Ruxolitinib improves the inflammatory microenvironment, restores glutamate homeostasis, and promotes functional recovery after spinal cord injury.

JOURNAL/nrgr/04.03/01300535-202419110-00030/figure1/v/2024-03-08T184507Z/r/image-tiff The inflammatory microenvironment and neurotoxicity can hinder neuronal regeneration and functional recovery after spinal cord injury. Ruxolitinib, a JAK-STAT inhibitor, exhibits effectiveness in autoimmune diseases, arthritis, and managing inflammatory cytokine storms. Although studies have shown the neuroprotective potential of ruxolitinib in neurological trauma, the exact mechanism by which it enhances functional recovery after spinal cord injury, particularly its effect on astrocytes, remains unclear. To address this gap, we established a mouse model of T10 spinal cord contusion and found that ruxolitinib effectively improved hindlimb motor function and reduced the area of spinal cord injury. Transcriptome sequencing analysis showed that ruxolitinib alleviated inflammation and immune response after spinal cord injury, restored EAAT2 expression, reduced glutamate levels, and alleviated excitatory toxicity. Furthermore, ruxolitinib inhibited the phosphorylation of JAK2 and STAT3 in the injured spinal cord and decreased the phosphorylation level of nuclear factor kappa-B and the expression of inflammatory factors interleukin-1ß, interleukin-6, and tumor necrosis factor-α. Additionally, in glutamate-induced excitotoxicity astrocytes, ruxolitinib restored EAAT2 expression and increased glutamate uptake by inhibiting the activation of STAT3, thereby reducing glutamate-induced neurotoxicity, calcium influx, oxidative stress, and cell apoptosis, and increasing the complexity of dendritic branching. Collectively, these results indicate that ruxolitinib restores glutamate homeostasis by rescuing the expression of EAAT2 in astrocytes, reduces neurotoxicity, and effectively alleviates inflammatory and immune responses after spinal cord injury, thereby promoting functional recovery after spinal cord injury.

Extradural contralateral S1 nerve root transfer for spastic lower limb paralysis.

The current study aims to ascertain the anatomical feasibility of transferring the contralateral S1 ventral root (VR) to the ipsilateral L5 VR for treating unilateral spastic lower limb paralysis. Six formalin-fixed (three males and three females) cadavers were used. The VR of the contralateral S1 was transferred to the VR of the ipsilateral L5. The sural nerve was selected as a bridge between the donor and recipient nerve. The number of axons, the cross-sectional areas and the pertinent distances between the donor and recipient nerves were measured. The extradural S1 VR and L5 VR could be separated based on anatomical markers of the dorsal root ganglion. The gross distance between the S1 nerve root and L5 nerve root was 31.31 (± 3.23) mm in the six cadavers, while that on the diffusion tensor imaging was 47.51 (± 3.23) mm in 60 patients without spinal diseases, and both distances were seperately greater than that between the outlet of S1 from the spinal cord and the ganglion. The numbers of axons in the S1 VRs and L5 VRs were 13414.20 (± 2890.30) and 10613.20 (± 2135.58), respectively. The cross-sectional areas of the S1 VR and L5 VR were 1.68 (± 0.26) mm 2 and 1.08 (± 0.26) mm 2, respectively. In conclusion, transfer of the contralateral S1 VR to the ipsilateral L5 VR may be an anatomically feasible treatment option for unilateral spastic lower limb paralysis.

Extradural Contralateral Ventral Root Transfer to Treat Lower Limb Motor Dysfunction in Paraplegia.

