Abstract
The cognitive function impairment may be related to the inflammation of the hippocampus in Parkinson's disease. Simvastatin can play a positive role in Parkinson's disease. The purpose of this study was to investigate whether simvastatin could improve behavioral disorders, especially depression, anxiety and cognitive function in mouse PD models, and further explore the molecular mechanism. In the present study, C57BL-6 mice underwent intraperitoneal injection of MPTP (30 mg/kg) once a day for 5 consecutive days. At the same time, simvastatin (10 mg/kg) was pretreated for 2 days before the Parkinson's disease model was established, and then continued for 5 days, and the control group underwent intraperitoneal injection of MK801 (dizocilpine, 0.2 mg/kg) and saline solution. Depression status was tested by a tail suspension test and a sucrose splash test, followed by an open-field test and an elevated plus maze test to determine anxiety levels. Spatial behavior and muscle status were measured with a water maze and a rotarod test. The expression of RNA and protein of N-methyl-d-aspartate receptor subtype 2B (NMDAR2B), nerve growth factor IB (Nur77), cyclooxygenase-2 (COX-2), and tumor necrosis factor (TNF) α were assayed by real-time polymerase chain reaction and Western blot. Our results showed that simvastatin can improve the cognitive function, anxiety, and depression of PD mice with MPTP injury. Simvastatin reversed the NMDAR2B increase, restored Nur77 downward, and reduced the expression of COX-2 and TNF-α in MPTP-treated mice. This role of simvastatin was consistent with MK801 in increasing the expression of Nur77 and inhibiting NMDAR2B and cytokines in MPTP-lesioned PD mice. These findings suggest that reversed the NMDAR2B increase, restored Nur77 downward, and reduced the expression of COX-2 and TNF-α in MPTP-treated mice may be one of the mechanisms that simvastatin improves cognitive functions, depression, and anxiety in MPTP-lesioned mice.
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Abbreviations
- PD:
-
Parkinson's disease
- MPTP:
-
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
- 6-OHDA:
-
6-Hydroxydopamine
- MPP+ :
-
1-Methyl-4-phenylpyridine
- TH:
-
Tyrosine hydroxylase
- COX-2:
-
Cyclooxygenase-2
- TNF-α:
-
Tumor necrosis factor alpha
- Nur77:
-
Nerve growth factor IB (NGFIB) also known as NR4A1
- NMDA:
-
N-methyl-d-aspartic acid
- NMDAR2B::
-
N-methyl d-aspartate receptor subtype 2B, also known as NR2B
- UPS:
-
Ubiquitin–proteasome system
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Acknowledgements
We acknowledge that this work was supported by the Natural Science Foundation of Henan Province (18230041033) and National Natural Science Fund (Grant No. U1304809).
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This study was approved by the Ethics Committee/Institutional Review Board of the First Affiliated Hospital of Henan University of Science and Technology. All animals were treated in accordance with the guidelines of the NIH’s Guide for the Care and Use of Laboratory Animals and followed the guidelines of the International Association for the Study of Pain (IASP).
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Yan, J., Liu, A., Fan, H. et al. Simvastatin Improves Behavioral Disorders and Hippocampal Inflammatory Reaction by NMDA-Mediated Anti-inflammatory Function in MPTP-Treated Mice. Cell Mol Neurobiol 40, 1155–1164 (2020). https://doi.org/10.1007/s10571-020-00804-7
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DOI: https://doi.org/10.1007/s10571-020-00804-7