Melatonin and minocycline for combinatorial therapy to improve functional and histopathological deficits following traumatic brain injury.
Melatonin and minocycline for combinatorial therapy to improve functional and histopathological deficits following traumatic brain injury.
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DOI：
10.1016/j.neulet.2010.11.003
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发表时间：
2011-01-13
影响因子：
2.5
通讯作者：
Pauly JR
中科院分区：
文献类型：
--
作者：
Kelso ML;Scheff NN;Scheff SW;Pauly JR
创伤性脑损伤（TBI）后的生化后遗症很多，随着继发性级联反应的进展，在不同的时间点影响许多不同的脑功能。由此产生的病理生理学的复杂性使得单一的治疗干预可能无法提供足够的益处，并且可能需要靶向不同途径的药物组合。研究最广泛的两种损伤机制是氧化应激和炎症。许多研究表明，靶向这些途径中的任一种的药理学药物可能会改善组织学和功能结局指标。我们假设，结合褪黑素，一种有效的抗氧化剂，米诺环素，一种抑菌剂，也抑制小胶质细胞，将提供更好的神经保护比单独使用任何一种药物。为了验证这一假设，我们采用2×2研究设计，对麻醉的成年雄性大鼠进行1.5 mm受控皮质撞击，并在急性损伤后阶段给予褪黑激素或溶媒，然后从第二天开始每日注射米诺环素或溶媒。使动物恢复5天，然后进行Morris水迷宫（MWM）测试以评估损伤后的认知功能。媒介物、褪黑激素、米诺环素或组合处理之间的MWM性能没有显著差异。在处死和进行神经保护的组织学检查后，我们没有观察到两组之间保留的皮质组织量的显著差异，也没有观察到[3 H]-PK 11195结合（活化小胶质细胞的标志物）的显著差异。这些结果表明，这两种药物都没有治疗效果，但剂量和/或给药问题可能起了作用。
The biochemical sequelae that follow traumatic brain injury (TBI) are numerous and affect many different brain functions at different points of time as the secondary cascades progress. The complexity of the resulting pathophysiology is such that a singular therapeutic intervention may not provide adequate benefit and a combination of drugs targeting different pathways may be needed. Two of the most widely studied injury mechanisms are oxidative stress and inflammation. Numerous studies have suggested that pharmacological agents targeting either of these pathways may produce an improvement in histological and functional outcome measures. We hypothesized that combining melatonin, a potent antioxidant, with minocycline, a bacteriostatic agent that also inhibit microglia, would provide better neuroprotection than either agent used alone. To test this hypothesis, we subjected anesthetized adult male rats to a 1.5 mm controlled cortical impact and administered melatonin or vehicle in the acute post-injury period followed by daily minocycline or vehicle injections beginning the following day in a 2×2 study design. The animals were allowed to recover for 5 days before undergoing Morris water maze (MWM) testing to assess cognitive functioning following injury. There was no significant difference in MWM performance between the vehicle, melatonin, minocycline, or combination treatments. Following sacrifice and histological examination for neuroprotection, we did not observe a significant difference between the groups in the amount of cortical tissue that was spared nor was there a significant difference in [3H]-PK11195 binding, a marker for activated microglia. These results suggest that neither drug has therapeutic efficacy, however dosing and/or administration issues may have played a role.
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DOI：
10.1073/pnas.96.23.13496
发表时间：
1999-11-09
影响因子：
11.1
作者：
Yrjänheikki, J;Tikka, T;Koistinaho, J
通讯作者：
Koistinaho, J
影响因子：
56.9
作者：
Nimmerjahn, A;Kirchhoff, F;Helmchen, F
通讯作者：
Helmchen, F
影响因子：
6.2
作者：
Lai, Aaron Y.;Todd, Kathryn G.
通讯作者：
Todd, Kathryn G.
影响因子：
4.8
作者：
Beni, SM;Kohen, R;Shohami, E
通讯作者：
Shohami, E
影响因子：
2.5
作者：
Ozdemir, D;Tugyan, K;Ozkan, H
通讯作者：
Ozkan, H