Propranolol reduces cognitive deficits, amyloid β levels, tau phosphorylation and insulin resistance in response to chronic corticosterone administration
Propranolol reduces cognitive deficits, amyloid β levels, tau phosphorylation and insulin resistance in response to chronic corticosterone administration
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DOI：
10.1017/s1461145712001393
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发表时间：
2013-07-01
影响因子：
4.8
通讯作者：
Ramirez, Maria J.
中科院分区：
文献类型：
--
作者：
Dobarro, Marta;Orejana, Lourdes;Ramirez, Maria J.
长期暴露于糖皮质激素不仅可能导致胰岛素抵抗或认知缺陷，而且也被认为是阿尔茨海默病等病理的风险因素。普萘洛尔是一种β-肾上腺素能拮抗剂，常用于治疗高血压或急性焦虑症。普萘洛尔（5毫克/公斤）的影响已被测试在一个模型中的慢性皮质酮给药（100微克/毫升，4周）的饮用水。皮质酮给药导致新物体识别试验中的认知障碍，普萘洛尔可逆转该现象。在皮质酮处理的小鼠海马中A β水平的增加被普萘洛尔处理抵消，据称是通过增加IDE表达。慢性皮质酮治疗诱导胰岛素抵抗的特征性反应，如外周胰岛素水平增加，胰岛素受体（pIR）活化减少和相关细胞内途径（pAkt）减少。这些作用可能与c-Jun N末端激酶1表达降低有关。同样，普萘洛尔能够抵消所有皮质酮诱导的作用。参与tau蛋白磷酸化的主要激酶之一，糖原合成酶激酶3 β（GSK 3 β），通过pAkt磷酸化而失活，发现皮质酮治疗后减少，普萘洛尔治疗后增加。pTau表达的伴随变化被发现。总体而言，这些数据进一步加强普萘洛尔作为与糖皮质激素-胰岛素抵抗的相互作用和阿尔茨海默病的相关细胞过程的发展相关的病理学的治疗剂的潜力。
Chronic exposure to glucocorticoids might result not only in insulin resistance or cognitive deficits, but it is also considered as a risk factor for pathologies such as Alzheimer's disease. Propranolol is a beta-adrenergic antagonist commonly used in the treatment of hypertension or acute anxiety. The effects of propranolol (5 mg/kg) have been tested in a model of chronic corticosterone administration (100 mu g/ml, 4 wk) in drinking water. Corticosterone administration led to cognitive impairment in the novel object recognition test that was reversed by propranolol. Increased levels of A beta in the hippocampus of corticosterone-treated mice were counteracted by propranolol treatment, purportedly through an increased IDE expression. Chronic corticosterone treatment induced responses characteristic of insulin resistance, as increased peripheral insulin levels, decreased activation of the insulin receptor (pIR) and decreased associated intracellular pathways (pAkt). These effects might be related to a decreased c-Jun N terminal kinase 1 expression. Again, propranolol was able to counteract all corticosterone-induced effects. One of the main kinases involved in tau phosphorylation, glycogen synthase kinase 3 beta (GSK3 beta), which is inactivated by phosphorylation by pAkt, was found to be decreased after corticosterone and increased after propranolol treatment. Concomitant changes in pTau expression were found. Overall, these data further strengthen the potential of propranolol as a therapeutic agent for pathologies associated with the interaction glucocorticoids-insulin resistance and the development of relevant cellular processes for Alzheimer's disease.