A novel antagonist of p75NTR reduces peripheral expansion and CNS trafficking of pro-inflammatory monocytes and spares function after traumatic brain injury

作者：Sangmi Lee, Aaron Mattingly, Amity Lin, Jeffrey Sacramento, Leda Mannent, Marie‐Noëlle Castel, Benoit Canolle, Sandrine Delbary-Gossart, Badia Ferzaz, Josh M. Morganti, Susanna Rosi, Adam R. Ferguson, Geoffrey T. Manley, Jacqueline C. Bresnahan, Michael S. Beattie · 发表于：Journal of Neuroinflammation · 年份：2016 · DOI：10.1186/s12974-016-0544-4 · 被引用次数：63 · 研究领域：Nerve injury and regeneration、Traumatic Brain Injury and Neurovascular Disturbances、Neuroinflammation and Neurodegeneration Mechanisms

BACKGROUND: Traumatic brain injury (TBI) results in long-term neurological deficits, which may be mediated in part by pro-inflammatory responses in both the injured brain and the circulation. Inflammation may be involved in the subsequent development of neurodegenerative diseases and post-injury seizures. The p75 neurotrophin receptor (p75NTR) has multiple biological functions, affecting cell survival, apoptotic cell death, axonal growth, and degeneration in pathological conditions. We recently found that EVT901, a novel piperazine derivative that inhibits p75NTR oligomerization, is neuroprotective, reduces microglial activation, and improves outcomes in two models of TBI in rats. Since TBI elicits both CNS and peripheral inflammation, we used a mouse model of TBI to examine whether EVT901 would affect peripheral immune responses and trafficking to the injured brain. METHODS: Cortical contusion injury (CCI)-TBI of the sensory/motor cortex was induced in C57Bl/6 wild-type mice and CCR2(+/RFP) heterozygote transgenic mice, followed by treatment with EVT901, a selective antagonist of p75NTR, or vehicle by i.p. injection at 4 h after injury and then daily for 7 days. Brain and blood were collected at 1 and 6 weeks after injury. Flow cytometry and histological analysis were used to determine peripheral immune responses and trafficking of peripheral immune cells into the lesion site at 1 and 6 weeks after TBI. A battery of behavioral tests administered over 6 weeks was used to eval...