PDF(Pubmed)
Abstract：
Intrapleural injections of cholera toxin B conjugated to saporin (CTB-SAP) selectively eliminates respiratory (e.g., phrenic) motor neurons, and mimics motor neuron death and respiratory deficits observed in rat models of neuromuscular diseases. Additionally, microglial density increases in the phrenic motor nucleus following CTB-SAP. This CTB-SAP rodent model allows us to study the impact of motor neuron death on the output of surviving phrenic motor neurons, and the underlying mechanisms that contribute to enhancing or constraining their output at 7 days (d) or 28d post-CTB-SAP injection. 7d CTB-SAP rats elicit enhanced phrenic long-term facilitation (pLTF) through the Gs-pathway (inflammation-resistant in naïve rats), while pLTF is elicited though the Gq-pathway (inflammation-sensitive in naïve rats) in control and 28d CTB-SAP rats. In 7d and 28d male CTB-SAP rats and controls, we evaluated the effect of cyclooxygenase-1/2 enzymes on pLTF by delivery of the nonsteroidal anti-inflammatory drug, ketoprofen (IP), and we hypothesized that pLTF would be unaffected by ketoprofen in 7d CTB-SAP rats, but pLTF would be enhanced in 28d CTB-SAP rats. In anesthetized, paralyzed and ventilated rats, pLTF was surprisingly attenuated in 7d CTB-SAP rats and enhanced in 28d CTB-SAP rats (both p < 0.05) following ketoprofen delivery. Additionally in CTB-SAP rats: 1) microglia were more amoeboid in the phrenic motor nucleus; and 2) cervical spinal inflammatory-associated factor expression (TNF-α, BDNF, and IL-10) was increased vs. controls in the absence of ketoprofen (p < 0.05). Following ketoprofen delivery, TNF-α and IL-10 expression was decreased back to control levels, while BDNF expression was differentially affected over the course of motor neuron death in CTB-SAP rats. This study furthers our understanding of factors (e.g., cyclooxygenase-1/2-induced inflammation) that contribute to enhancing or constraining pLTF and its implications for breathing following respiratory motor neuron death.
摘要：
胸腔内注射与皂草素结合的霍乱毒素B（CTB-SAP）选择性地消除了呼吸（例如，膈)运动神经元，并模拟在神经肌肉疾病大鼠模型中观察到的运动神经元死亡和呼吸缺陷。此外,CTB-SAP后膈运动核小胶质细胞密度增加。这种CTB-SAP啮齿动物模型使我们能够研究运动神经元死亡对存活的膈运动神经元输出的影响，以及在CTB-SAP注射后第7天（d）或第28天增加或限制其产量的潜在机制。7dCTB-SAP大鼠通过Gs途径引起增强的膈长期促进（pLTF）（幼稚大鼠的炎症抗性），而在对照组和28dCTB-SAP大鼠中，pLTF是通过Gq途径（幼稚大鼠对炎症敏感）引起的。在7d和28d雄性CTB-SAP大鼠和对照组中，我们评估了环氧合酶-1/2酶对pLTF的作用，酮洛芬（IP），我们假设pLTF在7dCTB-SAP大鼠中不会受到酮洛芬的影响，但pLTF在28dCTB-SAP大鼠中会增强。在麻醉中，瘫痪和通风的老鼠，在酮洛芬递送后,pLTF在7dCTB-SAP大鼠中令人惊讶地减弱,而在28dCTB-SAP大鼠中增强(两者p<0.05)。此外，在CTB-SAP大鼠中：1）小胶质细胞在膈运动核中更多的变形虫；2）宫颈脊髓炎症相关因子表达（TNF-α，BDNF,和IL-10）增加与在不存在酮洛芬的情况下进行对照(p<0.05)。酮洛芬分娩后，TNF-α和IL-10表达下降回到对照水平，而BDNF的表达在CTB-SAP大鼠的运动神经元死亡过程中受到差异影响。这项研究进一步加深了我们对因素的理解(例如，环氧合酶-1/2诱导的炎症）有助于增强或限制pLTF及其对呼吸运动神经元死亡后呼吸的影响。
