Human spinal GABA neurons alleviate spasticity and improve locomotion in rats with spinal cord injury

Gong, Chen-Zi; Zheng, Xiaolong; Guo, Fangliang; Wang, Yanan; Zhang, Song; Chen, Jing; Sun, Xuejiao; Shah, Sayed Zulfiqar Ali; Zheng, Yifeng; Li, Xiao; Yin, Yatao; Li, Qian; Huang, Xiaolin; Guo, Tie-Cheng; Han, Xiaohua; Zhang, Su‐Chun; Wang, Wei; Chen, Hong

doi:10.1016/j.celrep.2021.108889

Cited by 23 publications

(21 citation statements)

References 72 publications

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“…In both normal humans and rats, the amplitude of the H-reflex is attenuated by repeated activations at frequencies higher than 0.1 Hz ( Thompson et al, 1992 ; Hultborn et al, 1996 ). Rate-dependent depression (RDD) is reduced in individuals with SCI, and this effect is a reliable indicator of spasticity ( Grey et al, 2008 ; Boulenguez et al, 2010 ; Gong et al, 2021 ). We tested the RDD of the H-reflex at 12 weeks after SCI to assess whether long-term treatment with NMD alleviated spasticity-like symptoms.…”

Section: Resultsmentioning

confidence: 99%

“…Surgeries were conducted on adult female rats (260–300 g) at the age of 9–11 weeks. The procedure was similar to that described previously ( Gong et al, 2021 ). Briefly, rats were anesthetized with isoflurane (induction at 4%, maintenance at 2%) in oxygen.…”

Section: Methodsmentioning

confidence: 99%

“…The mechanical withdrawal threshold was measured with an electronic Von Frey apparatus (Electronic Von Frey Anesthesiometer 2450, IITC Life Sciences, Inc., Woodland, CA, United States) using a previously described procedure ( Parada et al, 2003 ; Gong et al, 2021 ). The application of the Von Frey test requires weight support, as evidenced by a score of 9 during BBB locomotor scoring ( Detloff et al, 2010 ; Fouad et al, 2020 ).…”

Section: Methodsmentioning

confidence: 99%

“…At 12 weeks post-SCI, the H-reflex was recorded by a Dantec Keypoint EMG Workstation (Natus, United States) as described previously ( Boulenguez et al, 2010 ; Gong et al, 2021 ). Briefly, the rats were anesthetized with 1.5% isoflurane in oxygen.…”

Section: Methodsmentioning

confidence: 99%

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Nimodipine Promotes Functional Recovery After Spinal Cord Injury in Rats

Guo

Zheng

et al. 2021

Front. Pharmacol.

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Spinal cord injury (SCI) is a devastating condition that results in severe motor, sensory, and autonomic dysfunction. The L-/T-type calcium channel blocker nimodipine (NMD) exerts a protective effect on neuronal injury; however, the protective effects of long-term administration of NMD in subjects with SCI remain unknown. Thus, the aim of this study was to evaluate the role of long-term treatment with NMD on a clinically relevant SCI model. Female rats with SCI induced by 25 mm contusion were subcutaneously injected with vehicle or 10 mg/kg NMD daily for six consecutive weeks. We monitored the motor score, hind limb grip strength, pain-related behaviors, and bladder function in this study to assess the efficacy of NMD in rats with SCI. Rats treated with NMD showed improvements in locomotion, pain-related behaviors, and spasticity-like symptoms, but not in open-field spontaneous activity, hind limb grip strength or bladder function. SCI lesion areas and perilesional neuronal numbers, gliosis and calcitonin gene-related peptide (CGRP+) fiber sprouting in the lumbar spinal cord and the expression of K+–Cl− cotransporter 2 (KCC2) on lumbar motor neurons were also observed to further explore the possible protective mechanisms of NMD. NMD-treated rats showed greater tissue preservation with reduced lesion areas and increased perilesional neuronal sparing. NMD-treated rats also showed improvements in gliosis, CGRP+ fiber sprouting in the lumbar spinal cord, and KCC2 expression in lumbar motor neurons. Together, these results indicate that long-term treatment with NMD improves functional recovery after SCI, which may provide a potential therapeutic strategy for the treatment of SCI.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Nimodipine Promotes Functional Recovery After Spinal Cord Injury in Rats

Guo

Zheng

et al. 2021

Front. Pharmacol.

