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Prog Neuropsychopharmacol Biol Psychiatry. 2018 Feb 2;81:250-261. doi: 10.1016/j.pnpbp.2017.09.017. Epub 2017 Sep 20.

The ameliorative effects and underlying mechanisms of dopamine D1-like receptor agonist SKF38393 on Aβ1-42-induced cognitive impairment.

Author information

1
Department of Pharmacology, China Pharmaceutical University, Nanjing 210009, China.
2
Department of Pharmacology, China Pharmaceutical University, Nanjing 210009, China. Electronic address: heling@cpu.edu.cn.

Abstract

Alzheimer's disease (AD) is an age-related neurodegenerative disease characterized by extracellular amyloid plaques and intracellular neurofibrillary tangles. It is the most common form of human cognitive decline and dementia. In this study, we aim to systematically investigate the ameliorative effects of dopamine D1-like receptor agonist SKF38393 on cognitive dysfunction and explore its underlying mechanisms. The Aβ1-42 was injected intracerebroventricularly to establish cognitive disorder model. Then, a series of behavior tests were used. In order to further study the mechanisms, some relevant protein was assessed by ELISA method and Western blot. The results in behavior tests revealed that SKF38393 significantly ameliorated all the test indexes compared with the model mice. Then SKF38393 increased phosphorylation of cAMP response element binding protein (CREB) and expression of Bcl-2 in Western blot analyses. Furthermore, in ELISA assay, SKF38393 significantly increased the brain-derived neurotrophic factor (BDNF) levels and reduced the β-site APP cleaving enzyme1 (BACE1) and Aβ1-42 levels in hippocampus and cortex of mice. However, compared with SKF38393-H, all these results were significantly reversed by the dopamine D1 receptor antagonist SCH23390. These results indicated that SKF38393 could ameliorate Aβ1-42-induced cognitive dysfunction in mice, which may be related to D1 receptor activation. It leads to the phosphorylation of CREB, which promote the expression of BDNF, Bcl-2 and decrease the expression of Aβ1-42 of mice. Our findings suggest that dopamine D1-like receptor may be a potential target for the treatment of AD and its agonists may become a novel drug in the future.

KEYWORDS:

Alzheimer's disease; Behavioral test; Cognitive impairment; Dopamine D1-like receptor; cAMP response element binding protein

PMID:
28939187
DOI:
10.1016/j.pnpbp.2017.09.017
[Indexed for MEDLINE]

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