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(Referência obtida automaticamente do Web of Science, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

Aldehyde dehydrogenase-2 regulates nociception in rodent models of acute inflammatory pain

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Autor(es):
Zambelli, Vanessa O. [1, 2] ; Gross, Eric R. [1, 3] ; Chen, Che-Hong [1] ; Gutierrez, Vanessa P. [2] ; Cury, Yara [2] ; Mochly-Rosen, Daria [1]
Número total de Autores: 6
Afiliação do(s) autor(es):
[1] Stanford Univ, Sch Med, Dept Chem & Syst Biol, Stanford, CA 94305 - USA
[2] Butantan Inst, Lab Pain & Signaling, BR-05503900 Sao Paulo - Brazil
[3] Stanford Univ, Sch Med, Dept Anesthesiol Perioperat & Pain Med, Stanford, CA 94305 - USA
Número total de Afiliações: 3
Tipo de documento: Artigo Científico
Fonte: Science Translational Medicine; v. 6, n. 251 AUG 27 2014.
Citações Web of Science: 33
Resumo

Exogenous aldehydes can cause pain in animal models, suggesting that aldehyde dehydrogenase-2 (ALDH2), which metabolizes many aldehydes, may regulate nociception. To test this hypothesis, we generated a knock-in mouse with an inactivating point mutation in ALDH2 (ALDH2{*}2), which is also present in human ALDH2 of similar to 540 million East Asians. The ALDH2{*}1/{*}2 heterozygotic mice exhibited a larger response to painful stimuli than their wild-type littermates, and this heightened nociception was inhibited by an ALDH2-selective activator (Alda-1). No effect on inflammation per se was observed. Using a rat model, we then showed that nociception tightly correlated with ALDH activity (R-2 = 0.90) and that reduced nociception was associated with less early growth response protein 1 (EGR1) in the spinal cord and less reactive aldehyde accumulation at the insult site (including acetaldehyde and 4-hydroxynonenal). Further, acetaldehyde-and formalin-induced nociceptive behavior was greater in the ALDH2{*}1/{*}2 mice than in the wild-type mice. Finally, Alda-1 treatment was even beneficial when given after the inflammatory agent was administered. Our data in rodent models suggest that the mitochondrial enzyme ALDH2 regulates nociception and could serve as a molecular target for pain control, with ALDH2 activators, such as Alda-1, as potential non-narcotic, cardiac-safe analgesics. Furthermore, our results suggest a possible genetic basis for East Asians' apparent lower pain tolerance. (AU)

Processo FAPESP: 11/08873-8 - Papel da aldeído desidrogenase 2 e do 4-hidroxinonenal na dor
Beneficiário:Vanessa Olzon Zambelli
Linha de fomento: Bolsas no Brasil - Pós-Doutorado
Processo FAPESP: 13/07467-1 - CeTICS - Centro de Toxinas, Imuno-Resposta e Sinalização Celular
Beneficiário:Hugo Aguirre Armelin
Linha de fomento: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
Processo FAPESP: 12/05035-4 - Papel da aldeído desidrogenase 2 e do 4-hidroxinonenal na dor
Beneficiário:Yara Cury
Linha de fomento: Auxílio à Pesquisa - Regular