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Amelioration of spinal cord injury in rats by blocking peroxynitrite/calpain activity.

ABSTRACT: BACKGROUND:Spinal cord injury (SCI) is one of the leading causes of disability and chronic pain. In SCI-induced pathology, homeostasis of the nitric oxide (NO) metabolome is lost. Major NO metabolites such as S-nitrosoglutathione (GSNO) and peroxynitrite are reported to play pivotal roles in regulating the activities of key cysteine proteases, calpains. While peroxynitrite (a metabolite of NO and superoxide) up regulates the activities of calpains leading to neurodegeneration, GSNO (a metabolite of NO and glutathione) down regulates the activities of calpains leading to neuroprotection. In this study, effect of GSNO on locomotor function and pain threshold and their relationship with the levels of peroxynitrite and the activity of calpain in the injured spinal cord were investigated using a 2-week rat model of contusion SCI. RESULTS:SCI animals were initially treated with GSNO at 2 h after the injury followed by a once daily dose of GSNO for 14 days. Locomotor function was evaluated by "Basso Beattie and Bresnahan (BBB) locomotor rating scale" and pain by mechanical allodynia. Peroxynitrite level, as expression of 3-nitrotyrosine (3-NT), calpain activity, as the degradation products of calpain substrate alpha II spectrin, and nNOS activity, as the expression phospho nNOS, were measured by western blot analysis. Treatment with GSNO improved locomotor function and mitigated pain. The treatment also reduced the levels of peroxynitrite (3-NT) and decreased activity of calpains. Reduced levels of peroxynitrite resulted from the GSNO-mediated inhibition of aberrant activity of neuronal nitric oxide synthase (nNOS). CONCLUSIONS:The data indicates that higher levels of 3-NT and aberrant activities of nNOS and calpains correlated with SCI pathology and functional deficits. Treatment with GSNO improved locomotor function and mitigated mechanical allodynia acutely post-injury. Because GSNO shows potential to ameliorate experimental SCI, we discuss implications for GSNO therapy in clinical SCI research.

SUBMITTER: Khan M

PROVIDER: S-EPMC6090709 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Amelioration of spinal cord injury in rats by blocking peroxynitrite/calpain activity.

Khan Mushfiquddin M Dhammu Tajinder S TS Singh Inderjit I Singh Avtar K AK

BMC neuroscience 20180813 1

<h4>Background</h4>Spinal cord injury (SCI) is one of the leading causes of disability and chronic pain. In SCI-induced pathology, homeostasis of the nitric oxide (NO) metabolome is lost. Major NO metabolites such as S-nitrosoglutathione (GSNO) and peroxynitrite are reported to play pivotal roles in regulating the activities of key cysteine proteases, calpains. While peroxynitrite (a metabolite of NO and superoxide) up regulates the activities of calpains leading to neurodegeneration, GSNO (a me ...[more]

PMID: 30103682

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Project description:BackgroundThere is emerging evidence that astaxanthin plays a significant role in protecting neuro-cells from apoptosis after central nervous system injury. Our study examined the effects of astaxanthin on neuro-cell apoptosis after spinal cord injury.MethodsOne hundred and forty-four healthy adult Sprague-Dawley rats were randomly divided into the experimental group, control group, and sham operation group (n=48). Spinal cord injury was induced using the modified Allen method in the control group and the experimental group; while in the sham operation group, the lamina was removed without spinal cord injury. The rats in the experimental group were given astaxanthin (75 mg/kg) by gavage immediately after the operation, and in the other groups were given the same amount of olive oil. Motor function was assessed by blood-brain barrier (BBB) scores. The malondialdehyde (MDA) content and the activity of superoxide dismutase (SOD) at 24 h was determined after the operation. The apoptosis index (AI) was determined at 6, 24, and 48 h after the operation. At 48 h after the operation, we calculated the water content of the spinal cord, the lesion ratio of the spinal cord, the ultrastructure of the spinal cord, and the ultrastructure score.ResultsThe BBB scores of the control and experimental groups were significantly lower than the sham operation group at each postoperative time (P<0.05), and the BBB score of the experimental group was significantly higher than the control group at 1-4 weeks postoperatively (P<0.05). At 24 hours postoperatively, MDA content was highest in the control group and lowest in the sham operation group, while SOD activity was highest in the sham operation group and lowest in the control group (P<0.05). At each time point postoperatively, the sham operation group had the lowest AI and the control group had the highest AI (P<0.05). At 48 h after the operation, the water content and the lesion ratio of the spinal cord, and the ultrastructure score were the lowest in the sham operation group and the highest in the control group (P<0.05).ConclusionsAstaxanthin significantly improved the motor function of rats with spinal cord injury.

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Amelioration of spinal cord injury in rats by blocking peroxynitrite/calpain activity.

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Amelioration of spinal cord injury in rats by blocking peroxynitrite/calpain activity.

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