Vogel Edward W, Morales Fatima N, Meaney David F, Bass Cameron R, Morrison Barclay
Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA.
Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA.
Exp Neurol. 2017 Jul;293:91-100. doi: 10.1016/j.expneurol.2017.03.025. Epub 2017 Mar 31.
Due to recent military conflicts and terrorist attacks, blast-induced traumatic brain injury (bTBI) presents a health concern for military and civilian personnel alike. Although secondary blast (penetrating injury) and tertiary blast (inertia-driven brain deformation) are known to be injurious, the effects of primary blast caused by the supersonic shock wave interacting with the skull and brain remain debated. Our group previously reported that in vitro primary blast exposure reduced long-term potentiation (LTP), the electrophysiological correlate of learning and memory, in rat organotypic hippocampal slice cultures (OHSCs) and that primary blast affects key proteins governing LTP. Recent studies have investigated phosphodiesterase-4 (PDE4) inhibition as a therapeutic strategy for reducing LTP deficits following inertia-driven TBI. We investigated the therapeutic potential of PDE4 inhibitors, specifically roflumilast, to ameliorate primary blast-induced deficits in LTP. We found that roflumilast at concentrations of 1nM or greater prevented deficits in neuronal plasticity measured 24h post-injury. We also observed a therapeutic window of at least 6h, but <23h. Additionally, we investigated molecular mechanisms that could elucidate this therapeutic effect. Roflumilast treatment (1nM delivered 6h post-injury) significantly increased total AMPA glutamate receptor 1 (GluR1) subunit expression, phosphorylation of the GluR1 subunit at the serine-831 site, and phosphorylation of stargazin at the serine-239/240 site upon LTP induction, measured 24h following injury. Roflumilast treatment significantly increased PSD-95 regardless of LTP induction. These findings indicate that further investigation into the translation of PDE4 inhibition as a therapy following bTBI is warranted.
由于近期的军事冲突和恐怖袭击，爆炸所致创伤性脑损伤（bTBI）对军事人员和平民的健康均构成了威胁。虽然已知二次爆炸（穿透伤）和三次爆炸（惯性驱动的脑变形）具有伤害性，但由超音速冲击波与颅骨和大脑相互作用引起的一次爆炸的影响仍存在争议。我们小组此前报道，在体外对大鼠海马脑片培养物（OHSCs）进行一次爆炸暴露会降低长期增强效应（LTP），而LTP是学习和记忆的电生理相关指标，并且一次爆炸会影响调控LTP的关键蛋白。最近的研究已将磷酸二酯酶4（PDE4）抑制作为一种治疗策略，用于减少惯性驱动的创伤性脑损伤后的LTP缺陷。我们研究了PDE4抑制剂，特别是罗氟司特，改善一次爆炸引起的LTP缺陷的治疗潜力。我们发现，浓度为1nM或更高的罗氟司特可预防损伤后24小时测得的神经元可塑性缺陷。我们还观察到至少6小时但小于23小时的治疗窗口。此外，我们研究了可能阐明这种治疗效果的分子机制。罗氟司特治疗（损伤后6小时给予1nM）在损伤后24小时测量时，在LTP诱导后显著增加了总AMPA谷氨酸受体1（GluR1）亚基的表达、GluR1亚基丝氨酸831位点的磷酸化以及stargazin丝氨酸239/240位点的磷酸化。无论是否诱导LTP，罗氟司特治疗均显著增加了PSD-95。这些发现表明，有必要进一步研究将PDE4抑制作为bTBI后的一种治疗方法。
