PMID- 30802709
OWN - NLM
STAT- MEDLINE
DCOM- 20200518
LR  - 20200518
IS  - 1873-3360 (Electronic)
IS  - 0306-4530 (Linking)
VI  - 104
DP  - 2019 Jun
TI  - Antipsychotics differentially regulate insulin, energy sensing, and inflammation 
      pathways in hypothalamic rat neurons.
PG  - 42-48
LID - S0306-4530(18)31143-0 [pii]
LID - 10.1016/j.psyneuen.2019.01.029 [doi]
AB  - INTRODUCTION: Second generation antipsychotic (AP)s remain the gold-standard 
      treatment for schizophrenia and are widely used on- and off-label for other 
      psychiatric illnesses. However, these agents cause serious metabolic 
      side-effects. The hypothalamus is the primary brain region responsible for whole 
      body energy regulation, and disruptions in energy sensing (e.g. insulin 
      signaling) and inflammation in this brain region have been implicated in the 
      development of insulin resistance and obesity. To elucidate mechanisms by which 
      APs may be causing metabolic dysregulation, we explored whether these agents can 
      directly impact energy sensing and inflammation in hypothalamic neurons. METHODS: 
      The rat hypothalamic neuronal cell line, rHypoE-19, was treated with olanzapine 
      (0.25-100 uM), clozapine (2.5-100 uM) or aripiprazole (5-20 uM). Western blots 
      measured the energy sensing protein AMPK, components of the insulin signaling 
      pathway (AKT, GSK3beta), and components of the MAPK pathway (ERK1/2, JNK, p38). 
      Quantitative real-time PCR was performed to determine changes in the mRNA 
      expression of interleukin (IL)-6, IL-10 and brain derived neurotrophic factor 
      (BDNF). RESULTS: Olanzapine (100 uM) and clozapine (100, 20 uM) significantly 
      increased pERK1/2 and pJNK protein expression, while aripiprazole (20 uM) only 
      increased pJNK. Clozapine (100 uM) and aripiprazole (5 and 20 uM) significantly 
      increased AMPK phosphorylation (an orexigenic energy sensor), and inhibited 
      insulin-induced phosphorylation of AKT. Olanzapine (100 uM) treatment caused a 
      significant increase in IL-6 while aripiprazole (20 uM) significantly decreased 
      IL-10. Olanzapine (100 uM) and aripiprazole (20 uM) increased BDNF expression. 
      CONCLUSIONS: We demonstrate that antipsychotics can directly regulate insulin, 
      energy sensing, and inflammatory pathways in hypothalamic neurons. Increased MAPK 
      activation by all antipsychotics, alongside olanzapine-associated increases in 
      IL-6, and aripiprazole-associated decreases in IL-10, suggests induction of 
      pro-inflammatory pathways. Clozapine and aripiprazole inhibition of 
      insulin-stimulated pAKT and increases in AMPK phosphorylation (an orexigenic 
      energy sensor) suggests impaired insulin action and energy sensing. Conversely, 
      olanzapine and aripiprazole increased BDNF, which would be expected to be 
      metabolically beneficial. Overall, our findings suggest differential effects of 
      antipsychotics on hypothalamic neuroinflammation and energy sensing.
CI  - Copyright (c) 2019. Published by Elsevier Ltd.
FAU - Kowalchuk, Chantel
AU  - Kowalchuk C
AD  - Centre for Addiction and Mental Health, 250 College Street, Toronto, Ontario, M5T 
      1R8, Canada; Institute of Medical Sciences, University of Toronto, 1 King's 
      College Circle, Toronto, Ontario, M5S 1A8, Canada.
FAU - Kanagasundaram, Pruntha
AU  - Kanagasundaram P
AD  - Centre for Addiction and Mental Health, 250 College Street, Toronto, Ontario, M5T 
      1R8, Canada.
FAU - Belsham, Denise D
AU  - Belsham DD
AD  - Department of Physiology, University of Toronto, 1 King's College Circle, 
      Toronto, Ontario, M5S 1A8, Canada. Electronic address: d.belsham@utoronto.ca.
FAU - Hahn, Margaret K
AU  - Hahn MK
AD  - Centre for Addiction and Mental Health, 250 College Street, Toronto, Ontario, M5T 
      1R8, Canada; Institute of Medical Sciences, University of Toronto, 1 King's 
      College Circle, Toronto, Ontario, M5S 1A8, Canada; Department of Psychiatry, 
      University of Toronto, 250 College Street, Toronto, Ontario, M5T 1R8, Canada. 
      Electronic address: margaret.hahn@camh.ca.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190201
PL  - England
TA  - Psychoneuroendocrinology
JT  - Psychoneuroendocrinology
JID - 7612148
RN  - 0 (Antipsychotic Agents)
RN  - 0 (Insulin)
RN  - 82VFR53I78 (Aripiprazole)
RN  - J60AR2IKIC (Clozapine)
RN  - N7U69T4SZR (Olanzapine)
SB  - IM
MH  - Animals
MH  - Antipsychotic Agents/metabolism/*pharmacology
MH  - Aripiprazole/metabolism/pharmacology
MH  - Cell Line
MH  - Clozapine/metabolism/pharmacology
MH  - Energy Metabolism/*drug effects
MH  - Hypothalamus/drug effects/metabolism
MH  - Inflammation/metabolism
MH  - Insulin/metabolism
MH  - Insulin Resistance/physiology
MH  - MAP Kinase Signaling System/drug effects/physiology
MH  - Neurons/*drug effects
MH  - Olanzapine/metabolism/pharmacology
MH  - Phosphorylation/drug effects
MH  - Rats
MH  - Schizophrenia/drug therapy/metabolism
MH  - Signal Transduction/drug effects
OTO - NOTNLM
OT  - Antipsychotic
OT  - Hypothalamus
OT  - Insulin signaling
EDAT- 2019/02/26 06:00
MHDA- 2020/05/19 06:00
CRDT- 2019/02/26 06:00
PHST- 2018/11/14 00:00 [received]
PHST- 2019/01/16 00:00 [revised]
PHST- 2019/01/31 00:00 [accepted]
PHST- 2019/02/26 06:00 [pubmed]
PHST- 2020/05/19 06:00 [medline]
PHST- 2019/02/26 06:00 [entrez]
AID - S0306-4530(18)31143-0 [pii]
AID - 10.1016/j.psyneuen.2019.01.029 [doi]
PST - ppublish
SO  - Psychoneuroendocrinology. 2019 Jun;104:42-48. doi: 
      10.1016/j.psyneuen.2019.01.029. Epub 2019 Feb 1.