期刊
PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR
卷 180, 期 -, 页码 92-100出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.pbb.2019.03.002
关键词
Simvastatin; Anti-depressant-like; NO-cGMP-K-ATP channels pathway; PPAR gamma receptors; Potentiation; Mouse forced swimming test
资金
- Dezful University of Medical Sciences, Dezful, Iran [IR.DUMS.REC.1396.26]
- Dezful University of Medical Sciences
Simvastatin, one of the lipophilic statins, has been shown to be effective in reducing depression in rodents. The present study aimed to investigate the potential antidepressant-like activity of simvastatin and the possible involvement of NO-cGMP-K-ATP channels pathway and PPAR gamma using forced swimming test (FST) in mice. In addition, the interaction between simvastatin and fluoxetine as a reference drug was examined. After assessment of locomotor behavior in the open-field test (OFT), FST was applied for evaluation of depressive behavior in mice. Simvastatin at doses (20, 30, and 40 mg/kg, i.p.) was administrated 30 min before the OFT or FST. To evaluate the involvement of NO-cGMP-K-ATP channels pathway, mice were pre-treated intraperitoneally with Larginine (a nitric oxide precursor, 750 mg/kg), L-NAME (a NOS inhibitor, 10 mg/kg), methylene blue (guanylyl cyclase inhibitor, 20 mg/kg), sildenafil (a PDE-5 inhibitor, 5 mg/kg), glibenclamide (ATP-sensitive K+ channel blocker, 1 mg/kg), and diazoxide (K+ channels opener, 10 mg/kg). Moreover, to clarify the probable involvement of PPAR gamma receptors, pioglitazone, a PPAR gamma agonist (5 mg/kg, i.p.), and GW9662, a PPAR gamma antagonist (2 mg/kg, i.p.), were pre-treated with simvastatin. Immobility time was significantly decreased after simvastatin injection. Administration of L-NAME, methylene blue, glibenclamide and pioglitazone in combination with the sub-effective dose of simvastatin (20 mg/kg, i.p.) reduced the immobility time in the FST compared to drugs alone, while co-administration of effective doses of simvastatin (30 mg/kg, i.p.) with c-arginine, sildenafil, diazoxide, and GW9662 prevented the antidepressant-like effect of simvastatin. In addition, simvastatin (20 mg/kg) potentiated the antidepressant-like effect of fluoxetine through the NO pathway. None of the drugs produced any significant alterations in locomotor activity using OFT. These results demonstrated that NO-cGMP-K-ATP channels pathway and PPAR gamma receptors may be involved in the antidepressant-like effect of simvastatin.
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