Xe postconditioning (50% Xe) was administered 1 h after 1 h of reperfusion. At reperfusion time points (2, 4, 6, and 24 h), rats were treated with spinal cord scans by MRI to assess the time of peak spinal cord injury after SCIRI. Subsequently, endoplasmic reticulum (ER) stress inhibitor sodium 4-phenylbutyrate (4-PBA) was administered by daily intraperitoneal injection (50 mg/kg) for 5 days before SCIRI. At 4 h after reperfusion, motor function, immunofluorescence staining, hematoxylin and eosin (HE) staining, Nissl staining, TUNEL staining, real-time reverse transcription polymerase chain (RT-PCR) reaction, and western blot analyses were performed to investigate the protective effects of Xe against SCIRI. In the rat I/R model, spinal cord edema peaked at reperfusion 4 h. SCIRI activated ER stress, which was located in neurons. Xe postconditioning remarkably alleviated hind limb motor function, reduced neuronal apoptosis rate, increased the number of normal neurons, and inhibited the expression of ER stress-related protein in spinal cord. Furthermore, the administration of the ER stress inhibitor 4-PBA strongly decreased ER stress-induced apoptosis following SCIRI. Xe postconditioning inhibits ER stress activation, which contributes to alleviate SCIRI by suppressing neuronal apoptosis.

Necrostatin-1 Attenuates Delayed Paraplegia after Transient Spinal Cord Ischemia in Rabbits by Inhibiting the Upregulation of Receptor-Interacting Protein Kinase 1 and 3.

BACKGROUND: Delayed-onset paraplegia is a disastrous complication after thoracoabdominal aortic open surgery and thoracic endovascular aortic repair. Studies have revealed that transient spinal cord ischemia caused by temporary occlusion of the aorta induces delayed motor neuron death owing to apoptosis and necroptosis. Recently, necrostatin-1 (Nec-1), a necroptosis inhibitor, has been reported to reduce cerebral and myocardial infarction in rats or pigs. In this study, we investigated the efficacy of Nec-1 in delayed paraplegia after transient spinal cord ischemia in rabbits and assessed the expression of necroptosis- and apoptosis-related proteins in motor neurons. METHODS: This study used rabbit transient spinal cord ischemia models using a balloon catheter. They were divided into a vehicle-treated group (n = 24), Nec-1-treated group (n = 24), and sham-controls (n = 6). In the Nec-1-treated group, 1 mg/kg of Nec-1 was intravascularly administered immediately before ischemia induction. Neurological function was assessed using the modified Tarlov score, and the spinal cord was removed 8 hr and 1, 2, and 7 days after reperfusion. Morphological changes were examined using hematoxylin and eosin staining. The expression levels of necroptosis-related proteins (receptor-interacting protein kinase [RIP] 1 and 3) and apoptosis-related proteins (Bax and caspase-8) were assessed using western blotting and histochemical analysis. We also performed double-fluorescence immunohistochemical studies of RIP1, RIP3, Bax, and caspase-8. RESULTS: Neurological function significantly improved in the Nec-1-treated group compared with that in the vehicle-treated group 7 days after reperfusion (median 3 and 0, P = 0.025). Motor neurons observed 7 days after reperfusion were significantly decreased in both groups compared with the sham group (vehicle-treated, P < 0.001; Nec-1-treated, P < 0.001). However, significantly more motor neurons survived in the Nec-1-treated group than in the vehicle-treated group (P < 0.001). Western blot analysis revealed RIP1, RIP3, Bax, and caspase-8 upregulation 8 hr after reperfusion in the vehicle-treated group (RIP1, P = 0.001; RIP3, P = 0.045; Bax, P = 0.042; caspase-8, P = 0.047). In the Nec-1-treated group, the upregulation of RIP1 and RIP3 was not observed at any time point, whereas that of Bax and caspase-8 was observed 8 hr after reperfusion (Bax, P = 0.029; caspase-8, P = 0.021). Immunohistochemical study revealed the immunoreactivity of these proteins in motor neurons. Double-fluorescence immunohistochemistry revealed the induction of RIP1 and RIP3, and that of Bax and caspase-8, in the same motor neurons. CONCLUSIONS: These data suggest that Nec-1 reduces delayed motor neuron death and attenuates delayed paraplegia after transient spinal cord ischemia in rabbits by selectively inhibiting necroptosis of motor neurons with minimal effect on their apoptosis.

