[Assessment of the in vitro and in vivo toxicity of 3,4-dihydroxyphenylacetaldehyde (DOPAL)].
This work was carried out in order to evaluate the in vitro and in vivo toxicity of 3,4-dihydroxyphenylacetaldehyde (DOPAL). This aldehyde is formed from dopamine (DA) by monoamine oxidases (MAO) and is mainly oxidised to 3,4-dihydroxyphenylacetic acid by brain aldehyde dehydrogenases (ALDH), or eventually reduced to 3,4-dihydroxyphenylethanol by aldose/aldehyde reductases. In vitro, catecholaminergic SH-SY5Y cells were incubated with DA and disulfiram (DSF), an irreversible inhibitor of ALDH. As evidenced by MTT assays, a 24-h treatment with 10(-4) M DA and/or 10(-6) M DSF followed by a 24-h incubation in a drug-free medium evidenced that the toxicity of each of these drugs was potentiated by the second drug. HPLC measurements demonstrated that this drug association induced an early DOPAL production that could result in a delayed cell toxicity. For in vivo studies, male Sprague-Dawley rats were treated with L-DOPA-benserazide, which increases the production of DOPAL by MAO, and DSF. An acute injection of DSF (100mg/kg i.p.) and L-DOPA/benserazide (100mg/kg+25mg/kg, 24h later) significantly increased the DOPAL striatal level. However, a 30-day treatment with DSF (100mg/kg i.p., once every two days) and L-DOPA/benserazide (100mg/kg+25mg/kg, twice a day) did not affect both indexes used to assess the integrity of the nigro-striatal dopaminergic terminals (i.e. the striatal content in DA and the binding to the vesicular monoamine transporter on striatal membranes). These results do not support the hypothesis of a DOPAL toxicity and argue against the toxicity of L-DOPA therapy.
Bonnet
J-J
JJ
Unité de Neuropsychopharmacologie Expérimentale, FRE2735 CNRS, IFRMP N degrees 23, 22 Boulevard Gambetta, F76183 Rouen Cedex. neuro.psyphar@univ-rouen.fr
Legros
H
H
Janin
Fr
F
Dourmap
N
N
Costentin
J
J
D015102:3,4-Dihydroxyphenylacetic Acid / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D007980:Levodopa / Q000494:pharmacology; D008297:Male; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D015102:3,4-Dihydroxyphenylacetic Acid; D007980:Levodopa; C007430:3,4-dihydroxyphenylacetaldehyde