Li Yazhou, Bader Miaad, Tamargo Ian, Rubovitch Vardit, Tweedie David, Pick Chaim G, Greig Nigel H
Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
Department of Anatomy and Anthropology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, 69978 Israel.
J Neurochem. 2015 Dec;135(6):1203-1217. doi: 10.1111/jnc.13169. Epub 2015 Jun 18.
Traumatic brain injury (TBI), a brain dysfunction for which there is no present effective treatment, is often caused by a concussive impact to the head and affects an estimated 1.7 million Americans annually. Our laboratory previously demonstrated that exendin-4, a long-lasting glucagon-like peptide 1 receptor (GLP-1R) agonist, has neuroprotective effects in cellular and animal models of TBI. Here, we demonstrate neurotrophic and neuroprotective effects of a different GLP-1R agonist, liraglutide, in neuronal cultures and a mouse model of mild TBI (mTBI). Liraglutide promoted dose-dependent proliferation in SH-SY5Y cells and in a GLP-1R over-expressing cell line at reduced concentrations. Pre-treatment with liraglutide rescued neuronal cells from oxidative stress- and glutamate excitotoxicity-induced cell death. Liraglutide produced neurotrophic and neuroprotective effects similar to those of exendin-4 in vitro. The cAMP/PKA/pCREB pathway appears to play an important role in this neuroprotective activity of liraglutide. Furthermore, our findings in cell culture were well-translated in a weight drop mTBI mouse model. Post-treatment with a clinically relevant dose of liraglutide for 7 days in mice ameliorated memory impairments caused by mTBI when evaluated 7 and 30 days post trauma. These data cross-validate former studies of exendin-4 and suggest that liraglutide holds therapeutic potential for the treatment of mTBI. Exendin-4, a long-lasting glucagon-like peptide 1 receptor (GLP-1R) agonist, has neuroprotective effects in cellular and animal models of traumatic brain injury (TBI). Here, we demonstrate neurotrophic and neuroprotective effects of a different GLP-1R agonist, liraglutide, in neuronal cultures and a mouse model of mild TBI (mTBI). Liraglutide promoted dose-dependent proliferation in SH-SY5Y cells and in a GLP-1R over-expressing cell line at reduced concentrations. Pretreatment with liraglutide rescued neuronal cells from oxidative stress- and glutamate excitotoxicity-induced cell death. Liraglutide produced neurotrophic and neuroprotective effects similar to those of exendin-4 in vitro, likely involving the cAMP/PKA/pCREB pathway. Our findings in cell culture were well-translated in a weight-drop mTBI mouse model. Post-treatment with a clinically relevant dose of liraglutide for 7 days in mice ameliorated memory impairments caused by mTBI.
创伤性脑损伤（TBI）是一种目前尚无有效治疗方法的脑功能障碍，通常由头部的震荡性撞击引起，每年估计影响170万美国人。我们实验室先前证明，艾塞那肽-4（exendin-4）是一种长效胰高血糖素样肽1受体（GLP-1R）激动剂，在TBI的细胞和动物模型中具有神经保护作用。在此，我们证明了另一种GLP-1R激动剂利拉鲁肽在神经元培养物和轻度TBI（mTBI）小鼠模型中的神经营养和神经保护作用。利拉鲁肽在较低浓度下可促进SH-SY5Y细胞和GLP-1R过表达细胞系中的剂量依赖性增殖。利拉鲁肽预处理可使神经元细胞免受氧化应激和谷氨酸兴奋性毒性诱导的细胞死亡。利拉鲁肽在体外产生了与艾塞那肽-4相似的神经营养和神经保护作用。cAMP/PKA/pCREB途径似乎在利拉鲁肽的这种神经保护活性中起重要作用。此外，我们在细胞培养中的发现很好地转化到了重量下降mTBI小鼠模型中。在小鼠中用临床相关剂量的利拉鲁肽进行7天的治疗后，在创伤后7天和30天进行评估时，改善了由mTBI引起的记忆障碍。这些数据交叉验证了先前关于艾塞那肽-4的研究，并表明利拉鲁肽在治疗mTBI方面具有治疗潜力。艾塞那肽-4是一种长效胰高血糖素样肽1受体（GLP-1R）激动剂，在创伤性脑损伤（TBI）的细胞和动物模型中具有神经保护作用。在此，我们证明了另一种GLP-1R激动剂利拉鲁肽在神经元培养物和轻度TBI（mTBI）小鼠模型中的神经营养和神经保护作用。利拉鲁肽在较低浓度下可促进SH-SY5Y细胞和GLP-1R过表达细胞系中的剂量依赖性增殖。利拉鲁肽预处理可使神经元细胞免受氧化应激和谷氨酸兴奋性毒性诱导的细胞死亡。利拉鲁肽在体外产生了与艾塞那肽-4相似的神经营养和神经保护作用，可能涉及cAMP/PKA/pCREB途径。我们在细胞培养中的发现很好地转化到了重量下降mTBI小鼠模型中。在小鼠中用临床相关剂量的利拉鲁肽进行7天的治疗后，改善了由mTBI引起的记忆障碍。
