Therapeutic Model for Experimental Spinal Cord Injury in the Rat: I. Mortality and Motor Deficit

Perot, Phanor L.; Lee, William A.; Hsu, Chung Y.; Hogan, Edward L.; Cox, Russell D.; Gross, Alan J.

doi:10.1089/cns.1987.4.149

Cited by 46 publications

(29 citation statements)

References 10 publications

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“…Rats were anesthetized with ketamine (80mg/kg)/xylazene (10mg/kg), and laminectomy was performed at T10. The spine was immobilized with a spinal stereotactic device, and SCI was induced using a modified method by Perot of dropping a constant weight (5 gm) from a height of 8 cm onto an impounder (0.3 cm in diameter) gently placed on the spinal cord (48, 49). ENOblock was purchased from Bioscience (Catalog No.…”

Section: Methodsmentioning

confidence: 99%

Targeting Enolase in Reducing Secondary Damage in Acute Spinal Cord Injury in Rats

et al. 2017

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Spinal cord injury (SCI) is a complex debilitating condition leading to permanent life-long neurological deficits. The complexity of SCI suggests that a concerted multi-targeted therapeutic approach is warranted to optimally improve function. Damage to spinal cord is complicated by an increased detrimental response from secondary injury factors mediated by activated glial cells and infiltrating macrophages. While elevation of enolase especially Neuron Specific Enolase (NSE) in glial and neuronal cells is believed to trigger inflammatory cascades in acute SCI, alteration of NSE and its subsequent effects in acute SCI remains unknown. This study measured NSE expression levels and key inflammatory mediators after acute SCI and investigated the role of ENOblock, a novel small molecule inhibitor of enolase, in a male Sprague-Dawley (SD) rat SCI model. Serum NSE levels as well as cytokines/chemokines and metabolic factors were evaluated in injured animals following treatment with vehicle alone or ENOblock using Discovery assay. Spinal cord samples were also analyzed for NSE and MMPs 2 and 9 as well as glial markers by Western blotting. The results indicated a significant decrease in serum inflammatory cytokines/chemokines and NSE, alterations of metabolic factors and expression of MMPs in spinal cord tissues after treatment with ENOblock (100μg/kg, twice). These results support the hypothesis that activation of glial cells and inflammation status can be modulated by regulation of NSE expression and activity. Analysis of SCI tissue samples by immunohistochemistry confirmed that ENOblock decreased gliosis which may have occurred through reduction of elevated NSE in rats. Overall, elevation of NSE is deleterious as it promotes extracellular degradation and production of inflammatory cytokines/chemokines and metabolic factors which activates glia and damages neurons. Thus, reduction of NSE by ENOblock may have potential therapeutic implications in acute SCI.

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Section: Methodsmentioning

confidence: 99%

Targeting Enolase in Reducing Secondary Damage in Acute Spinal Cord Injury in Rats

et al. 2017

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“…Spinal cord injury was carried out using the modified weight-drop method [16]. Adult male Sprague-Dawley rats (n=120, 280 to 300 g weight) were anesthetized with intraperitoneal injections of a mixture containing 75 mg/kg ketamine and 20 mg/kg xylazine.…”

Section: Animals and Surgerymentioning

confidence: 99%

Soluble epoxide hydrolase inhibition provides multi-target therapeutic effects in rats after spinal cord injury

