Selective adenosine A2A receptor agonists and antagonists protect against spinal cord injury through peripheral and central effects.
Selective adenosine A2A receptor agonists and antagonists protect against spinal cord injury through peripheral and central effects.
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选择性腺苷A2A受体激动剂和拮抗剂通过外周和中心作用预防脊髓损伤。
DOI：
10.1186/1742-2094-8-31
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发表时间：
2011-04-12
影响因子：
9.3
通讯作者：
Pedata F
中科院分区：
文献类型：
--
作者：
Paterniti I;Melani A;Cipriani S;Corti F;Mello T;Mazzon E;Esposito E;Bramanti P;Cuzzocrea S;Pedata F
脊髓损伤（SCI）后的永久性功能缺陷是由机械损伤和涉及炎症的继发组织反应引起的。 SCI 后不久腺苷和谷氨酸释放增加是后遗症的一个组成部分，可能是导致功能缺陷的原因。腺苷 A2A 受体在中枢性缺血/创伤中的作用仍有待阐明。在我们之前的研究中，我们已经证明，在 SCI 后全身施用腺苷 A2A 受体选择性激动剂 CGS21680，可以防止组织损伤、运动功能障碍和不同的炎症读数。在这项工作中，我们研究了 SCI 后全身给药的腺苷 A2A 受体拮抗剂 SCH58261 对相同参数的影响。我们研究了激动剂和拮抗剂的主要作用机制位于外周或中枢部位的假设。脊髓损伤是由小鼠四级 T5-T8 椎板切除术暴露的 SC 的硬膜外压迫引起的。采用三种给药方案：通过腹膜内注射进行短期全身给药、通过微型渗透泵进行长期给药以及直接注射到脊髓中。全身施用 SCH58261（0.01 mg/kg 腹腔注射。SCI 后 1、6 和 10 小时）可减少 SCI 后 24 小时的脱髓鞘和 TNF-α、Fas-L、PAR、Bax 表达水平以及 JNK 丝裂原激活蛋白激酶 (MAPK) 的激活。通过微型渗透泵输送 10 天的慢性 SCH58261 给药，可改善 SCI 后长达 10 天的神经功能缺损。腺苷 A2A 受体在脊髓中由星形胶质细胞、小胶质细胞和少突胶质细胞生理性表达。 SCI 后不久（24 小时），这些受体在神经元中表现出增强的表达。腹腔内施用的A2A激动剂和拮抗剂均降低了A2A受体的表达，排除了A2A激动剂的神经保护作用是由于A2A受体脱敏所致的可能性。当A2A拮抗剂和激动剂集中注射到受伤的SC时，只有SCH58261表现出神经保护作用，而CGS21680则无效。我们的结果表明，A2A 拮抗剂通过作用于位于中心的 A2A 受体来预防 SCI。阻断 A2A 受体可能会降低兴奋毒性。相反，A2A 激动剂提供的神经保护作用可能主要是由于外周效应。
Permanent functional deficits following spinal cord injury (SCI) arise both from mechanical injury and from secondary tissue reactions involving inflammation. Enhanced release of adenosine and glutamate soon after SCI represents a component in the sequelae that may be responsible for resulting functional deficits. The role of adenosine A2A receptor in central ischemia/trauma is still to be elucidated. In our previous studies we have demonstrated that the adenosine A2A receptor-selective agonist CGS21680, systemically administered after SCI, protects from tissue damage, locomotor dysfunction and different inflammatory readouts. In this work we studied the effect of the adenosine A2A receptor antagonist SCH58261, systemically administered after SCI, on the same parameters. We investigated the hypothesis that the main action mechanism of agonists and antagonists is at peripheral or central sites. Spinal trauma was induced by extradural compression of SC exposed via a four-level T5-T8 laminectomy in mouse. Three drug-dosing protocols were utilized: a short-term systemic administration by intraperitoneal injection, a chronic administration via osmotic minipump, and direct injection into the spinal cord. SCH58261, systemically administered (0.01 mg/kg intraperitoneal. 1, 6 and 10 hours after SCI), reduced demyelination and levels of TNF-α, Fas-L, PAR, Bax expression and activation of JNK mitogen-activated protein kinase (MAPK) 24 hours after SCI. Chronic SCH58261 administration, by mini-osmotic pump delivery for 10 days, improved the neurological deficit up to 10 days after SCI. Adenosine A2A receptors are physiologically expressed in the spinal cord by astrocytes, microglia and oligodendrocytes. Soon after SCI (24 hours), these receptors showed enhanced expression in neurons. Both the A2A agonist and antagonist, administered intraperitoneally, reduced expression of the A2A receptor, ruling out the possibility that the neuroprotective effects of the A2A agonist are due to A2A receptor desensitization. When the A2A antagonist and agonist were centrally injected into injured SC, only SCH58261 appeared neuroprotective, while CGS21680 was ineffective. Our results indicate that the A2A antagonist protects against SCI by acting on centrally located A2A receptors. It is likely that blockade of A2A receptors reduces excitotoxicity. In contrast, neuroprotection afforded by the A2A agonist may be primarily due to peripheral effects.
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影响因子：
4.2
作者：
Baptiste, DC;Fehlings, MG
通讯作者：
Fehlings, MG
影响因子：
4.2
作者：
Farooque, M;Hillered, L;Olsson, Y
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Olsson, Y
DOI：
10.1124/jpet.106.108076
发表时间：
2006-10-01
影响因子：
3.5
作者：
Cuzzocrea, Salvatore;Genovese, Tiziana;Wang, Zhao-Qi
通讯作者：
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影响因子：
2.9
作者：
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通讯作者：
Stone, TW
影响因子：
1.7
作者：
Corsi, C;Melani, A;Pedata, F
通讯作者：
Pedata, F