Multitarget-directed cotreatment with cilostazol and aripiprazole for augmented neuroprotection against oxidative stress-induced toxicity in HT22 mouse hippocampal cells.
Eur J Pharmacol
; 857: 172454, 2019 Aug 15.
Article
em En
| MEDLINE
| ID: mdl-31202803
ABSTRACT
Cerebrovascular dysfunction is crucially associated with cognitive impairment and a high prevalence of psychotic symptoms in the vascular dementia characterized by oxidative stress and multifactorial neurodegeneration. In this study, the significant decrease in BDNF expression in HT22â¯cells due to H2O2 (0.25â¯mM) was little affected by either aripiprazole (1⯵M) or cilostazol (1⯵M) alone, but significantly increased by cotreatment with both drugs. Even in the presence of H2O2, P-CK2α (Tyr 255), nuclear P-CREB (Ser 133), and nuclear P-ß-catenin (Ser 675) levels were significantly increased in a synergistic manner by aripiprazole plus cilostazol cotreatment. Aripiprazole and cilostazol cotreatment synergistically increased P-GSK-3ß (Ser 9) level. Nrf2/HO-1 expression was significantly elevated time- and concentration-dependently by either aripiprazole or cilostazol. In line with these, concurrent treatment with aripiprazole (1⯵M) plus cilostazol (1⯵M) significantly increased Nrf2 and HO-1 expression in a synergistic manner, accompanying with increased ARE luciferase activity, while each drug monotherapy showed little effects. Consequently, this cotreatment synergistically ameliorated the attenuated neurite outgrowth induced by H2O2 in the HT22â¯cells, and these were inhibited by K252A (inhibitor of BDNF receptor), TBCA (CK2 inhibitor), imatinib (ß-catenin inhibitor) and ZnPP (inhibitor of HO-1), indicating that BDNF, P-CK2α, ß-catenin and HO-1 activation are implicated in the enhanced neurite outgrowth. This study highlights that cotreatment with low concentrations of aripiprazole and cilostazol synergistically elicits neuroprotective effects by overcoming oxidative stress-evoked neurotoxicity associated with increased neurite outgrowth, providing a rationale for the use of this combinatorial treatment in vascular dementia.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fármacos Neuroprotetores
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Aripiprazol
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Cilostazol
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Hipocampo
Tipo de estudo:
Risk_factors_studies
Limite:
Animals
Idioma:
En
Revista:
Eur J Pharmacol
Ano de publicação:
2019
Tipo de documento:
Article