OLANZAPINE ACTIVATES HEPATIC MAMMALIAN TARGET of RAPAMYCIN (MTOR): NEW MECHANISTIC INSIGHT INTO METABOLIC DYSREGULATION WITH ATYPICAL ANTIPSYCHOTIC DRUGS.

OLANZAPINE ACTIVATES HEPATIC MAMMALIAN TARGET OF RAPAMYCIN (mTOR): NEW MECHANISTIC INSIGHT INTO METABOLIC DYSREGULATION WITH ATYPICAL ANTIPSYCHOTIC DRUGS.

J Pharmacol Exp Ther. 2013 Aug 7;
Schmidt RH, Jokinen JD, Massey VL, Falkner KC, Shi X, Yin X, Zhang X, Beier JI, Arteel GE

Olanzapine (OLZ) is an effective treatment for schizophrenia and other disorders, but causes weight gain and metabolic syndrome. Most studies to date have focused on potential effects of OLZ on CNS mediation of weight; however, peripheral changes in liver or other key metabolic organs may also play a role in systemic effects of OLZ. The purpose of this study was to therefore investigate the effects of OLZ on hepatic metabolism in a mouse model of OLZ exposure. Female C57Bl/6J mice were administered OLZ (8 mg/kg/d) or vehicle subcutaneously by osmotic minipumps for 28 days. Liver and plasma were taken at sacrifice for biochemical analyses and for GCxGC-TOF MS metabolomics analysis. OLZ increased body weight, fat pad mass, and liver-to-body weight ratio without commensurate increase in food consumption, indicating that OLZ altered energy expenditure. Expression and biochemical analyses indicated that OLZ induced anaerobic glycolysis and caused a ‘pseudo-fasted’ state, which depleted hepatic glycogen reserves; OLZ caused similar effects in cultured HepG2 cells, as determined by Seahorse analysis. Metabolomic analysis indicated that OLZ increased hepatic concentrations of amino acids that can alter metabolism via the mTOR pathway; indeed, hepatic mTOR signaling was robustly increased by OLZ. Interestingly, OLZ concomitantly activated AMPK signaling. Taken together, these data suggest that disturbances in glucose and lipid metabolism caused by OLZ in liver may be mediated, at least in part, via simultaneous activation of both catabolic (AMPK) and anabolic (mTOR) pathways, and yield new insight into the metabolic side effects of this drug. HubMed – drug

Evaluation of Oatp and Mrp2 Activities in Hepatobiliary Excretion using Newly Developed Positron Emission Tomography (PET) Tracer, [11C]Dehydropravastatin, in Rats.

J Pharmacol Exp Ther. 2013 Aug 7;
Shingaki T, Takashima T, Ijuin R, Zhang X, Onoue T, Katayama Y, Okauchi T, Hayashinaka E, Cui Y, Wada Y, Suzuki M, Maeda K, Kusuhara H, Sugiyama Y, Watanabe Y

We developed a pravastatin derivative, (11)C-labeled dehydropravastatin ([(11)C]DPV), as a PET probe for non-invasive measurement of hepatobiliary transport, and conducted pharmacokinetic analysis in rats as a feasibility study for future clinical study. Transport activities of DPV in freshly isolated rat hepatocytes and rMrp2-expressing membrane vesicles were similar to those of pravastatin. Rifampicin diminished the uptake of DPV and pravastatin by the hepatocytes, with similar inhibition potency. [(11)C]DPV underwent biotransformation to produce at least two metabolites in rat, but metabolism of [(11)C]DPV occurred negligibly in human hepatocytes for 90-min incubation. After intravenous injection, [(11)C]DPV was mainly distributed to the liver and kidneys, where the tissue uptake clearances (CLuptake,liver and CLuptake,kidney) were blood-flow-limited (73.6 ± 4.8 and 24.6 ± 0.6 ml/min/kg, respectively). Systemic elimination of [(11)C]DPV was delayed in rifampicin-treated rat and an Mrp2-deficient mutant rat, EHBR. Rifampicin treatment decreased both CLuptake,liver and CLuptake,kidney of [(11)C]DPV by 30% (P < 0.05), whereas these parameters were unchanged in EHBR. Meanwhile, the canalicular efflux clearance (CLint,bile) of [(11)C]DPV, which was 12.2 ± 1.5 ml/min/kg in the control rat, decreased by 60% and 89% in rifampicin-treated rat and EHBR (P < 0.05), respectively. These results indicate that [(11)C]DPV is taken up into the liver by Oatps and excreted into bile by Mrp2 in rat, and that rifampicin may inhibit Mrp2 as well as Oatps, and consequently increase systemic exposure of [(11)C]DPV. PET using [(11)C]DPV is feasible for studies prior to the future clinical investigation of OATP and MRP2 functionality, especially for personalized medicine. HubMed – drug

Arctigenin Effectively Ameliorates Memory Impairment in Alzheimer’s Disease Model Mice Targeting Both ?-Amyloid Production and Clearance.

J Neurosci. 2013 Aug 7; 33(32): 13138-49
Zhu Z, Yan J, Jiang W, Yao XG, Chen J, Chen L, Li C, Hu L, Jiang H, Shen X

Alzheimer’s disease (AD) chiefly characterizes a progressively neurodegenerative disorder of the brain, and eventually leads to irreversible loss of intellectual abilities. The ?-amyloid (A?)-induced neurodegeneration is believed to be the main pathological mechanism of AD, and A? production inhibition or its clearance promotion is one of the promising therapeutic strategies for anti-AD research. Here, we report that the natural product arctigenin from Arctium lappa (L.) can both inhibit A? production by suppressing ?-site amyloid precursor protein cleavage enzyme 1 expression and promote A? clearance by enhancing autophagy through AKT/mTOR signaling inhibition and AMPK/Raptor pathway activation as investigated in cells and APP/PS1 transgenic AD model mice. Moreover, the results showing that treatment of arctigenin in mice highly decreased A? formation and senile plaques and efficiently ameliorated AD mouse memory impairment strongly highlight the potential of arctigenin in anti-AD drug discovery. HubMed – drug