Evaluation of ADMA-DDAH-NOS axis in specific brain areas following nitroglycerin administration: study in an animal model of migraineReportar como inadecuado

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The Journal of Headache and Pain

, 16:74

First Online: 13 August 2015Received: 30 April 2015Accepted: 30 July 2015


BackgroundNitric oxide NO is known to play a key role in migraine pathogenesis, but modulation of NO synthesis has failed so far to show efficacy in migraine treatment. Asymmetric dimethylarginine ADMA is a NO synthase NOS inhibitor, whose levels are regulated by dimethylarginine dimethylaminohydrolase DDAH. Systemic administration of nitroglycerin or glyceryl trinitrate, GTN is a NO donor that consistently induces spontaneous-like headache attacks in migraneurs. GTN administration induces an increase in neuronal NOS nNOS that is simultaneous with a hyperalgesic condition. GTN administration has been used for years as an experimental animal model of migraine. In order to gain further insights in the precise mechanisms involved in the relationships between NO synthesis and migraine, we analyzed changes induced by GTN administration in ADMA levels, DDHA-1 mRNA expression and the expression of neuronal and endothelial NOS nNOS and eNOS in the brain. We also evaluated ADMA levels in the serum.

MethodsMale Sprague–Dawley rats were injected with GTN 10 mg-kg, i.p. or vehicle and sacrificed 4 h later. Brain areas known to be activated by GTN administration were dissected out and utilized for the evaluation of nNOS and eNOS expression by means of western blotting. Cerebral and serum ADMA levels were measured by means of ELISA immunoassay. Cerebral DDAH-1 mRNA expression was measured by means of RT-PCR. Comparisons between experimental groups were performed using the Mann Whitney test.

ResultsADMA levels and nNOS expression increased in the hypothalamus and medulla following GTN administration. Conversely, a significant decrease in DDAH-1 mRNA expression was observed in the same areas. By contrast, no significant change was reported in eNOS expression. GTN administration did not induce any significant change in serum levels of ADMA.

ConclusionThe present data suggest that ADMA accumulates in the brain after GTN administration via the inhibition of DDAH-1. This latter may represent a compensatory response to the excessive local availability of NO, released directly by GTN or synthetized by nNOS. These findings prompt an additional mediator ADMA in the modulation of NO axis following GTN administration and offer new insights in the pathophysiology of migraine.

KeywordsNitroglycerin Migraine Rat brain nNOS eNOS ADMA DDAH AbbreviationsGTNNitroglycerin or Glyceryl trinitrate

ADMAAsymmetric dimethylarginine

NONitric oxide, nNOS, neuronal nitric oxide synthase

eNOSendothelial nitric oxide synthase

NMMANG-monomethyl-l-arginine l-

SDMAω NG,N′G-symmetric dimethylarginine

DDAHdimethylarginine dimethylaminohydrolase

Andrea Ferrigno and Chiara Demartini contributed equally to this work.

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Autor: Rosaria Greco - Andrea Ferrigno - Chiara Demartini - Annamaria Zanaboni - Antonina Stefania Mangione - Fabio Blandini - Giu

Fuente: https://link.springer.com/

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