期刊
CELLULAR PHYSIOLOGY AND BIOCHEMISTRY
卷 44, 期 5, 页码 1726-1740出版社
KARGER
DOI: 10.1159/000485778
关键词
Traumatic brain injury; gamma-secretase; Neurogenic acute lung injury; Microglia
资金
- Ministry of Science and Technology (Taiwan) [MOST 104-2314-B-384-003-MY3, MOST 106-2314-B-384-001-MY3]
- Chi Mei Medical Center (Taiwan) [CMFHT 10504]
Background/Aims: In response to traumatic brain injury (TBI), activated microglia exhibit changes in their morphology from the resting ramified phenotype toward the activated hypertrophic or amoeboid phenotype. Here, we provide the first description of the mechanism underlying the neuroprotective effects of gamma-secretase inhibitors on TBI outcomes in rats. Methods: The neuroprotective effects of gamma-secretase inhibitors such as LY411575 or CHF5074 on TBI-induced neurotoxicity were analysed using a neurological motor function evaluation, cerebral contusion assay, immunohistochemical staining for microglia phenotypes, lung injury score and Evans Blue dye extravasation assay of brain and lung oedema. Results: Hypertrophic or amoeboid microglia accumulated in the injured cortex, the blood-brain-barrier was disrupted and neurological deficits and acute lung injury were observed 4 days after TBI in adult rats. However, a subcutaneous injection of LY411575 (5 mg/kg) or CHF5074 (30 mg/kg) immediately after TBI and once daily for 3 consecutive days post-TBI significantly attenutaed the accumulation of hypertrophic microglia in the injured brain, neurological injury, and neurogenic acute lung injury. Conclusion: Gamma-secretase inhibitors attenuated neurotrauma and neurogenic acute lung injury in rats by reducing the accumulation of hypertrophic microglia in the vicinity of the lesion. (c) 2017 The Author(s) Published by S. Karger AG, Basel
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