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Betahistine co-treatment ameliorates dyslipidemia induced by chronic olanzapine treatment in rats through modulation of hepatic AMPKα-SREBP-1 and PPARα-dependent pathways
- Source :
- Pharmacological Research. 100:36-46
- Publication Year :
- 2015
- Publisher :
- Elsevier BV, 2015.
-
Abstract
- Second-generation antipsychotics including olanzapine are associated with weight gain, dyslipidemia and other metabolic disorders. Both animal and clinical studies have shown that co-treatment with betahistine (a histamine H1 receptor agonist/H3 receptor antagonist) is effective in controlling olanzapine-induced weight gain. In the present study, we investigate whether co-treatment with betahistine is able to prevent dyslipidemia induced by chronic olanzapine treatment and the underlying mechanisms. Female rats were orally administered with olanzapine (1 mg/kg, t.i.d.) for 3.5 consecutive weeks and then a 2.5-week drug withdrawal. Then, rats were divided into 4 groups for 5 weeks treatment: (1) vehicle, (2) olanzapine-only (1 mg/kg, t.i.d.), (3) betahistine-only (9.6 mg/kg, t.i.d.), and (4) olanzapine and betahistine (O+B) co-treatment. After completing treatment, hepatic mRNA expression was measured by qRT-PCR, while the protein levels were detected by western blot. In our study, olanzapine-only treatment significantly increased triglyceride accumulation and non-esterified fatty acids (NEFA), and upregulated mRNA expression of sterol regulatory element binding protein 1 (SREBP-1) and its target genes, while these alterations were ameliorated by O+B co-treatment. Hepatic AMP-activated protein kinase α (AMPKα) was activated in the O+B co-treatment group, with a significant reduction in nuclear SREBP-1 protein expression but an increased expression of peroxisome proliferator-activated receptor-α (PPARα) and its-responsive molecule(CPT1A), compared with olanzapine-only treatment. In addition, olanzapine significantly increased hepatic histamine H1 receptors, while O+B co-treatment significantly reversed them to normal levels. This study provided the first evidence that betahistine could act on hepatic H1 receptors via modulation of AMPKα-SREBP-1 and PPARα-dependent pathways to ameliorate olanzapine-induced dyslipidemia in rats.
- Subjects :
- medicine.medical_specialty
Histamine H1 receptor
AMP-Activated Protein Kinases
Weight Gain
Rats, Sprague-Dawley
Benzodiazepines
chemistry.chemical_compound
NEFA
Internal medicine
medicine
Animals
PPAR alpha
Betahistine
Receptors, Histamine H1
Receptor
Dyslipidemias
Pharmacology
biology
business.industry
medicine.disease
Rats
Endocrinology
Liver
chemistry
Olanzapine
HMG-CoA reductase
biology.protein
Female
Sterol Regulatory Element Binding Protein 1
H3 receptor antagonist
business
Dyslipidemia
Histamine
Antipsychotic Agents
medicine.drug
Subjects
Details
- ISSN :
- 10436618
- Volume :
- 100
- Database :
- OpenAIRE
- Journal :
- Pharmacological Research
- Accession number :
- edsair.doi.dedup.....1c565195807d6309ebd9a20e93285cde