STUDY DESIGN: Eight cadavers were included in this anatomical study. OBJECTIVE: This study aimed to confirm the anatomical feasibility of extradural transfer of the contralateral T11 ventral root (VR) to the ipsilateral L2 level and the contralateral L1 VR to the ipsilateral L3 level to restore lower limb function in cases of paraplegia. SUMMARY OF BACKGROUND DATA: Motor dysfunction due to hemiplegia significantly affects the daily life of patients. To date, unlike in cases of upper limb dysfunction, there are few studies on the surgical management of lower limb movement dysfunction. MATERIALS AND METHODS: Eight cadavers were included in this study to confirm the feasibility of the nerve transfer. After separating the VR and dorsal root at each level, the VRs at the T11 and L1 levels were anastomosed with the VRs of L2 and L3, respectively. The length of the VRs of donor roots and the distance between the donor and recipient nerves were measured. H&E staining was performed to verify the number of axons and the cross-sectional area of the VRs. Lumbar x-rays of 60 healthy adults were used to measure the distance between the donor and recipient nerves. RESULTS: After exposing the bilateral extradural each root, the VRs could be easily isolated from the whole root. The distance between the VRs of T11 and L2, L1, and L3 was significantly longer than the length of the donor nerve. Therefore, the sural nerve was used for grafting. The measurements performed on the lumbar x-rays of the 60 healthy adults confirmed the results. The number of axons and cross-sectional area of the VRs were measured. CONCLUSION: Our study confirmed the anatomical feasibility of transferring the VRs of T11 to L2 and that of L1 to L3 to restore lower limb function in cases of hemiplegia. LEVEL OF EVIDENCE: 5.

A comparison of robot-assisted and fluoroscopy-assisted kyphoplasty in the treatment of multi-segmental osteoporotic vertebral compression fractures.

Osteoporotic vertebral compression fracture (OVCF) has become a major public health issue that becomes more pressing with increasing global aging. Percutaneous kyphoplasty (PKP) is an effective treatment for OVCF. Robot-assisted PKP has been utilized in recent years to improve accuracy and reduce complications. However, the effectiveness of robot-assisted PKP in the treatment of multi-segmental OVCF has yet to be proved. This study was designed to compare the efficacy of robot-assisted and conventional fluoroscopy-assisted multi-segmental PKP. A total of 30 cases with multi-segmental OVCF between April 2019 and April 2021 were included in this study. Fifteen cases were assigned to the robot-assisted PKP group (robot group) and 15 cases to the conventional fluoroscopy-assisted PKP group (conventional fluoroscopy group). The number of fluoroscopic exposures, fluoroscopic dose, operation time, cement leakage rate, visual analog scale (VAS) score, vertebral kyphosis angle (VKA), and height of fractured vertebral body (HFV) were compared between the 2 groups. The number of fluoroscopic exposures, fluoroscopic doses, and cement leakage rates in the robot group were lower than in the conventional fluoroscopy group ( P<0.05) while the operative time in the robot group was longer than in the conventional fluoroscopy group ( P<0.05). VAS score and VKA were decreased and HFV was increased after surgery in both groups ( P<0.05). Therefore, robot-assisted PKP for the treatment of multi-segmental OVCF can reduce the number of fluoroscopic exposures, fluoroscopic doses, and cement leakage compared to conventional treatment. As such, robot-assisted PKP has good application prospects and is potentially more effective in the treatment of multi-segmental OVCF.

Ruxolitinib attenuates secondary injury after traumatic spinal cord injury.

Excessive inflammation post-traumatic spinal cord injury (SCI) induces microglial activation, which leads to prolonged neurological dysfunction. However, the mechanism underlying microglial activation-induced neuroinflammation remains poorly understood. Ruxolitinib (RUX), a selective inhibitor of JAK1/2, was recently reported to inhibit inflammatory storms caused by SARS-CoV-2 in the lung. However, its role in disrupting inflammation post-SCI has not been confirmed. In this study, microglia were treated with RUX for 24 hours and then activated with interferon-γ for 6 hours. The results showed that interferon-γ-induced phosphorylation of JAK and STAT in microglia was inhibited, and the mRNA expression levels of pro-inflammatory cytokines tumor necrosis factor-α, interleukin-1ß, interleukin-6, and cell proliferation marker Ki67 were reduced. In further in vivo experiments, a mouse model of spinal cord injury was treated intragastrically with RUX for 3 successive days, and the findings suggest that RUX can inhibit microglial proliferation by inhibiting the interferon-γ/JAK/STAT pathway. Moreover, microglia treated with RUX centripetally migrated toward injured foci, remaining limited and compacted within the glial scar, which resulted in axon preservation and less demyelination. Moreover, the protein expression levels of tumor necrosis factor-α, interleukin-1ß, and interleukin-6 were reduced. The neuromotor function of SCI mice also recovered. These findings suggest that RUX can inhibit neuroinflammation through inhibiting the interferon-γ/JAK/STAT pathway, thereby reducing secondary injury after SCI and producing neuroprotective effects.