| Summary: | 博士 === 國立臺灣大學 === 醫學工程學研究所 === 101 === Background: Treating and managing neurological sequelae of traumatic brain injury (TBI) patients are difficult and keep challenging medical stuff despite of the advancement of technology. Many drugs that proved efficacy in experimental models failed to show the benefits in the treatment of TBI population, so as many reviews did not support that those efficacy treatment in animal models effected. There is strong need of well-designed and controlled animal models with an integrative, multi-mechanism approach for drug discovery and study in order to establish definitive treatment standards for this patient population;
For that a proper understanding of animal trials requires that diverse aspects and mechanisms of the injury be taken into account, and it is well studied that TBI initiates a neuroinflammatory cascade that contributes to neuronal damage and behavioral impairment, this study was undertaken to investigate the effects of wogonin, a flavonoid with potent anti-inflammatory properties, on functional and histological outcomes, brain edema, and toll-like receptor 4 (TLR4)- and nuclear factor kappa B (NF-kappa B)-related signaling pathways in mice following TBI.
Methodology/Principal Findings: Mice subjected to controlled cortical impact injury were injected with wogonin 20, 40, or 50 mg‧kg-1) or vehicle 10 min after injury. Behavioral studies, histology analysis, and measurement of blood-brain barrier (BBB) permeability and brain water content were carried out to assess the effects of wogonin. Levels of TLR4/NF-kappa B-related inflammatory mediators were also examined. Treatment with 40 mg‧kg-1 wogonin significantly improved functional recovery and reduced contusion volumes up to post-injury day 28. Wogonin also significantly reduced neuronal death, BBB permeability, and brain edema beginning at day 1. These changes were associated with a marked reduction in leukocyte infiltration, microglial activation, TLR4 expression, NF-kappa B binding activity, matrix metalloproteinase-9 activity, and expression of inflammatory mediators, including interleukin-1beta, interleukin-6, macrophage inflammatory protein-2, and cyclooxygenase-2.
Conclusions/Significance: Our results show that post-injury wogonin treatment improved long-term functional and histological outcomes, reduced brain edema, and attenuated the TLR4/NF-kappa B-mediated inflammatory response in mouse TBI. The neuroprotective effects of wogonin may be related to modulation of the TLR4/NF-kappa B signaling pathway. On the other hand, we have set up an efficacy evaluation system and mechanism exploration system of therapeutic agents for TBI by experimental animal brain injury model- controlled cortical impaction (CCI) injury model. Three major groups of evaluation tests including: (1) functional evaluation (2) anatomical and histological evaluation (3) Biomolecular evaluation are introduced and integrated into our platform. And we also have demonstrated the feasibility and practicability of our CCI injury model with an integrative, multi-mechanism approach through the experiment of wogonin. Prospectively, with this practable CCI model we are capable to expand our research to different fields of neuroprotection, or neuroregeneration like cell therapies; also the integration of the new technology and equipment mentioned in contents, which are well characterized with real-time acquisition, non-sample destruction or minimal sample requirement, operation in living cell or tissue; and the practical benefits of time-saving, less consumables requirement, would make great progression of research in neuroscience .
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