DL-3-n-butylphthalide induced neuroprotection, regenerative repair, functional recovery and psychological benefits following traumatic brain injury in mice

• Type of Material: Article
• Authors: Yingying Zhao, Capital Medical University; Jin Hwan Lee, Emory University; Dongdong Chen, Emory University; Xiaohuan Gu, Emory University; Asha Caslin, Emory University; Jimei Li, Capital Medical University; Shan Ping Yu, Emory University; Ling Wei, Emory University
• Language: English
• Date: 2017-12-01
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2017 Elsevier Ltd
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.neuint.2017.03.017
• Title of Journal or Parent Work: Neurochemistry International
• ISSN: 0197-0186
• Volume: 111
• Start Page: 82
• End Page: 92
• Grant/Funding Information: This study was supported by NS075338 (LW), NS085568 (LW/SPY), NS091585 (LW), AHA Postdoctoral Fellowship 15POST25680013 (JHL), and a VA Merit grant RX000666 (SPY).
• Keywords: ADULT-RAT HIPPOCAMPUS; PHARMACOLOGICALLY INDUCED HYPOTHERMIA; Life Sciences & Biomedicine; Traumatic brain injury; NEURAL STEM; Biochemistry & Molecular Biology; HEAD-INJURY; Neurosciences; NBP; PARKINSONS-DISEASE; PROGENITOR CELLS; Inflammation; Regeneration; NITRIC-OXIDE; DENTATE GYRUS; CHIRAL 3-N-BUTYLPHTHALIDE; FOCAL CEREBRAL-ISCHEMIA; Neurosciences & Neurology; Depression; Science & Technology
• Research Categories: Biology, Neuroscience; Psychology, Physiological

Abstract

Previous investigations suggest that DL-3-n-butylphthalide (NBP) is a promising multifaceted drug for the treatment of stroke. It is not clear whether NBP can treat traumatic brain injury (TBI) and what could be the mechanisms of therapeutic benefits. To address these issues, TBI was induced by a controlled cortical impact in adult male mice. NBP (100 mg/kg) or saline was intraperitoneally administered within 5 min after TBI. One day after TBI, apoptotic events including caspase-3/9 activation, cytochrome c release from the mitochondria, and apoptosis-inducing factor (AIF) translocation into the nucleus in the pericontusion region were attenuated in NBP-treated mice compared to TBI-saline controls. In the assessment of the nuclear factor kappa-light-chain-enhancer of activated B (NF-κB) pathway, NBP ameliorated the p65 expression and the p-IκB-α/IκB-α ratio, indicating reduced NF-κB activation. Consistently, NBP reduced the upregulation of proinflammatory cytokines such as tumor necrotizing factor-alpha (TNF-α) and interleukin-1beta (IL-1β) after TBI. In sub-acute treatment experiments, NBP was intranasally delivered once daily for 3 days. At 3 days after TBI, this repeated NBP treatment significantly reduced the contusion volume and cell death in the pericontusion region. In chronic experiments up to 21 days after TBI, continues daily intranasal NBP treatment increased neurogenesis, angiogenesis, and arteriogenesis in the post-TBI brain, accompanied with upregulations of regenerative genes including brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), endothelial-derived nitric oxide synthase (eNOS), and matrix metallopeptidase 9 (MMP-9). The NBP treatment significantly improved sensorimotor functional recovery and reduced post-TBP depressive behavior. These new findings demonstrate that NBP shows multiple therapeutic benefits after TBI.