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“…The motor ability of modeling mice was evaluated by TreadScan according to the protocol of a published study [32]. In brief, prior to the test day, mice were trained to walk on the motor-driven treadmill belt at a speed of 6 cm/s in 1 min for three times, during three consecutive days.…”

Section: Treadscan Analysismentioning

confidence: 99%

Transforming growth factor-β1 protects against LPC-induced cognitive deficit by attenuating pyroptosis of microglia via NF-κB/ERK1/2 pathways

Xie

Chen

Liu

et al. 2022

J Neuroinflammation

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Background Demyelinating diseases in central nervous system (CNS) are a group of diseases characterized by myelin damage or myelin loss. Transforming growth factor beta1 (TGF-β1) is widely recognized as an anti-inflammatory cytokine, which can be produced by both glial and neuronal cells in CNS. However, the effects of TGF-β1 on demyelinating diseases and its underlying mechanisms have not been well investigated. Methods A demyelinating mouse model using two-point injection of lysophosphatidylcholine (LPC) to the corpus callosum in vivo was established. Exogenous TGF-β1 was delivered to the lesion via brain stereotactic injection. LFB staining, immunofluorescence, and Western blot were applied to examine the severity of demyelination and pyroptosis process in microglia. Morris water maze test was used to assess the cognitive abilities of experimental mice. Furthermore, lipopolysaccharide (LPS) was applied to induce pyroptosis in primary cultured microglia in vitro, to explore potential molecular mechanism. Results The degree of demyelination in LPC-modeling mice was found improved with supplement of TGF-β1. Besides, TGF-β1 treatment evidently ameliorated the activated proinflammatory pyroptosis of microglia, with downregulated levels of the key pyroptosis effector Gasdermin D (GSDMD), inflammasomes, and cleaved-IL-1β, which effectively attenuated neuroinflammation in vivo. Evaluated by behavioral tests, the cognitive deficit in LPC-modeling mice was found mitigated with application of TGF-β1. Mechanistically, TGF-β1 could reverse pyroptosis-like morphology in LPS-stimulated primary cultured microglia observed by scanning electron microscopy, as well as decrease the protein levels of cleaved-GSDMD, inflammasomes, and cleaved-IL-1β. Activation of ERK1/2 and NF-κB pathways largely abolished the protective effects of TGF-β1, which indicated that TGF-β1 alleviated the pyroptosis possibly via regulating NF-κB/ERK1/2 signal pathways. Conclusions Our studies demonstrated TGF-β1 notably relieved the demyelinating injury and cognitive disorder in LPC-modeling mice, by attenuating the inflammatory pyroptosis of microglia via ERK1/2 and NF-κB pathways. Targeting TGF-β1 activity might serve as a promising therapeutic strategy in demyelinating diseases.

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Current treatments after spinal cord injury: Cell engineering, tissue engineering, and combined therapies

Shen

Cao

et al. 2022

Smart Medicine

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Both traumatic and non‐traumatic spinal cord injuries (SCIs) can be categorized as damages done to our central nervous system (CNS). The patients' physical and mental health may suffer greatly because of traumatic SCI. With the widespread use of motor vehicles and increasingly aged population, the occurrence of SCI is more frequent than before, creating a considerable burden to global public health. The regeneration process of the spinal cord is hampered by a series of events that occur following SCI like edema, hemorrhage, formation of cystic cavities, and ischemia. An effective strategy for the treatment of SCI and functional recovery still has not been discovered; however, recent advances have been made in bioengineering fields that therapies based on cells, biomaterials, and biomolecules have proved effective in the repair of the spinal cord. In the light of worldwide importance of treatments for SCI, this article aims to provide a review of recent advances by first introducing the physiology, etiology, epidemiology, and mechanisms of SCI. We then put emphasis on the widely used clinical treatments and bioengineering strategies (cell‐based, biomaterial‐based, and biomolecule‐based) for the functional regeneration of the spinal cord as well as challenges faced by scientists currently. This article provides scientists and clinicians with a comprehensive outlook on the recent advances of preclinical and clinical treatments of SCI, hoping to help them find keys to the functional regeneration of SCI.

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Human spinal GABA neurons alleviate spasticity and improve locomotion in rats with spinal cord injury

Abstract: Highlights d Spinal GABA interneurons are efficiently generated from hPSCs d Human GABA neurons synapse with host spinal neurons d Cell transplantation mitigates spasticity in SCI rats d Therapeutic effect of GABA neurons depends on activity of grafted neurons

Cited by 23 publications

References 72 publications

Nimodipine Promotes Functional Recovery After Spinal Cord Injury in Rats

Nimodipine Promotes Functional Recovery After Spinal Cord Injury in Rats

Transforming growth factor-β1 protects against LPC-induced cognitive deficit by attenuating pyroptosis of microglia via NF-κB/ERK1/2 pathways

Current treatments after spinal cord injury: Cell engineering, tissue engineering, and combined therapies

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