Hung-Jung Lin1,2, Chien-Chin Hsu1,2, Chung-Ching Chio3, Yu-Feng Tian3,4, Mao-Tsun Lin5, Ting-Wei Lin1, Chih-Hsien Chang6, Ching-Ping Chang5,7. 1. Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan, Taiwan. 2. Department of Emergency Medicine, Chi Mei Medical Center, Tainan, Taiwan. 3. Department of Surgery, Chi Mei Medical Center, Tainan, Taiwan. 4. Department of Health and Nutrition, Chia Nan University of Pharmacy and Science, Tainan, Taiwan. 5. Department of Medical Research, Chi Mei Medical Center, Tainan, Taiwan. 6. Department of Medicine, Cheng-Kung University School of Medicine, Tainan, Taiwan. 7. The Ph.D. Program for Neural Regenerative Medicine, Taipei Medical University, Taipei, Taiwan.
Abstract
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 γ-secretase inhibitors on TBI outcomes in rats. METHODS: The neuroprotective effects of γ-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.
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 γ-secretase inhibitors on TBI outcomes in rats. METHODS: The neuroprotective effects of γ-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.
Authors: Elvira Ruslanovna Akhmetzyanova; Anna Viktorovna Timofeeva; Davran Khudaishukurovich Sabirov; Alexander Alexandrovich Kostennikov; Alexander Alexandrovich Rogozhin; Victoria James; S S Arkhipova; Albert Anatolevich Rizvanov; Yana Olegovna Mukhamedshina Journal: Front Mol Neurosci Date: 2022-02-24 Impact factor: 5.639
Authors: Maha Saber; Amanda D Rice; Immaculate Christie; Rebecca G Roberts; Kenneth S Knox; Peter Nakaji; Rachel K Rowe; Ting Wang; Jonathan Lifshitz Journal: Shock Date: 2021-02-01 Impact factor: 3.454