Intranasal administration of polysulfide prevents neurodegeneration in spinal cord and rescues mice from delayed paraplegia after spinal cord ischemia.

BACKGROUND: Delayed paraplegia is a devastating complication of thoracoabdominal aortic surgery. Hydrogen sulfide (H2S) was reported to be protective in a mouse model of spinal cord ischemia and the beneficial effect of H2S has been attributed to polysulfides. The objective of this study was to investigate the effects of polysulfides on delayed paraplegia after spinal cord ischemia. METHODS AND RESULTS: Spinal cord ischemia was induced in male and female C57BL/6J mice by clamping the aortic arch and the left subclavian artery. Glutathione trisulfide (GSSSG), glutathione (GSH), glutathione disulfide (GSSG), or vehicle alone was administered intranasally at 0, 8, 23, and 32 h after surgery. All mice treated with vehicle alone developed paraplegia within 48 h after surgery. GSSSG, but not GSH or GSSG, prevented paraplegia in 8 of 11 male mice (73%) and 6 of 8 female mice (75%). Intranasal administration of 34S-labeled GSSSG rapidly increased 34S-labeled sulfane sulfur species in the lumbar spinal cord. In mice treated with intranasal GSSSG, there were increased sulfane sulfur levels, and decreased neurodegeneration, microglia activation, and caspase-3 activation in the lumbar spinal cord. In vitro studies using murine primary cortical neurons showed that GSSSG increased intracellular levels of sulfane sulfur. GSSSG, but not GSH or GSSG, dose-dependently improved cell viability after oxygen and glucose deprivation/reoxygenation (OGD/R). Pantethine trisulfide (PTN-SSS) also increased intracellular sulfane sulfur and improved cell viability after OGD/R. Intranasal administration of PTN-SSS, but not pantethine, prevented paraplegia in 6 of 9 male mice (66%). CONCLUSIONS: Intranasal administration of polysulfides rescued mice from delayed paraplegia after transient spinal cord ischemia. The neuroprotective effects of GSSSG were associated with increased levels of polysulfides and sulfane sulfur in the lumbar spinal cord. Targeted delivery of sulfane sulfur by polysulfides may prove to be a novel approach to the treatment of neurodegenerative diseases.

Dexmedetomidine postconditioning alleviates spinal cord ischemia-reperfusion injury in rats via inhibiting neutrophil infiltration, microglia activation, reactive gliosis and CXCL13/CXCR5 axis activation.

PURPOSE: Spinal cord ischemia-reperfusion (I/R) injury is an unresolved complication and its mechanisms are still not completely understood. Here, we studied the neuroprotective effects of dexmedetomidine (DEX) postconditioning against spinal cord I/R injury in rats and explored the possible mechanisms. MATERIALS AND METHODS: In the study, rats were randomly divided into five groups: sham group, I/R group, DEX0.5 group, DEX2.5 group, and DEX5 group. I/R injury was induced in experimental rats; 0.5 µg/kg, 2.5 µg/kg, 5 µg/kg DEX were intravenously injected upon reperfusion respectively. Neurological function, histological assessment, and the disruption of blood-spinal cord barrier (BSCB) were evaluated via the BBB scoring, hematoxylin and eosin staining, Evans Blue (EB) extravasation and spinal cord edema, respectively. Neutrophil infiltration was evaluated via Myeloperoxidase (MPO) activity. Microglia activation and reactive gliosis was evaluated via ionized calcium-binding adapter molecule-1(IBA-1) and glial fibrillary acidic protein (GFAP) immunofluorescence, respectively. The expression of C-X-C motif ligand 13 (CXCL13), C-X-C chemokine receptor type 5(CXCR5), caspase-3 was determined by western blotting. The expression levels of interleukin 6(IL-6), tumor necrosis factor-α(TNF-α), IL-1ß were determined by ELISA assay. RESULTS: DEX postconditioning preserved neurological assessment scores, improved histological assessment scores, attenuated BSCB leakage after spinal cord I/R injury. Neutrophil infiltration, microglia activation and reactive gliosis were also inhibited by DEX postconditioning. The expression of CXCL13, CXCR5, caspase-3, IL-6, TNF-α, IL-1ß were reduced by DEX postconditioning. CONCLUSIONS: DEX postconditioning alleviated spinal cord I/R injury, which might be mediated via inhibition of neutrophil infiltration, microglia activation, reactive gliosis and CXCL13/CXCR5 axis activation.

