Yu-Long Lan1,2,3,4, Xun Wang1,2, Yu-Jie Zou5, Jin-Shan Xing1,2, Jia-Cheng Lou1,2, Shuang Zou4, Bin-Bin Ma1,2, Yan Ding6, Bo Zhang7,8. 1. Department of Neurosurgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, China. 2. Department of Neurosurgery, Shenzhen People's Hospital, Shenzhen, China. 3. Department of Pharmacy, Dalian Medical University, Dalian, 116044, China. 4. Department of Physiology, Dalian Medical University, Dalian, 116044, China. 5. Department of Nursing, The First Affiliated Hospital of Dalian Medical University, Dalian, 116023, China. 6. Department of Pediatrics, Children's Hospital of Boston, Harvard Medical School, Boston, MA, 02115, USA. 7. Department of Neurosurgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, China. zhangbodlykdx@126.com. 8. Department of Neurosurgery, Shenzhen People's Hospital, Shenzhen, China. zhangbodlykdx@126.com.
Abstract
OBJECTIVE: Traumatic brain injury (TBI) is a significant cause of death and long-term deficits in motor and cognitive functions for which there are currently no effective chemotherapeutic drugs. Bazedoxifene (BZA) is a third-generation selective estrogen receptor modulator (SERM) and has been investigated as a treatment for postmenopausal osteoporosis. It is generally safe and well tolerated, with favorable endometrial and breast safety profiles. Recent findings have shown that SERMs may have therapeutic benefits; however, the role of BZA in the treatment of TBI and its molecular and cellular mechanisms remain poorly understood. The aim of the present study was to examine the neuroprotective effects of BZA on early TBI in rats and to explore the underlying mechanisms of these effects. MATERIALS AND METHODS: TBI was induced using a modified weight-drop method. Neurological deficits were evaluated according to the neurological severity score (NSS). Morris water maze and open-field behavioral tests were used to test cognitive functions. Brain edema was measured by brain water content, and impairments in the blood-brain barrier (BBB) were evaluated by expression analysis of tight junction-associated proteins, such as occludin and zonula occludens-1 (ZO-1). Neuronal injury was assessed by hematoxylin and eosin (H&E) staining. LC-MS/MS analysis was performed to determine the ability of BZA to cross the BBB. RESULTS: Our results indicated that BZA attenuated the impaired cognitive functions and the increased BBB permeability of rats subjected to TBI through activation of inflammatory cascades. In vivo experiments further revealed that BZA provided this neuroprotection by suppressing TBI-induced activation of the MAPK/NF-κB signaling pathway. Thus, mechanically, the anti-inflammatory effects of BZA in TBI may be partially mediated by blocking the MAPK signaling pathway. CONCLUSIONS: These findings suggest that BZA might attenuate neurological deficits and BBB damage to protect against TBI by blocking the MAPK/NF-κB signaling pathway.
OBJECTIVE:Traumatic brain injury (TBI) is a significant cause of death and long-term deficits in motor and cognitive functions for which there are currently no effective chemotherapeutic drugs. Bazedoxifene (BZA) is a third-generation selective estrogen receptor modulator (SERM) and has been investigated as a treatment for postmenopausal osteoporosis. It is generally safe and well tolerated, with favorable endometrial and breast safety profiles. Recent findings have shown that SERMs may have therapeutic benefits; however, the role of BZA in the treatment of TBI and its molecular and cellular mechanisms remain poorly understood. The aim of the present study was to examine the neuroprotective effects of BZA on early TBI in rats and to explore the underlying mechanisms of these effects. MATERIALS AND METHODS: TBI was induced using a modified weight-drop method. Neurological deficits were evaluated according to the neurological severity score (NSS). Morris water maze and open-field behavioral tests were used to test cognitive functions. Brain edema was measured by brain water content, and impairments in the blood-brain barrier (BBB) were evaluated by expression analysis of tight junction-associated proteins, such as occludin and zonula occludens-1 (ZO-1). Neuronal injury was assessed by hematoxylin and eosin (H&E) staining. LC-MS/MS analysis was performed to determine the ability of BZA to cross the BBB. RESULTS: Our results indicated that BZA attenuated the impaired cognitive functions and the increased BBB permeability of rats subjected to TBI through activation of inflammatory cascades. In vivo experiments further revealed that BZA provided this neuroprotection by suppressing TBI-induced activation of the MAPK/NF-κB signaling pathway. Thus, mechanically, the anti-inflammatory effects of BZA in TBI may be partially mediated by blocking the MAPK signaling pathway. CONCLUSIONS: These findings suggest that BZA might attenuate neurological deficits and BBB damage to protect against TBI by blocking the MAPK/NF-κB signaling pathway.
Authors: Barry S Komm; Yogendra P Kharode; Peter V N Bodine; Heather A Harris; Chris P Miller; C Richard Lyttle Journal: Endocrinology Date: 2005-06-16 Impact factor: 4.736
Authors: Amy K Wagner; Anthony E Kline; Dianxu Ren; Lauren A Willard; Michael K Wenger; Ross D Zafonte; C Edward Dixon Journal: Behav Brain Res Date: 2007-04-20 Impact factor: 3.332
Authors: Victoria Kaupp; Kinga G Blecharz-Lang; Christina Dilling; Patrick Meybohm; Malgorzata Burek Journal: Neural Regen Res Date: 2023-01 Impact factor: 6.058
Authors: Alice Jacquens; Edward J Needham; Elisa R Zanier; Vincent Degos; Pierre Gressens; David Menon Journal: Int J Mol Sci Date: 2022-09-23 Impact factor: 6.208
Authors: Megan Conlon; Carson D Poltorack; Giovanni C Forcina; David A Armenta; Melodie Mallais; Marcos A Perez; Alex Wells; Alexis Kahanu; Leslie Magtanong; Jennifer L Watts; Derek A Pratt; Scott J Dixon Journal: Nat Chem Biol Date: 2021-03-08 Impact factor: 15.040