Protection from olanzapine-induced metabolic toxicity in mice by acetaminophen and tetrahydroindenoindole.
OBJECTIVE
In mice and in humans, treatment with the second-generation antipsychotic drug olanzapine (OLZ) produces excessive weight gain, adiposity and secondary metabolic complications, including loss of glucose and insulin homeostasis. In mice consuming a high-fat (HF) diet, a similar phenotype develops, which is inhibited by the analgesic acetaminophen (APAP) and by the antioxidant tetrahydroindenoindole (THII). Therefore, we examined the ability of APAP and THII to prevent metabolic changes in mice receiving OLZ.


METHODS
C57BL/6J mice received either a normal diet or a HF diet, and were administered daily dosages of OLZ (3 mg kg(-1) body weight), alone or with APAP (30 mg kg(-1) body weight) or THII (4.5 mg kg(-1) body weight), for 10 weeks. Parameters of body composition and metabolism, including glucose and insulin homeostasis and oxidative stress, were examined.


RESULTS
OLZ treatment doubled the HF diet-induced increases in body weight and percent body fat. These increases were partially prevented by both APAP and THII, although food consumption was constant in all groups. The THII protection was associated with an increase in whole body and mitochondrial respiration. OLZ also exacerbated, and both APAP and THII prevented, HF diet-induced loss of glucose tolerance and insulin resistance. As increased body fat promotes insulin resistance by a pathway involving oxidative stress, we evaluated production of reactive oxygen and lipid peroxidation in white adipose tissue (WAT). HF diet caused an increase in lipid peroxidation, NADPH-dependent O(2) uptake and H(2)O(2) production, which were further exacerbated by OLZ. APAP, THII and the NADPH oxidase inhibitor, diphenyleneiodonium chloride, each abolished oxidative stress in WAT.


CONCLUSIONS
We conclude that both APAP and THII intervene in the development of obesity and metabolic complications associated with OLZ treatment.
Shertzer
H G
HG
Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, OH 45267-0056, USA. shertzhg@ucmail.uc.edu
Kendig
E L
EL
Nasrallah
H A
HA
Johansson
E
E
Genter
M B
MB
D000082:Acetaminophen / Q000378:metabolism / Q000627:therapeutic use*; D000273:Adipose Tissue / Q000378:metabolism; D052436:Adipose Tissue, White / Q000187:drug effects / Q000503:physiopathology; D000818:Animals; D000975:Antioxidants / Q000378:metabolism / Q000627:therapeutic use*; D014150:Antipsychotic Agents / Q000009:adverse effects*; D001569:Benzodiazepines / Q000009:adverse effects*; D001835:Body Weight; D004041:Dietary Fats / Q000008:administration & dosage / Q000378:metabolism; D005260:Female; D007211:Indoles / Q000008:administration & dosage*; D007333:Insulin Resistance; D015227:Lipid Peroxidation; D051379:Mice; D008810:Mice, Inbred C57BL; D019255:NADPH Oxidases / Q000378:metabolism; D009765:Obesity / Q000139:chemically induced / Q000517:prevention & control*; D000077152:Olanzapine; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology
D000975:Antioxidants; D014150:Antipsychotic Agents; D004041:Dietary Fats; D007211:Indoles; D001569:Benzodiazepines; C090686:4b,5,9b,10-tetrahydroindeno(1,2-b)indole; D000082:Acetaminophen; D019255:NADPH Oxidases; D000077152:Olanzapine