Dexmedetomidine Attenuates Spinal Cord Ischemia-reperfusion Injury in Rabbits by Decreasing Oxidation and Apoptosis.

BACKGROUND: In brain ischemia, dexmedetomidine (DEX) prevents glutamate and norepinephrine changes, increases nerve conduction, and prevents apoptosis, but the mechanisms are poorly understood. OBJECTIVE: This study aimed at examining the protective effect and function of DEX on spinal cord ischemia-reperfusion injury (SCIRI) and whether the effect is mediated by oxidative stress and apoptosis (with the involvement of Bcl-2, Bax, mitochondria, and Caspase-3). METHODS: Rabbits were randomly divided into the sham group, infusion/reperfusion (I/R) group, and DEX+I/R group. SCIRI was induced by occluding the aorta just caudal to the left renal artery for 40 min, followed by reperfusion. DEX was continuously administered for 60 min before clamping. The animals were evaluated for neuronal functions. Spinal cord tissues were examined for SOD activity and MDA content. Bcl-2, Bax, and Caspase-3 expressions were detected by western blotting. TUNEL staining was used for apoptosis. RESULTS: With the extension of reperfusion time, the hind limbs' neurological function in the DEX+I/R group gradually improved, but it became worse in the I/R group (all P<0.05 vs. the other time points within the same groups). Compared with I/R, DEX decreased MDA and increased SOD (P<0.01), upregulated Bcl-2 protein expression (P<0.05), downregulated Bax expression (P<0.05), decreased caspase-3 expression (P<0.05), prevented histological changes in neurons, and decreased the apoptotic index of the TUNEL labeling (P<0.05). CONCLUSION: DEX could attenuate SCIRI in rabbits by improving the oxidative stress status, regulating the expression of apoptosis-related proteins, and decreasing neuronal apoptosis.

Effects of Dexmedetomidine Administered Through Different Routes on Kidney Tissue in Rats with Spinal Cord Ischaemia-Reperfusion Injury.

Background: Ischaemia-reperfusion (IR) injury, which can be encountered during surgical procedures involving the abdominal aorta, is a complex process that affects distant organs, such as the heart, liver, kidney, and lungs, as well as the lower extremities. In this study, we aimed to contribute to the limited literature by investigating the protective effect of dexmedetomidine, which was administered through different routes, on kidney tissue in rats with spinal cord IR injury. Methods: A total of 30 rats were randomly divided into five groups: control (C group), IR (IR group), IR-intraperitoneal dexmedetomidine (IRIPD group), IR-intrathecal dexmedetomidine (IRITD group), and IR-intravenous dexmedetomidine (IRIVD group). The spinal cord IR model was established. Dexmedetomidine was administered at doses of 100 µg/kg intraperitoneally, 3 µg/kg intrathecally, and 9 µg/kg intravenously. Histopathologic parameters in kidney tissue samples taken at the end of the reperfusion period and biochemical parameters in serum were evaluated. Results: When examined histopathologically, tubular dilatation was found to be significantly reduced in the IRIVD, IRITD, and IRIPD groups compared with the IR group (p = 0.012, all). Vascular vacuolization and hypertrophy were significantly decreased in the IRIVD, IRITD, and IRIPD groups compared with the IR group (p = 0.006, all). Tubular cell degeneration and necrosis were significantly reduced in the IRIVD, IRITD, and IRIPD groups compared with the IR group (p = 0.008, p = 0.08, and p = 0.030, respectively). Lymphocyte infiltration was significantly decreased in the IRIVD and IRITD groups compared with the IR group (p = 0.006 and p = 0.06, respectively). Conclusion: It was observed that dexmedetomidine administered by different routes improved the damage caused by IR in kidney histopathology. We think that the renoprotective effects of dexmedetomidine administered intravenously and intrathecally before IR in rats are greater.

Tanshinone Protects against Spinal Cord Ischemia-Reperfusion Injury by Inhibiting JNK Activity.

