Wilson Nicole M, Gurney Mark E, Dietrich W Dalton, Atkins Coleen M
Department of Neurological Surgery, The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
Tetra Discovery Partners, Grand Rapids, Michigan, United States of America.
PLoS One. 2017 May 19;12(5):e0178013. doi: 10.1371/journal.pone.0178013. eCollection 2017.
Traumatic brain injury (TBI) initiates a deleterious inflammatory response that exacerbates pathology and worsens outcome. This inflammatory response is partially mediated by a reduction in cAMP and a concomitant upregulation of cAMP-hydrolyzing phosphodiesterases (PDEs) acutely after TBI. The PDE4B subfamily, specifically PDE4B2, has been found to regulate cAMP in inflammatory cells, such as neutrophils, macrophages and microglia. To determine if PDE4B regulates inflammation and subsequent pathology after TBI, adult male Sprague Dawley rats received sham surgery or moderate parasagittal fluid-percussion brain injury (2 ± 0.2 atm) and were then treated with a PDE4B - selective inhibitor, A33, or vehicle for up to 3 days post-surgery. Treatment with A33 reduced markers of microglial activation and neutrophil infiltration at 3 and 24 hrs after TBI, respectively. A33 treatment also reduced cortical contusion volume at 3 days post-injury. To determine whether this treatment paradigm attenuated TBI-induced behavioral deficits, animals were evaluated over a period of 6 weeks after surgery for forelimb placement asymmetry, contextual fear conditioning, water maze performance and spatial working memory. A33 treatment significantly improved contextual fear conditioning and water maze retention at 24 hrs post-training. However, this treatment did not rescue sensorimotor or working memory deficits. At 2 months after surgery, atrophy and neuronal loss were measured. A33 treatment significantly reduced neuronal loss in the pericontusional cortex and hippocampal CA3 region. This treatment paradigm also reduced cortical, but not hippocampal, atrophy. Overall, these results suggest that acute PDE4B inhibition may be a viable treatment to reduce inflammation, pathology and memory deficits after TBI.
创伤性脑损伤（TBI）引发有害的炎症反应，会加剧病理变化并恶化预后。这种炎症反应部分是由TBI后急性发生的cAMP减少以及cAMP水解磷酸二酯酶（PDEs）的伴随上调所介导的。已发现PDE4B亚家族，特别是PDE4B2，可调节炎症细胞（如中性粒细胞、巨噬细胞和小胶质细胞）中的cAMP。为了确定PDE4B是否调节TBI后的炎症和后续病理变化，成年雄性Sprague Dawley大鼠接受假手术或中度矢状旁流体冲击性脑损伤（2±0.2个大气压），然后在术后长达3天的时间里用PDE4B选择性抑制剂A33或赋形剂进行治疗。A33治疗分别在TBI后3小时和24小时降低了小胶质细胞活化和中性粒细胞浸润的标志物。A33治疗还在损伤后3天减少了皮质挫伤体积。为了确定这种治疗模式是否减轻了TBI诱导的行为缺陷，在术后6周的时间里对动物进行了前肢放置不对称、情境恐惧条件反射、水迷宫表现和空间工作记忆的评估。A33治疗在训练后24小时显著改善了情境恐惧条件反射和水迷宫记忆保持。然而，这种治疗并未挽救感觉运动或工作记忆缺陷。在术后2个月，测量了萎缩和神经元丢失情况。A33治疗显著减少了挫伤周围皮质和海马CA3区的神经元丢失。这种治疗模式还减少了皮质萎缩，但未减少海马萎缩。总体而言，这些结果表明急性抑制PDE4B可能是减轻TBI后炎症、病理变化和记忆缺陷的一种可行治疗方法。
