title: Induction of a Proinflammatory Response in Cortical Astrocytes by the Major Metabolites Accumulating in HMG-CoA Lyase Deficiency: the Role of ERK Signaling Pathway in Cytokine Release.
abstract: 3-Hydroxy-3-methylglutaric aciduria (HMGA) is an inherited metabolic disorder caused by 3-hydroxy-3-methylglutaryl-CoA lyase deficiency. It is biochemically characterized by predominant tissue accumulation and high urinary excretion of 3-hydroxy-3-methylglutarate (HMG) and 3-methylglutarate (MGA). Affected patients commonly present acute symptoms during metabolic decompensation, including vomiting, seizures, and lethargy/coma accompanied by metabolic acidosis and hypoketotic hypoglycemia. Although neurological manifestations are common, the pathogenesis of brain injury in this disease is poorly known. Astrocytes are important for neuronal protection and are susceptible to damage by neurotoxins. In the present study, we investigated the effects of HMG and MGA on important parameters of redox homeostasis and cytokine production in cortical cultured astrocytes. The role of the metabolites on astrocyte mitochondrial function (thiazolyl blue tetrazolium bromide (MTT) reduction) and viability (propidium iodide incorporation) was also studied. Both organic acids decreased astrocytic mitochondrial function and the concentrations of reduced glutathione without altering cell viability. In contrast, they increased reactive species formation (2'-7'-dichlorofluorescein diacetate (DCFHDA) oxidation), as well as IL-1β, IL-6, and TNF α release through the ERK signaling pathway. Taken together, the data indicate that the principal compounds accumulating in HMGA induce a proinflammatory response in cultured astrocytes that may possibly be involved in the neuropathology of this disease.
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos No 2600 - Anexo, 90035-003, Porto Alegre, RS, Brazil.
authors.forename: Carolina Gonçalves
authors.initials: CG
authors.lastname: Fernandes
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos No 2600 - Anexo, 90035-003, Porto Alegre, RS, Brazil.
authors.forename: Marília Danyelle Nunes
authors.initials: MDN
authors.lastname: Rodrigues
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos No 2600 - Anexo, 90035-003, Porto Alegre, RS, Brazil.
authors.forename: Bianca
authors.initials: B
authors.lastname: Seminotti
authors.affiliation: Laboratorio de Aminoácidos Excitadores, Instituto Nacional de Neurología y Neurocirugía, SSA, Mexico City, Mexico.
authors.forename: Ana Laura
authors.initials: AL
authors.lastname: Colín-González
authors.affiliation: Laboratorio de Aminoácidos Excitadores, Instituto Nacional de Neurología y Neurocirugía, SSA, Mexico City, Mexico.
authors.forename: Abel
authors.initials: A
authors.lastname: Santamaria
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos No 2600 - Anexo, 90035-003, Porto Alegre, RS, Brazil.
authors.forename: André
authors.initials: A
authors.lastname: Quincozes-Santos
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos No 2600 - Anexo, 90035-003, Porto Alegre, RS, Brazil. mwajner@ufrgs.br.|Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil. mwajner@ufrgs.br.
authors.forename: Moacir
authors.initials: M
authors.lastname: Wajner
mesh_terms: D000101:Acetyl-CoA C-Acetyltransferase / Q000172:deficiency* / Q000378:metabolism; D000592:Amino Acid Metabolism, Inborn Errors / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D048430:Cell Shape / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000473:pathology*; D016207:Cytokines / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology; D005911:Gliosis / Q000378:metabolism / Q000473:pathology; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors / Q000378:metabolism; D007249:Inflammation / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D015093:Meglutol / Q000031:analogs & derivatives / Q000378:metabolism; D055442:Metabolome / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D011524:Protoporphyrins / Q000494:pharmacology; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000975:Antioxidants; D016207:Cytokines; D005419:Flavonoids; D016328:NF-kappa B; D011524:Protoporphyrins; D017382:Reactive Oxygen Species; C017803:zinc protoporphyrin; C033686:3-methylglutaric acid; D015093:Meglutol; D006419:Heme Oxygenase (Decyclizing); D000101:Acetyl-CoA C-Acetyltransferase; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
keywords: 3-Hydroxy-3-methylglutaric aciduria; Astrocytes; Cytokine production; ERK pathway; Oxidative stress; Proinflammatory response