Spinal cord reperfusion injury as a secondary damage after primary spinal cord injury is an important factor causing nerve cell damage. In this study, we aim to investigate the effects and mechanisms of tanshinone (TAE) in the rabbit spinal cord during ischemia-reperfusion. New Zealand white rabbits were randomly divided into 3 groups: sham-operated group (5 rabbits), ischemia-reperfusion group (0.9% TAE was administered intraperitoneally 30 min before ischemia, and 4 groups of 5 rabbits each according to different time periods of reperfusion: group A reperfused for 0.5 h, group B reperfused for 2 h, group C reperfused for 8 h, and group D reperfused for 24 h), and TAE group (an ischemia-reperfused for 24 h). Group A was reperfused for 0.5 h, group B for 2 h, group C for 8 h, group D for 24 h, and group TAE (TAE was applied 30 min before ischemia reperfusion, grouped as ischemia-reperfusion group). The expression of JNK (c-Jun NH2-terminal Kinase) and phosphorylation-JNK (p-JNK) in spinal cord tissues of each group were detected by Western blot. Light and electron microscopy showed that early apoptosis started in group B in the ischemia-reperfusion group, while early apoptosis appeared only in group D in the tanshinone intervention group. Western blot showed that p-JNK expression started in group B in the ischemia-reperfusion group and gradually increased with the prolongation of ischemia time, while p-JNK expression only increased in group D in the tanshinone intervention group. In the tanshinone intervention group, p-JNK was activated only in group D and its activity was less than that in the ischemia-reperfusion group; the protein expression of JNK did not change significantly in both groups. Spinal cord ischemia-reperfusion can cause spinal cord injury by activating the signaling molecule JNK (MRPKs family), and early tanshinone intervention can partially inhibit this injury. Our finding provides a new idea and theoretical basis for clinical treatment of spinal cord ischemia-reperfusion injury.

Astragalin Protects against Spinal Cord Ischemia Reperfusion Injury through Attenuating Oxidative Stress-Induced Necroptosis.

Spinal cord ischemia/reperfusion (SCI/R) injury is a devastating complication usually occurring after thoracoabdominal aortic surgery. However, it remains unsatisfactory for its intervention by using pharmacological strategies. Oxidative stress is a main pharmacological process involved in SCI/R, which will elicit downstream programmed cell death such as the novel defined necroptosis. Astragalin is a bioactive natural flavonoid with a wide spectrum of pharmacological activities. Herein, we firstly evaluated the effect of astragalin to oxidative stress as well as the possible downstream necroptosis after SCI/R in mice. Our results demonstrated that astragalin improves the ethological score and histopathological deterioration of SCI/R mice. Astragalin mitigates oxidative stress and ameliorates inflammation after SCI/R. Astragalin blocks necroptosis induced by SCI/R. That is, the amelioration of astragalin to the motoneuron injury and histopathological changes. Indicators of oxidative stress, inflammation, and necroptosis after SCI/R were significantly blocked. Summarily, we firstly illustrated the protection of astragalin against SCI/R through its blockage to the necroptosis at downstream of oxidative stress.

Biochemical, pathological and ultrastructural investigation of whether lamotrigine has neuroprotective efficacy against spinal cord ischemia reperfusion injury.

INTRODUCTION: Lamotrigine, an anticonvulsant drug with inhibition properties of multi-ion channels, has been shown to be able to attenuates secondary neuronal damage by influencing different pathways. The aim of this study was to look into whether lamotrigine treatment could protect the spinal cord from experimental spinal cord ischemia-reperfusion injury. MATERIALS AND METHODS: Thirty-two rats, eight rats per group, were randomly assigned to the sham group in which only laparotomy was performed, and to the ischemia, methylprednisolone and lamotrigine groups, where the infrarenal aorta was clamped for thirty minutes to induce spinal cord ischemia-reperfusion injury. Tissue samples belonging to spinal cords were harvested from sacrificed animals twenty-four hours after reperfusion. Tumor necrosis factor-alpha levels, interleukin-1 beta levels, nitric oxide levels, superoxide dismutase activity, catalase activity, glutathione peroxidase activity, malondialdehyde levels and caspase-3 activity were studied. Light and electron microscopic evaluations were also performed to reveal the pathological alterations. Basso, Beattie, and Bresnahan locomotor scale and the inclined-plane test was used to evaluate neurofunctional status at the beginning of the study and just before the animals were sacrificed. RESULTS: Lamotrigine treatment provided significant improvement in the neurofunctional status by preventing the increase in cytokine expression, increased lipid peroxidation and oxidative stress, depletion of antioxidant enzymes activity and increased apoptosis, all of which contributing to spinal cord damage through different paths after ischemia reperfusion injury. Furthermore, lamotrigine treatment has shown improved results concerning the histopathological and ultrastructural scores and the functional tests. CONCLUSION: These results proposed that lamotrigine may be a useful therapeutic agent to prevent the neuronal damage developing after spinal cord ischemia-reperfusion injury.

