PMID- 34842277
OWN - NLM
STAT- MEDLINE
DCOM- 20220331
LR  - 20220401
IS  - 1754-8411 (Electronic)
IS  - 1754-8403 (Print)
IS  - 1754-8403 (Linking)
VI  - 15
IP  - 1
DP  - 2022 Jan 1
TI  - The rat rotenone model reproduces the abnormal pattern of central catecholamine 
      metabolism found in Parkinson's disease.
LID - 10.1242/dmm.049082 [doi]
LID - dmm049082
AB  - Recent reports indicate that Parkinson's disease (PD) involves specific 
      functional abnormalities in residual neurons - decreased vesicular sequestration 
      of cytoplasmic catecholamines via the vesicular monoamine transporter (VMAT) and 
      decreased aldehyde dehydrogenase (ALDH) activity. This double hit builds up the 
      autotoxic metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL), the focus of the 
      catecholaldehyde hypothesis for the pathogenesis of PD. An animal model is needed 
      that reproduces this abnormal catecholamine neurochemical pattern. Adult rats 
      received subcutaneous vehicle or the mitochondrial complex 1 inhibitor rotenone 
      (2 mg/kg/day via a minipump) for 10 days. Locomotor activity was recorded, and 
      striatal tissue sampled for catechol contents and catechol ratios that indicate 
      the above abnormalities. Compared to vehicle, rotenone reduced locomotor activity 
      (P=0.002), decreased tissue dopamine concentrations (P=0.00001), reduced indices 
      of vesicular sequestration (3,4-dihydroxyphenylacetic acid (DOPAC)/dopamine) and 
      ALDH activity (DOPAC/DOPAL) (P=0.0025, P=0.036), and increased DOPAL levels 
      (P=0.04). The rat rotenone model involves functional abnormalities in 
      catecholaminergic neurons that replicate the pattern found in PD putamen. These 
      include a vesicular storage defect, decreased ALDH activity and DOPAL build-up. 
      The rat rotenone model provides a suitable in vivo platform for studying the 
      catecholaldehyde hypothesis.
CI  - (c) 2022. Published by The Company of Biologists Ltd.
FAU - Landau, Regev
AU  - Landau R
AUID- ORCID: 0000-0002-8515-9349
AD  - Neuroautonomic Service, Chaim Sheba Medical Center, Affiliated with the Tel Aviv 
      University Sackler Faculty of Medicine, Tel-HaShomer 5265601 Ramat Gan, Israel.
FAU - Halperin, Reut
AU  - Halperin R
AD  - Neuroautonomic Service, Chaim Sheba Medical Center, Affiliated with the Tel Aviv 
      University Sackler Faculty of Medicine, Tel-HaShomer 5265601 Ramat Gan, Israel.
FAU - Sullivan, Patti
AU  - Sullivan P
AD  - Autonomic Medicine Section, Clinical Neurosciences Program, Division of 
      Intramural Research, National Institute of Neurological Disorders and Stroke, 
      National Institutes of Health, Bethesda, MD 20892-0151, USA.
FAU - Zibly, Zion
AU  - Zibly Z
AUID- ORCID: 0000-0003-1718-0821
AD  - Department of Neurosurgery, Chaim Sheba Medical Center, Affiliated with the Tel 
      Aviv University Sackler Faculty of Medicine, Tel-HaShomer 5265601 Ramat Gan, 
      Israel.
FAU - Leibowitz, Avshalom
AU  - Leibowitz A
AUID- ORCID: 0000-0003-2622-4750
AD  - Neuroautonomic Service, Chaim Sheba Medical Center, Affiliated with the Tel Aviv 
      University Sackler Faculty of Medicine, Tel-HaShomer 5265601 Ramat Gan, Israel.
FAU - Goldstein, David S
AU  - Goldstein DS
AUID- ORCID: 0000-0002-5709-9940
AD  - Autonomic Medicine Section, Clinical Neurosciences Program, Division of 
      Intramural Research, National Institute of Neurological Disorders and Stroke, 
      National Institutes of Health, Bethesda, MD 20892-0151, USA.
FAU - Sharabi, Yehonatan
AU  - Sharabi Y
AUID- ORCID: 0000-0002-7566-988X
AD  - Neuroautonomic Service, Chaim Sheba Medical Center, Affiliated with the Tel Aviv 
      University Sackler Faculty of Medicine, Tel-HaShomer 5265601 Ramat Gan, Israel.
LA  - eng
PT  - Journal Article
PT  - Research Support, N.I.H., Intramural
DEP - 20220124
PL  - England
TA  - Dis Model Mech
JT  - Disease models & mechanisms
JID - 101483332
RN  - 0 (Catecholamines)
RN  - 03L9OT429T (Rotenone)
RN  - 102-32-9 (3,4-Dihydroxyphenylacetic Acid)
RN  - VTD58H1Z2X (Dopamine)
SB  - IM
MH  - 3,4-Dihydroxyphenylacetic Acid/metabolism
MH  - Animals
MH  - Catecholamines
MH  - Dopamine/metabolism
MH  - *Parkinson Disease/pathology
MH  - Rats
MH  - *Rotenone/pharmacology
PMC - PMC8807569
OTO - NOTNLM
OT  - Aldehyde dehydrogenase
OT  - Catechol
OT  - Catecholamine
OT  - DOPAL
OT  - Dopamine
OT  - Lewy body diseases
OT  - Norepinephrine
OT  - Parkinson's disease
OT  - Rotenone
OT  - Vesicular uptake
COIS- Competing interests The authors declare no competing or financial interests.
EDAT- 2021/11/30 06:00
MHDA- 2022/04/01 06:00
PMCR- 2022/01/24
CRDT- 2021/11/29 09:04
PHST- 2021/04/27 00:00 [received]
PHST- 2021/11/18 00:00 [accepted]
PHST- 2021/11/30 06:00 [pubmed]
PHST- 2022/04/01 06:00 [medline]
PHST- 2021/11/29 09:04 [entrez]
PHST- 2022/01/24 00:00 [pmc-release]
AID - 274082 [pii]
AID - DMM049082 [pii]
AID - 10.1242/dmm.049082 [doi]
PST - ppublish
SO  - Dis Model Mech. 2022 Jan 1;15(1):dmm049082. doi: 10.1242/dmm.049082. Epub 2022 
      Jan 24.