Reinert Kaela R S, Umphlet Claudia D, Quattlebaum Ariana, Boger Heather A
Department of Neurosciences and Center on Aging, Medical University of South Carolina, 173 Ashley Ave, BSB Suite 403, MSC 510, Charleston, SC 29425, USA.
Department of Neurosciences and Center on Aging, Medical University of South Carolina, 173 Ashley Ave, BSB Suite 403, MSC 510, Charleston, SC 29425, USA.
Brain Res. 2014 Apr 4;1557:164-70. doi: 10.1016/j.brainres.2014.02.005. Epub 2014 Feb 8.
Inflammation has been implicated in the pathology of several neurodegenerative diseases, including Parkinson׳s disease (PD). Studies using the endotoxin lipopolysaccharide (LPS), a potent inflammogen, show that systemic insults can trigger prolonged microglial activation and pro-inflammatory cytokine production leading to degeneration of substantia nigra (SN) dopamine (DA) neurons, mimicking idiopathic PD. Because rapid effects of LPS on SN neurons had not been investigated previously, the focus of this study is to assess time-dependent alterations in SN neuroinflammation, DAergic neurons, and neuronal signaling cascades following LPS administration. LPS (5mg/kg, i.p.) or saline (0.9% NaCl) was administered to 8-month-old male mice. At 3h, 5h, and 12h post-injection, the morphology of the SN was assessed using antibodies directed against tyrosine hydroxylase (TH, DAergic marker), Iba-1 (pan-microglial marker), phospho-ERK, and phospho-CREB (signaling). LPS administration significantly reduced TH-immunoreactivity (ir) at all time-points with the greatest reduction observed at 12h post-injection. Reduced TH-ir was accompanied by a significant increase in activated microglia at all time-points following LPS. By 12h post-injection, LPS-treated mice exhibited activated as well as reactive microglia, which can result in neuronal damage. These data demonstrate that the initial reduction in TH-ir observed after an LPS injection was not concomitant with morphological alterations in microglial cells, even though a significant increase in phospho-ERK was observed in glial cells as soon as 3h post-injection. It is possible that the initial alteration in DA phenotype (TH reduction) may perpetuate an inflammatory response that persists and leads to further DAergic damage.
炎症与包括帕金森病（PD）在内的几种神经退行性疾病的病理过程有关。使用内毒素脂多糖（LPS，一种强力炎症原）的研究表明，全身性损伤可引发小胶质细胞的长期激活和促炎细胞因子的产生，导致黑质（SN）多巴胺（DA）神经元变性，类似于特发性PD。由于先前尚未研究LPS对SN神经元的快速作用，本研究的重点是评估LPS给药后SN神经炎症、DA能神经元和神经元信号级联反应随时间的变化。将LPS（5mg/kg，腹腔注射）或生理盐水（0.9%NaCl）给予8月龄雄性小鼠。在注射后3小时、5小时和12小时，使用针对酪氨酸羟化酶（TH，DA能标记物）、Iba-1（全小胶质细胞标记物）、磷酸化ERK和磷酸化CREB（信号传导）的抗体评估SN的形态。LPS给药在所有时间点均显著降低TH免疫反应性（ir），在注射后12小时观察到最大程度的降低。LPS给药后所有时间点，TH-ir降低均伴有活化小胶质细胞的显著增加。到注射后12小时，LPS处理的小鼠表现出活化的以及反应性的小胶质细胞，这可导致神经元损伤。这些数据表明，LPS注射后观察到的TH-ir最初降低与小胶质细胞的形态改变并不伴随，尽管在注射后3小时胶质细胞中就观察到磷酸化ERK显著增加。有可能DA表型的最初改变（TH降低）可能使持续存在并导致进一步DA能损伤的炎症反应永久化。