Chen

Huang

et al. 2015

Mol Neurobiol

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Multiple players are involved in motor and sensory dysfunctions after spinal cord injury (SCI). Therefore, therapeutic approaches targeting these various players in the damage cascade hold considerable promise for the treatment of traumatic spinal cord injury. Soluble epoxide hydrolase (sEH) is an endogenous key enzyme in the metabolic conversion and degradation of P450 eicosanoids called epoxyeicosatrienoic acids (EETs). sEH inhibition has been shown to provide neuroprotective effects upon multiple elements of neurovascular unit under cerebral ischemia. However, its role in the pathological process after SCI remains unclear. In this study, we tested the hypothesis that sEH inhibition may have therapeutic effects in preventing secondary damage in rats after traumatic SCI. sEH was widely expressed in spinal cord tissue, mainly confined to astrocytes, and neurons. Administration of sEH inhibitor AUDA significantly suppressed local inflammatory responses as indicated by the reduced microglia activation and IL-1 β expression, as well as the decreased infiltration of neutrophils and T lymphocytes. Meanwhile, reactive astrogliosis was remarkably attenuated. Furthermore, treatment of AUDA improved angiogenesis, inhibited neuron cells apoptosis, alleviated demyelination and formation of cavity and improved motor recovery. Together, these results provide the first in vivo evidence that sEH inhibition could exert multiple targets protective effects after SCI in rats. sEH may thereby serve as a promising multi-mechanism therapeutic target for the treatment of SCI.

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“…All animal experiments were performed in accordance with the ''Guide for the Care and Use of Laboratory Animals'' of the US Department of Health and Humans Services (National Institutes of Health, Bethesda, MD, USA) and approved by the Institutional Animal Care and Use Committee (IACUC) at the Medical University of South Carolina (Charleston, SC, USA). Induction of injury was performed using the modified weight-drop method, as previously described in detail [20]. A schematic diagram is presented to show induction of SCI and collection of specific spinal cord segments for analysis ( Fig.…”

Section: Animal Care and Induction Of Scimentioning

confidence: 99%

Direct Evidence for Calpain Involvement in Apoptotic Death of Neurons in Spinal Cord Injury in Rats and Neuroprotection with Calpain Inhibitor

et al. 2007

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To demonstrate calpain involvement in neurodegeneration in rat spinal cord injury (SCI), we examined SCI segments for DNA fragmentation, neurons for calpain overexpression, neuronal death, and neuroprotection with calpain inhibitor (E-64-d). After the induction of SCI (40 g cm force) on T12, rats were treated within 15 min with vehicle (DMSO) or E-64-d. Sham animals underwent laminectomy only. Animals were sacrificed at 24 h, and five 1-cm long spinal cord segments were collected: two rostral (S1 and S2), one lesion (S3), and two caudal segments (S4 and S5). Agarose gel electrophoresis of DNA samples isolated from the SCI segments showed both random and internucleosomal DNA fragmentation indicating occurrence of necrosis as well as apoptosis mostly in the lesion, moderately in caudal, and slightly in rostral segments from SCI rats. Treatment of SCI rats with E-64-d (1 mg/kg) reduced DNA fragmentation in all segments. The lesion and adjacent caudal segments (S3 and S4) were further investigated by in situ double-immunofluorescent labelings that showed increase in calpain expression in neurons in SCI rats and decrease in calpain expression in SCI rats treated with E-64-d. In situ combined TUNEL and double-immunofluorescent labelings directly detected co-localization of neuronal death and calpain overexpressin in SCI rats treated with only vehicle while attenuation of neuronal death in SCI rats treated with E-64-d. Previous studies from our laboratory indirectly showed neuroprotective effect of E-64-d in SCI rats. Our current results provide direct in situ evidence for calpain involvement in neuronal death and neuroprotective efficacy of E-64-d in lesion and penumbra in SCI rats.

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Therapeutic Model for Experimental Spinal Cord Injury in the Rat: I. Mortality and Motor Deficit

Cited by 46 publications

References 10 publications

Targeting Enolase in Reducing Secondary Damage in Acute Spinal Cord Injury in Rats

Targeting Enolase in Reducing Secondary Damage in Acute Spinal Cord Injury in Rats

Soluble epoxide hydrolase inhibition provides multi-target therapeutic effects in rats after spinal cord injury

Direct Evidence for Calpain Involvement in Apoptotic Death of Neurons in Spinal Cord Injury in Rats and Neuroprotection with Calpain Inhibitor

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