The protective effect of Cyclosporin A upon N-acetylaspartate and mitochondrial dysfunction following experimental diffuse traumatic brain injury
The protective effect of Cyclosporin A upon N-acetylaspartate and mitochondrial dysfunction following experimental diffuse traumatic brain injury
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DOI：
10.1089/neu.2004.21.1154
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发表时间：
2004-09-01
影响因子：
4.2
通讯作者：
Vagnozzi, R
中科院分区：
文献类型：
--
作者：
Signoretti, S;Marmarou, A;Vagnozzi, R
损伤前后给药环孢素A （CsA）通过改善线粒体损伤显示出神经保护作用。本研究的目的是评估CsA对n -乙酰天冬氨酸（NAA）还原和ATP损失的影响，这是线粒体功能障碍和生物能量损伤的两个敏感标志。将成年雄性Sprague-Dawley大鼠暴露于碰撞加速创伤性脑损伤（2 m/450 g），随机分为鞘内CsA/载药组（n = 12）、静脉CsA/载药组（n = 18）和假手术组（n = 12）。鞘内治疗包括损伤后（30分钟）池内灌注CsA或Vehicle （0.15 mL, 10 mg/kg）。静脉给药包括损伤后30分钟连续1小时输注20或35 mg/kg CsA或Vehicle。损伤后6 h，采用HPLC定量分析全脑NAA和ATP水平。鞘内给药后CsA显示出显著的神经保护作用，使NAA减少30% (p < 0.001)， ATP损失恢复26% （p < 0.005）。静脉给药20mg /kg后，NAA恢复36%，ATP恢复39% (P < 0.001)，而静脉给药35mg /kg后，NAA恢复39% （P < 0.001）。综上所述，CsA具有恢复ATP和钝化NAA还原的作用。在这个模型中，静脉输注35mg /kg似乎是最佳的治疗策略。这些发现有助于CsA实现神经保护，保留线粒体功能的概念，并为临床环境中CsA的评估提供了理论依据，磁共振光谱可以监测脑损伤患者的NAA和ATP。
Pre- and post-injury Cyclosporin A (CsA) administration has shown neuroprotective properties by ameliorating mitochondrial damage. The aim of this study was to assess the effect of CsA upon N-acetylaspartate (NAA) reduction and ATP loss, two sensitive markers of mitochondrial dysfunction and bioenergetic impairment. Adult male Sprague-Dawley rats were exposed to impact acceleration traumatic brain injury (2 m/450 g) and randomized into the following experimental groups: intrathecal CsA/vehicle treated (n = 12), intravenous CsA/vehicle treated (n = 18) and sham (n = 12). Intrathecal treatment consisted of post-injury (30 min) cisternal bolus of CsA or Vehicle (0.15 mL, 10 mg/kg). Intravenous administration consisted of 30 min post-injury continuous 1hour infusion of either 20 or 35 mg/kg CsA or Vehicle. Quantitative HPLC analysis of whole brain samples was performed 6 h post-injury for levels of NAA and ATP. Following intrathecal delivery CsA demonstrated significant neuroprotection blunting a 30% NAA reduction (p < 0.001) and restoring 26% of the ATP loss (p < 0.005). The 20 mg/kg intravenous dose failed to ameliorate the biochemical damages while the 35 mg/kg dosage showed 36% NAA recovery and 39% ATP restoration (P < 0.001). In conclusion, CsA is capable of restoring ATP and blunting NAA reduction. Intravenous infusion of 35 mg/kg appears to be the optimal therapeutic strategy in this model. These findings contribute to the notion that CsA achieves neuroprotection, preserving mitochondrial function, and provides a rationale for the assessment of CsA in the clinical setting where MR spectroscopy can monitor NAA and ATP in brain-injured patients.