Low-Dose Aspirin Upregulates Tyrosine Hydroxylase and Increases Dopamine Production in Dopaminergic Neurons: Implications for Parkinson's Disease.
Low-Dose Aspirin Upregulates Tyrosine Hydroxylase and Increases Dopamine Production in Dopaminergic Neurons: Implications for Parkinson's Disease.
复制标题
DOI：
10.1007/s11481-018-9808-3
复制
发表时间：
2019-06
期刊：
影响因子：
--
通讯作者：
Pahan K
中科院分区：
文献类型：
--
作者：
Rangasamy SB;Dasarathi S;Pahan P;Jana M;Pahan K
增加帕金森病患者黑质中残留的多巴胺能神经元的功能是一个重要的研究领域，因为它最终可能补偿这种损失。虽然酪氨酸羟化酶(TH)是多巴胺(DA)生物合成途径中的限速酶，但目前还没有有效的药物或分子来上调TH并增加黑质多巴胺能神经元中DA的产生。这项研究强调了阿司匹林在刺激多巴胺能神经元TH表达和增加DA水平方面的重要性。低剂量阿司匹林可增加小鼠MN9D多巴胺能神经元细胞TH的表达和DA的产生。相应地，口服阿司匹林可增加正常C57/BL6小鼠和老龄A53Tα-SYN转基因小鼠黑质TH的表达，上调纹状体DA的水平。口服阿司匹林还可以改善正常小鼠和A53T转基因小鼠的运动能力。在机制研究中，我们发现TH基因启动子中存在cAMP反应元件(Cre)，阿司匹林能迅速诱导多巴胺能神经元细胞中cAMP反应元件结合(CREB)的激活。阿司匹林治疗还增加了C57/BL6小鼠黑质中磷酸化CREB的水平。通过siRNA敲除CREB来抑制阿司匹林诱导的TH的表达，以及将CREB募集到TH基因启动子上，提示阿司匹林通过CREB刺激多巴胺能神经元中TH的转录。这些结果突出了阿司匹林刺激TH-DA途径的新特性，这可能对帕金森病患者有益。
Increasing the function of residual dopaminergic neurons in the nigra of PD patients is an important area of research as it may eventually compensate the loss. Although tyrosine hydroxylase (TH) is the rate-limiting enzyme in the dopamine (DA) biosynthesis pathway, there are no effective drugs/molecules to upregulate TH and increase the production of DA in nigral dopaminergic neurons. This study underlines the importance of aspirin in stimulating the expression of TH and increasing the level of DA in dopaminergic neurons. At low doses, aspirin increased the expression of TH and the production of DA in mouse MN9D dopaminergic neuronal cells. Accordingly, oral administration of aspirin increased the expression of TH in the nigra and upregulated the level of DA in striatum of normal C57/BL6 mice and aged A53T α-syn transgenic mice. Oral aspirin also improved locomotor activities of normal mice and A53T transgenic mice. While investigating mechanisms, we found the presence of cAMP response element (CRE) in the promoter of TH gene and the rapid induction of cAMP response element binding (CREB) activation by aspirin in dopaminergic neuronal cells. Aspirin treatment also increased the level of phospho-CREB in the nigra of C57/BL6 mice. The abrogation of aspirin-induced expression of TH by siRNA knockdown of CREB and the recruitment of CREB to the TH gene promoter by aspirin suggest that aspirin stimulates the transcription of TH in dopaminergic neurons via CREB. These results highlight a new property of aspirin in stimulating the TH-DA pathway, which may be beneficial in PD patients.
登录
查看更多内容
DOI：
10.4049/jimmunol.0801734
发表时间：
2009-04-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Mondal S;Roy A;Pahan K
通讯作者：
Pahan K
影响因子：
6.2
作者：
Khasnavis, Saurabh;Pahan, Kalipada
通讯作者：
Pahan, Kalipada
DOI：
10.4049/jimmunol.1102624
发表时间：
2012-07-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Corbett GT;Roy A;Pahan K
通讯作者：
Pahan K
影响因子：
4.4
作者：
Jana M;Ghosh S;Pahan K
通讯作者：
Pahan K
DOI：
10.1073/pnas.0400569101
发表时间：
2004-06-22
影响因子：
11.1
作者：
Benner, EJ;Mosley, RL;Gendelman, HE
通讯作者：
Gendelman, HE