title: DL-3-n-butylphthalide induced neuroprotection, regenerative repair, functional recovery and psychological benefits following traumatic brain injury in mice.
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.
authors.affiliation: Laboratories of Stem Cell Biology and Neural Regeneration and Function Recovery, Department of Neurology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China; Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA, 30322, USA.
authors.forename: Yingying
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA, 30322, USA; Center for Visual and Neurocognitive Rehabilitation Atlanta, VA Medical Center, Decatur, GA, 30033, USA.
authors.forename: Jin Hwan
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA, 30322, USA; Center for Visual and Neurocognitive Rehabilitation Atlanta, VA Medical Center, Decatur, GA, 30033, USA.
authors.forename: Dongdong
authors.initials: D
authors.lastname: Chen
authors.affiliation: Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA, 30322, USA; Center for Visual and Neurocognitive Rehabilitation Atlanta, VA Medical Center, Decatur, GA, 30033, USA.
authors.forename: Xiaohuan
authors.initials: X
authors.lastname: Gu
authors.affiliation: Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA, 30322, USA.
authors.forename: Asha
authors.initials: A
authors.lastname: Caslin
authors.affiliation: Laboratories of Stem Cell Biology and Neural Regeneration and Function Recovery, Department of Neurology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China.
authors.forename: Jimei
authors.initials: J
authors.lastname: Li
authors.affiliation: Laboratories of Stem Cell Biology and Neural Regeneration and Function Recovery, Department of Neurology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China; Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA, 30322, USA; Center for Visual and Neurocognitive Rehabilitation Atlanta, VA Medical Center, Decatur, GA, 30033, USA.
authors.forename: Shan Ping
authors.initials: SP
authors.lastname: Yu
authors.affiliation: Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA, 30322, USA; Department of Neurology, Emory University School of Medicine, Atlanta, GA, 30322, USA. Electronic address: lwei7@emory.edu.
authors.forename: Ling
authors.initials: L
authors.lastname: Wei
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001572:Benzofurans / Q000494:pharmacology*; D000070642:Brain Injuries, Traumatic / Q000188:drug therapy*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D000066829:Neuroprotection / Q000502:physiology*; D020127:Recovery of Function / Q000187:drug effects*; D015398:Signal Transduction / Q000502:physiology; D015854:Up-Regulation
chemical_list: D001572:Benzofurans; D016207:Cytokines; D053583:Interleukin-1beta; D016328:NF-kappa B; C027125:3-n-butylphthalide
keywords: Depression; Inflammation; NBP; Regeneration; Traumatic brain injury