The therapeutic profile of rolipram, PDE target and mechanism of action as a neuroprotectant following spinal cord injury.
The therapeutic profile of rolipram, PDE target and mechanism of action as a neuroprotectant following spinal cord injury.
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DOI：
10.1371/journal.pone.0043634
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Pearse DD
中科院分区：
文献类型：
--
作者：
Schaal SM;Garg MS;Ghosh M;Lovera L;Lopez M;Patel M;Louro J;Patel S;Tuesta L;Chan WM;Pearse DD
脊髓损伤(SCI)后的损伤程度可以通过各种神经保护方案来减轻，其中包括通过给予磷酸二酯酶4(PDE4)抑制剂罗利普兰来维持环磷酸腺苷(CAMP)的水平。本研究旨在确定罗利普兰对大鼠脊髓挫伤后的最佳神经保护剂量、治疗途径和治疗窗口，以及其突出的PDE靶点和可能的保护机制。皮下注射罗利普兰或控释剂(10%乙醇)(皮下注射)。于伤后2wk每天观察少突胶质细胞、神经元和中央有髓轴突的保存情况。0.1 mg/kg~1.0 mg/kg剂量(给药后1h)可提高神经元存活率；0.5 mg/kg~1.0 mg/kg保护的少突胶质细胞和1.0 mg/kg剂量组对中央有髓轴突的保护效果最佳。乙醇也显示了显著的神经元和寡聚保护作用；尽管提供的保存明显少于罗利普兰。随后通过不同的途径(静脉注射，S.C.)使用该最佳罗利普兰剂量，1.0 mg/kg。或口服，1hPI)，表明静脉注射。尽管所有途径都是有效的，但给药产生了最显著和最一致的细胞和轴突保护。静脉注射治疗窗的检查。在脊髓损伤后1~48h开始给予罗利普兰(1.0 mg/kg)对脊髓损伤后2 h的神经保护作用最强，但延迟给药至48 h仍可观察到其保护作用。重要的是，根据BBB评分，使用最优的罗利普兰方案显著改善了脊髓损伤后的运动功能。最后，我们展示了脊髓损伤后PDE4A、B和D的表达和磷酸化以及细胞因子表达和免疫细胞浸润的变化。我们证明，罗利普兰抑制脊髓损伤诱导的PDE4B1和PDE4A5的产生、PDE4A5的磷酸化、MCP-1的表达和免疫细胞的渗透，同时阻止损伤后IL-10的减少。这项工作支持将罗利普兰用作脊髓损伤后的急性神经保护剂，并为其治疗应用确定了最佳给药方案和靶点。
The extent of damage following spinal cord injury (SCI) can be reduced by various neuroprotective regimens that include maintaining levels of cyclic adenosine monophosphate (cyclic AMP), via administration of the phosphodiesterase 4 (PDE4) inhibitor Rolipram. The current study sought to determine the optimal neuroprotective dose, route and therapeutic window for Rolipram following contusive SCI in rat as well as its prominent PDE target and putative mechanism of protection. Rolipram or vehicle control (10% ethanol) was given subcutaneously (s.c.) daily for 2 wk post-injury (PI) after which the preservation of oligodendrocytes, neurons and central myelinated axons was stereologically assessed. Doses of 0.1 mg/kg to 1.0 mg/kg (given at 1 h PI) increased neuronal survival; 0.5 mg to 1.0 mg/kg protected oligodendrocytes and 1.0 mg/kg produced optimal preservation of central myelinated axons. Ethanol also demonstrated significant neuronal and oligo-protection; though the preservation provided was significantly less than Rolipram. Subsequent use of this optimal Rolipram dose, 1.0 mg/kg, via different routes (i.v., s.c. or oral, 1 h PI), demonstrated that i.v. administration produced the most significant and consistent cyto- and axo- protection, although all routes were effective. Examination of the therapeutic window for i.v. Rolipram (1.0 mg/kg), when initiated between 1 and 48 h after SCI, revealed maximal neuroprotection at 2 h post-SCI, although the protective efficacy of Rolipram could still be observed when administration was delayed for up to 48 h PI. Importantly, use of the optimal Rolipram regimen significantly improved locomotor function after SCI as measured by the BBB score. Lastly we show SCI-induced changes in PDE4A, B and D expression and phosphorylation as well as cytokine expression and immune cell infiltration. We demonstrate that Rolipram abrogates SCI-induced PDE4B1 and PDE4A5 production, PDE4A5 phosphorylation, MCP-1 expression and immune cell infiltration, while preventing post-injury reductions in IL-10. This work supports the use of Rolipram as an acute neuroprotectant following SCI and defines an optimal administration protocol and target for its therapeutic application.
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影响因子：
4.8
作者：
Bethea, JR;Dietrich, WD
通讯作者：
Dietrich, WD
影响因子：
82.9
作者：
Crowe, MJ;Bresnahan, JC;Beattie, MS
通讯作者：
Beattie, MS
影响因子：
--
作者：
ABERCROMBIE, M
通讯作者：
ABERCROMBIE, M
DOI：
10.1152/ajplung.00384.2003
发表时间：
2004-08-01
影响因子：
4.9
作者：
Barber, R;Baillie, GS;Van Heeke, G
通讯作者：
Van Heeke, G
影响因子：
8.3
作者：
Aronowski, J;Strong, R;Grotta, JC
通讯作者：
Grotta, JC