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/Iκ3-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.

Effects of dl‐3‐n‐butylphthalide on serum lipoprotein‐associated phospholipase A2 and hypersensitive C‐reactive protein levels in acute cerebral infarction

“…A large number of experiments at home and abroad have revealed that NBP can regulate brain energy metabolism (Yan, Wang, Yao, Liu, & Xiao, ), protect the mitochondria (Min et al, ), promote normal blood flow in the ischemic area (Xu et al, ), inhibit oxidative stress and platelet aggregation (Li et al, ; Zhao, Li, Zhang, Chen, & Li, ), and prevent the vigorous apoptosis of cells (Min et al, ). In addition, Chinese scholars found that NBP plays a neuroprotective role by acting on multiple active targets (Wang et al, ; Zhao et al, ). Furthermore, some scholars considered that the effective rate of NBP in treating ACI can reach 76%–93% (Offner et al, ).…”

“…Hence, the early assessment of disease severity and its timely targeted treatment have become the focus of study on cerebral infarction (Chen & Wang, ; Kidwell, Liebeskind, Starkman, & Saver, ). Dl‐3‐n‐butylphthalide (NBP) is a new class of nationally approved drug in China (Zhao et al, ; Tang et al, ), which has been widely used in clinic. Lipoprotein‐associated phospholipase A2 (Lp‐PLA2) is a new inflammatory marker (Wang, Hu, et al, ; Zhou, Liu, Shi, Huang, & Zhou, ), and its application in the treatment of atherosclerotic cardiovascular and cerebrovascular diseases has attracted much attention in recent years.…”

Dl-NBP (Dl-3-N-Butylphthalide) Treatment Promotes Neurological Functional Recovery Accompanied by the Upregulation of White Matter Integrity and HIF-1α/VEGF/Notch/Dll4 Expression

“…Previous study showed that NBP improved rats' functional recovery following spinal cord injury (He et al, 2017), induced neuro-protection, regenerative repair, and functional recovery after traumatic brain injury in mice (Zhao et al, 2017). It also improved chronic cerebral ischemia-induced cognitive deficits in rats and enhanced functional recovery in the endothelin-1-induced focal permanent stroke model (Sun et al, 2017b).…”

Dl‐3n‐butylphthalide improves traumatic brain injury recovery via inhibiting autophagy‐induced blood‐brain barrier disruption and cell apoptosis

“…24 Additionally, our previous work suggested that Dl-NBP ameliorates locomotor functional recovery in animal model of spinal cord injury (SCI) 25 and L-NBP enhances cognitive function in Alzheimer's disease. 28 However, the mechanisms underlying the protective effect of Dl-NBP in acute TBI has not previously been investigated. 27 Recently, it is reported that Dl-NBP promotes regenerative repair and functional recovery of mice after TBI.…”