PMID- 27278758
OWN - NLM
STAT- MEDLINE
DCOM- 20170404
LR  - 20181113
IS  - 1573-6903 (Electronic)
IS  - 0364-3190 (Linking)
VI  - 41
IP  - 10
DP  - 2016 Oct
TI  - Experimental Evidence that 3-Methylglutaric Acid Disturbs Mitochondrial Function 
      and Induced Oxidative Stress in Rat Brain Synaptosomes: New Converging 
      Mechanisms.
PG  - 2619-2626
AB  - 3-Methylglutaric acid (3MGA) is an organic acid that accumulates in various 
      organic acidemias whose patients present neurodegeneration events in children 
      coursing with metabolic acidurias. Limited evidence describes the toxic 
      mechanisms elicited by 3MGA in the brain. Herein, we explored the effects of 3MGA 
      on different toxic endpoints in synaptosomal and mitochondrial-enriched fractions 
      of adult rat brains to provide novel information on early mechanisms evoked by 
      this metabolite. At 1 and 5 mM concentration, 3MGA increased lipid peroxidation, 
      but decreased mitochondrial function only at 5 mM concentration. Despite less 
      intense effects were obtained at 1 mM concentration, its co-administration with 
      the kynurenine pathway (KP) metabolite and N-methyl-D-aspartate receptor (NMDAr) 
      agonist, quinolinic acid (QUIN, 50 and 100 microM), produced toxic synergism on 
      markers of oxidative stress and mitochondrial function. The toxicity of 3MGA per 
      se (5 mM) was prevented by the cannabinoid receptor agonist WIN55,212-2 and the 
      NMDAr antagonist kynurenic acid (KYNA), suggesting cannabinoid and glutamatergic 
      components in the 3MGA pattern of toxicity. The synergic model (3MGA + QUIN) was 
      also sensitive to KYNA and the antioxidant S-allylcysteine, but not to the nitric 
      oxide synthase inhibitor L-nitroarginine methyl ester. These findings suggest 
      various underlying mechanisms involved in the neurotoxicity of 3MGA that may 
      possibly contribute to the neurodegeneration observed in acidemias.
FAU - Colin-Gonzalez, Ana Laura
AU  - Colin-Gonzalez AL
AD  - Laboratorio de Aminoacidos Excitadores, Instituto Nacional de Neurologia y 
      Neurocirugia, S.S.A., 14269, Mexico City, Mexico.
FAU - Paz-Loyola, Ariana Lizbeth
AU  - Paz-Loyola AL
AD  - Laboratorio de Aminoacidos Excitadores, Instituto Nacional de Neurologia y 
      Neurocirugia, S.S.A., 14269, Mexico City, Mexico.
FAU - de Lima, Maria Eduarda
AU  - de Lima ME
AD  - Universidade Federal do Pampa, Uruguaiana, Brazil.
FAU - Galvan-Arzate, Sonia
AU  - Galvan-Arzate S
AD  - Departamento de Neuroquimica, Instituto Nacional de Neurologia y Neurocirugia, 
      S.S.A., Mexico City, Mexico.
FAU - Seminotti, Bianca
AU  - Seminotti B
AD  - Departamento de Bioquimica, Instituto de Ciencias Basicas da Saude, Universidade 
      Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
FAU - Ribeiro, Cesar Augusto Joao
AU  - Ribeiro CA
AD  - Departamento de Bioquimica, Instituto de Ciencias Basicas da Saude, Universidade 
      Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
FAU - Leipnitz, Guilhian
AU  - Leipnitz G
AD  - Departamento de Bioquimica, Instituto de Ciencias Basicas da Saude, Universidade 
      Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
FAU - Souza, Diogo Onofre
AU  - Souza DO
AD  - Departamento de Bioquimica, Instituto de Ciencias Basicas da Saude, Universidade 
      Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
FAU - Wajner, Moacir
AU  - Wajner M
AD  - Departamento de Bioquimica, Instituto de Ciencias Basicas da Saude, Universidade 
      Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
AD  - Servico de Genetica Medica, Hospital de Clinicas de Porto Alegre, Porto Alegre, 
      RS, Brazil.
FAU - Santamaria, Abel
AU  - Santamaria A
AD  - Laboratorio de Aminoacidos Excitadores, Instituto Nacional de Neurologia y 
      Neurocirugia, S.S.A., 14269, Mexico City, Mexico. absada@yahoo.com.
LA  - eng
PT  - Journal Article
DEP - 20160609
PL  - United States
TA  - Neurochem Res
JT  - Neurochemical research
JID - 7613461
RN  - 0 (Antioxidants)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (Receptors, Cannabinoid)
RN  - 3Q0P190C7B (3-methylglutaric acid)
RN  - CLA99KCD53 (Meglutol)
SB  - IM
MH  - Animals
MH  - Antioxidants/pharmacology
MH  - Brain/*drug effects/metabolism
MH  - Lipid Peroxidation/drug effects
MH  - Male
MH  - Meglutol/*analogs & derivatives/pharmacology
MH  - Mitochondria/*drug effects/metabolism
MH  - Oxidative Stress/*drug effects
MH  - Rats, Wistar
MH  - Reactive Oxygen Species/metabolism
MH  - Receptors, Cannabinoid/metabolism
MH  - Synaptosomes/*drug effects/metabolism
OTO - NOTNLM
OT  - 3-Methylglutaric acid
OT  - Cannabinoid system
OT  - Excitotoxicity
OT  - Mitochondrial dysfunction
OT  - Organic acidurias
OT  - Oxidative stress
OT  - Toxic organic acids
EDAT- 2016/06/10 06:00
MHDA- 2017/04/05 06:00
CRDT- 2016/06/10 06:00
PHST- 2016/03/29 00:00 [received]
PHST- 2016/06/01 00:00 [accepted]
PHST- 2016/05/23 00:00 [revised]
PHST- 2016/06/10 06:00 [pubmed]
PHST- 2017/04/05 06:00 [medline]
PHST- 2016/06/10 06:00 [entrez]
AID - 10.1007/s11064-016-1973-2 [pii]
AID - 10.1007/s11064-016-1973-2 [doi]
PST - ppublish
SO  - Neurochem Res. 2016 Oct;41(10):2619-2626. doi: 10.1007/s11064-016-1973-2. Epub 
      2016 Jun 9.