Perillaldehyde Alleviates Spinal Cord Ischemia-Reperfusion Injury Via Activating the Nrf2 Pathway.

BACKGROUND: Spinal Cord ischemia-reperfusion injury (SCII) is one of the most destructive complications in thoracic-abdominal aortic surgery, which can cause physical abnormalities, paralysis and even brain death. Evidence has shown that perillaldehyde (PAH) can ameliorate rat's cerebra ischemia-reperfusion injury. However, the effect of PAH on SCII remains unknown. METHODS: The current study established SCII rat models and oxygen and glucose deprivation/reoxygenation-induced BV2 microglia models to explore whether PAH could alleviate SCII symptoms and to investigate underlying mechanism. RESULTS: SCII rats underwent severe neurologic motor dysfunction and histopathologic injury compared with the normal rats, which are exhibited by loss of motor neurons and decrease of nissl bodies. Treatment with PAH significantly ameliorated motor dysfunction and neuron damage. PAH downregulated the expression of NLR family pyrin domain containing 3, cleaved/pro caspase-1, interleukin-1ß and interleukin-18 in spinal cord tissues of SCII rats. Besides, the contents of oxidative stress-related factors superoxide dismutase, manganese-dependent superoxide dismutase, catalase and glutathione peroxidase were significantly increased and malondialdehyde content was decreased after PAH treatment. PAH treatment upregulated the expression of nuclear factor-E2-related factor 2 and heme oxygenase-1 in spinal cord tissues of SCII rats. Our in vitro study confirmed that PAH inhibited microglial activation by activating the nuclear factor-E2-related factor 2/heme oxygenase-1 pathway, exhibited by alleviated inflammation and oxidative stress. CONCLUSIONS: This study elucidates that PAH has the potential value for treating SCII, which provides an experimental basis for clinical trials in the future.

Downregulation of LncRNA Gas5 inhibits apoptosis and inflammation after spinal cord ischemia-reperfusion in rats.

Spinal cord ischemia-reperfusion injury(SCII)affects nerve function through many mechanisms, which are complex and not fully understood. Recently, accumulating evidence has indicated that long noncoding RNAs (lncRNAs) play an increasingly important role in SCII. We investigated the role of lncRNA growth arrest-specific 5(Gas5) in a rat SCII model, and its effects on apoptosis and inflammation possibly by modulating MMP-7, cleaved caspase-3 and IL-1ß. LncRNA Gas5 and MMP-7 were knocked down by intrathecal siRNA injection. Neurological assessment and TUNEL assay were performed. The RNA and protein expression levels of lncRNA Gas5, MMP-7, cleaved caspase-3 and IL-1ß were determined by PCR and Western blotting, respectively. MMP-7 localization was visualized by double-immunofluorescence. SCII induced functional impairment in the hind limb, and the expression of lncRNA Gas5 was highest at 24 h after SCII. LncRNA Gas5 downregulation inhibited the RNA and protein expression of MMP-7, as well as the protein expression of cleaved caspase-3 and IL-1ß. LncRNA Gas5 downregulation reduced the number of TUNEL-positive and MMP-7-positive double-labeled cells. Therefore, lncRNA Gas5 downregulation alleviated hind limb functional impairment and improved neuronal apoptosis after SCII. MMP-7 downregulation also inhibited apoptosis and inflammation and alleviated damage. Pretreatment with intrathecal injection of si-lncRNA Gas5 and si-MMP-7 reduced the expression levels of cleaved caspase-3 and IL-1ß, protecting nerve function after SCII. These results show that lncRNA Gas5 plays an important role in SCII, perhaps by inhibiting MMP-7, cleaved caspase-3 and IL-1ß. LncRNA Gas5 downregulation could be a promising therapeutic approach in the SCII treatment.

