Mitochondria and NMDA receptor-dependent toxicity of berberine sensitizes neurons to glutamate and rotenone injury.
Mitochondria and NMDA receptor-dependent toxicity of berberine sensitizes neurons to glutamate and rotenone injury.
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DOI：
10.1371/journal.pone.0107129
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Huttunen HJ
中科院分区：
文献类型：
--
作者：
Kysenius K;Brunello CA;Huttunen HJ
包括2型糖尿病和阿尔茨海默病在内的代谢和年龄相关疾病的全球发病率正在上升。除了传统的药物治疗外，补充和替代医学的候选药物正在积极寻求进一步的药物开发。黄连素是一种传统上用作抗生素的营养药物，最近已被提出作为一种多靶点保护剂，用于预防2型糖尿病、血脂异常、缺血性脑损伤和神经退行性疾病，如帕金森病和阿尔茨海默病。然而，黄连素的安全性仍然存在争议，因为孤立的报告表明存在急性毒性、心动过缓和神经退行性变加重的风险。我们报告说，低微摩尔小檗碱导致快速的依赖于多巴胺的毒性，其特征在于线粒体肿胀，氧化应激增加，线粒体膜电位降低和ATP含量耗尽的原代神经元。小檗碱不诱导半胱天冬酶-3活化，并且所产生的神经毒性不受泛半胱天冬酶抑制剂治疗的影响。有趣的是，美金刚和MK-801对NMDA受体的抑制完全阻断了小檗碱诱导的神经毒性。此外，亚毒性纳摩尔浓度的小檗碱足以使神经元对谷氨酸兴奋毒性和鱼藤酮损伤敏感。我们的研究强调了需要进一步的安全性评估黄连素，特别是由于其倾向于在中枢神经系统中积累和潜在的神经毒性的风险，由于黄连素的生物利用度增加。
The global incidence of metabolic and age-related diseases, including type 2 diabetes and Alzheimer's disease, is on the rise. In addition to traditional pharmacotherapy, drug candidates from complementary and alternative medicine are actively being pursued for further drug development. Berberine, a nutraceutical traditionally used as an antibiotic, has recently been proposed to act as a multi-target protective agent against type 2 diabetes, dyslipidemias, ischemic brain injury and neurodegenerative diseases, such as Parkinson's and Alzheimer's disease. However, the safety profile of berberine remains controversial, as isolated reports suggest risks with acute toxicity, bradycardia and exacerbation of neurodegeneration. We report that low micromolar berberine causes rapid mitochondria-dependent toxicity in primary neurons characterized by mitochondrial swelling, increased oxidative stress, decreased mitochondrial membrane potential and depletion of ATP content. Berberine does not induce caspase-3 activation and the resulting neurotoxicity remains unaffected by pan-caspase inhibitor treatment. Interestingly, inhibition of NMDA receptors by memantine and MK-801 completely blocked berberine-induced neurotoxicity. Additionally, subtoxic nanomolar concentrations of berberine were sufficient to sensitize neurons to glutamate excitotoxicity and rotenone injury. Our study highlights the need for further safety assessment of berberine, especially due to its tendency to accumulate in the CNS and the risk of potential neurotoxicity as a consequence of increasing bioavailability of berberine.
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影响因子：
3.8
作者：
Fukui, Masayuki;Choi, Hye Joung;Zhu, Bao Ting
通讯作者：
Zhu, Bao Ting
影响因子：
4.2
作者：
Durairajan, Siva Sundara Kumar;Liu, Liang-Feng;Li, Min
通讯作者：
Li, Min
DOI：
10.1042/bss0660085
发表时间：
1999-01-01
期刊：
MITOCHONDRIA AND CELL DEATH
影响因子：
--
作者：
Greenamyre, JT;MacKenzie, G;Stephans, SE
通讯作者：
Stephans, SE
DOI：
10.3390/molecules16086732
发表时间：
2011-08-09
期刊：
Molecules (Basel, Switzerland)
影响因子：
--
作者：
Ji HF;Shen L
通讯作者：
Shen L
影响因子：
1.9
作者：
Cannillo, Margherita;Frea, Simone;Gaita, Fiorenzo
通讯作者：
Gaita, Fiorenzo