Licofelone modulates neuroinflammation and attenuates mechanical hypersensitivity in the chronic phase of spinal cord injury.
Licofelone modulates neuroinflammation and attenuates mechanical hypersensitivity in the chronic phase of spinal cord injury.
复制标题
DOI：
10.1523/jneurosci.6128-11.2013
复制
发表时间：
2013-01-09
期刊：
影响因子：
--
通讯作者：
Grill RJ
中科院分区：
文献类型：
--
作者：
Dulin JN;Karoly ED;Wang Y;Strobel HW;Grill RJ
炎症是影响创伤性脊髓损伤 (SCI) 早期急性期结果的主要因素。众所周知，受伤脊髓内的促炎信号传导会驱动神经感觉处理的病理改变，并在损伤后早期塑造功能结果。然而，目前尚不清楚炎症是否持续到损伤的慢性阶段或在损伤后很长时间内影响感觉处理。为了研究这些可能性，我们在大鼠中度胸椎挫伤后 9 个月进行了生化和行为评估。我们发现，慢性脊髓病变部位的促炎脂质介质白三烯 B4 和前列腺素 E2 水平升高。此外，通过代谢组学分析，我们检测到促氧化和炎症代谢物水平升高，以及慢性病变部位内多种生物途径的改变。我们发现，用 COX/5-LOX 双重抑制剂 licofelone 对慢性损伤大鼠进行 28 天治疗，病变部位内源性抗氧化剂和抗炎代谢物的水平升高。此外，利可氟隆治疗降低了后爪对机械刺激的过敏性，但没有降低热刺激的过敏性，这表明机械敏感性在损伤的慢性阶段受到促炎信号的调节。总之，这些发现为 SCI 慢性期脊髓组织内的炎症和氧化应激提供了新的证据，并证明了炎症调节在损伤慢性期中机械敏感性的作用。
Inflammation is a major factor shaping outcome during the early, acute phase of traumatic spinal cord injury (SCI). It is known that pro-inflammatory signaling within the injured spinal cord drives pathological alterations in neurosensory processing and shapes functional outcome early after injury. However, it is unclear whether inflammation persists into the chronic phase of injury or shapes sensory processing long after injury. In order to investigate these possibilities, we have performed biochemical and behavioral assessments 9 months after moderate thoracic spinal contusion injury in the rat. We have found that levels of the pro-inflammatory lipid mediators leukotriene B4 and prostaglandin E2 are elevated in the chronic spinal cord lesion site. Additionally, using metabolomic profiling, we have detected elevated levels of pro-oxidative and inflammatory metabolites, along with alterations in multiple biological pathways within the chronic lesion site. We found that 28-day treatment of chronically-injured rats with the dual COX/5-LOX inhibitor licofelone elevated levels of endogenous anti-oxidant and anti-inflammatory metabolites within the lesion site. Furthermore, licofelone treatment reduced hypersensitivity of hindpaws to mechanical, but not thermal, stimulation, indicating that mechanical sensitivity is modulated by pro-inflammatory signaling in the chronic phase of injury. Together, these findings provide novel evidence of inflammation and oxidative stress within spinal cord tissue far into the chronic phase of SCI, and demonstrate a role for inflammatory modulation of mechanical sensitivity in the chronic phase of injury.