Intra-arterial thrombolytic therapy for acute anterior spinal artery stroke.

BACKGROUND AND IMPORTANCE: Spinal cord infarction is rare but can be extremely disabling. Prompt diagnosis and treatment of these infarcts is important for patient outcomes. While intravenous thrombolytic therapy is a well-established form of treatment in circumstances of cerebral stroke, it has only recently been successfully used in a few incidents of spinal cord ischemia. We present a case of anterior spinal artery (ASA) territory ischemia treated with ASA intra-arterial thrombolytic therapy. CLINICAL PRESENTATION: A 52-year-old male presented with acute onset of severe lumbar pain, rapidly progressing paraplegia and loss of pain and temperature sensation, with preservation of proprioception and vibratory sensation at the L1 level and below on the right and at the L3 level and below on the left. MRI showed restricted diffusion involving the cord at and below L1 level, with normal cord T2 signal. Digital subtraction spinal angiography showed ASA cutoff in the descending limb at the level of L1. Intra-arterial tissue plasminogen activator (t-PA) combined with verapamil and eptifibatide was administered within the ASA and the patient had significant neurological improvement immediately postoperatively and at 8-month clinical follow-up. CONCLUSION: Direct ASA intra-arterial thrombolysis is feasible, and this drug combination might be an effective therapy for spinal stroke.

Assessment of the neuroprotective effects of (-)-epigallocatechin-3-gallate on spinal cord ischemia-reperfusion injury in rats.

Objective: Paraplegia or paraparesis due to spinal cord ischemia is one of the complications following thoracoabdominal aortic surgery. Recent studies revealed the neuroprotective effects of (-)-epigallocatechin-3-gallate (EGCG) on a variety of neurological disorders. The purpose of this study was to determine the neuroprotective effects of EGCG following spinal cord ischemia-reperfusion injury (IRI).Design: The present study was conducted on four groups of rats each as follows: Sham-operated group (laparotomy alone); Control group (with IRI); EGCGI group (50-mg/kg, i.p., before IRI), and EGCGII group (50-mg/kg, i.p., after IRI). Neurological function evaluated with motor deficit index (MDI) test. Spinal cord samples were taken 48 h after IRI and studied for determination of malodialdehyde (MDA) level, histopathology, and immunohistochemistry of caspase-3, TNF-α, and iNOS.Setting: Mazandaran University of Medical Sciences, Sari, Iran.Results: The level of MDA was significantly decreased in EGCG-treated rats. Attenuated caspase-3, TNF-α, and iNOS expression could be significantly detected in the EGCG-treated rats. Also, EGCG reduced the extent of degeneration of the spinal cord neurons, in addition to a significant reduction of MDI.Conclusion: The results suggest that pre- and post-treatment with EGCG may be effective in protecting spinal cord from IRI.

Neuroprotective effect of neuregulin-1ß on spinal cord ischemia reperfusion injury.

Objective: This study was designed to see if neuregulin-1ß (NRG-1ß) plays a protective role in spinal cord ischemia and reperfusion injury (SCII).Design: Animal research.Setting: China.Participants: NA.Interventions: Forty-eight SD rats were randomly divided into control group (n = 16), SCII model group (n = 16) and NRG-1ß-treated group (n = 16). In control group, the abdominal aorta was isolated but not clipped. The rats in NRG-1ß-treated group were treated with 10µg/kg NRG-1ß during developing SCII model.Outcome Measures: Neurological scores were evaluated. At 3, 6, 12 and 24 h after the reperfusion, rats were killed. Pathological changes of spinal cord were assessed with HE staining, and immunohistochemical staining of matrix metalloproteinases-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1). MMP-9 and TIMP-1 mRNA levels were assessed using real-time PCR.Results: NRG-1ß reduced the damage of SCII in the rats. The expression of MMP-9 protein and mRNA in NRG-1ß treatment group was significantly lower than the model group (P < 0.05) at 6 h, 12 h and 24 h after the perfusion. The expression of TIMP-1 protein and mRNA in the treatment group was significantly higher than the model group at 12 h and 24 h after the perfusion.Conclusion: NRG-1ß reduced the reperfusion damage in rat model of SCII, in which process MMP-9 and TIMP-1 were probably involved.