| Summary: Spinal cord injury (SCI) is commonly encountered in clinical orthopaedics and neurosurgery. According to statistics gathered by the National Institutes of Health, it is estimated that every year 7, 000 to 10, 000 people in the United States sustain a SCI, resulting in a prevalence of more than 20, 0000 American children and adults now living with the sequel of a SCI. In China, the number of patients with SCI is significantly larger than in USA. It is easy to understand that the result of a SCI involves a lot of suffering, including living with permanent paralysis in arms and/or legs. Recently many scientists have focused their interest on this field, and have acquired important new insights. The aim is to clarify the mechanism of SCI and to look for possible ways of treatment. The pathological sequelae associated with traumatic SCI include white and gray matter damage resulting from the primary injury and a progressive secondary injury cascade that begins with the elevation of excitatory amino acids. The NMDA receptor (NMDAR) and nitric oxide synthase (NOS) are known to play important roles in the progression of secondary injury initiated by brain and spinal cord injury.Agmatine (decarboxylated arginine) is an endogenous neuromodulator found in brain and other tissues with both NMDAR antagonist and NOS inhibitor activities. Pretreatment and/or treatment with agmatine prevents the development of opioid tolerance, reduces infarct size after global cerebral ischemia, attenuates the extent of neuronal loss following excitotoxic spinal cord injury, and alleviates pain behaviors associated with excitotoxic lesions in the spinal cord. Based on this evidence, we hypothesized that agmatine may have neuroprotective effects following traumatic SCI. The purpose of the present study was to evaluate the effects of agmatine on neurological function following traumatic injury using a clinically relevant modes of SCI.In present series of experiments, endogenous agmatine was first detected both in normal and injured rats' spinal cord by high-performance liquid chromatography (HPLC) with flurorescence detection and OPA derivatization. Then we observed the neuroprotective effect on secondary spinal cord injury of agmatine by studying Baffour's neurological function score, electrophysiological (including both MEP and SEP) and histopathological changes. Furthermore, the animal model of spinal cord injury was established. The changes of the expression of iNOS mRNA and activity of iNOS protein after spinal cord injury and after administration of agmatine were detected by using RT-PCR and isotope labeling assay in rats. The main results of our research are asfollows:1. The endogenous agmatine level in naive rats' spinal cord were 0.643±0.111μg/g wet weight. After spinal cord injury, the concentration had a transient drop followed by significantly increase, although the peak concentration was extremely lower than what it needed to take its neuroprotective effect in vitro.2. Exogenous agmatine administered systemically for 3 weeks after spinal cord injury significantly improves neurological function and reduces tissue damage. This suggests that agmatine may be a processing therapeutic target for treatment of acute spinal injury.3. The expressions of nNOS and eNOS upregulated obviously in the early stage after spinal cord injury and there was no remarkable effect with treatment of exogenous agmatine. iNOS mRNA had little change in the early injury stage, while upregulated 72h after injury and reached its peak concentration after one week. It was confirmed initially that treatment with agmatine could obviously reduce the expression of iNOS mRNS.4. cNOS activity increased at early stage after spinal cord injury while iNOS did at later stage. Agmatine could hardly influence the activity of NOS within their normal ranges, whereas obviously inhibit the over-regulated NOS activity. This evidence along with the selectively inhibiting expression of iNOS mRNA at the level of transcription is of importance with...
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