Dopamine‐Derived 1‐Methyl‐6,7‐Dihydroxyisoquinolines as Hydroxyl Radical Promoters and Scavengers in the Rat Brain: In Vivo and In Vitro Studies

The effects of derivatives of dopamine-derived isoquinoline, (R)-1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline [or (R)-salsolinol] on hydroxyl radical production were studied in vivo and in vitro. As reported previously, (R)-salsolinol is N-methylated in the brain into N-methyl-(R)-salsolinol, which is further oxidized into the 1,2-dimethyl-6,7-dihydroxyisoquinolinium ion. Using in vivo microdialysis, we measured hydroxyl radical levels in the rat striatum by HPLC after derivatization to 2,3-dihydroxybenzoic acid with salicylic acid. (R)-Salsolinol and the isoquinolinium ion (40 and 200 microM) and N-methyl-(R)-salsolinol (200 microM) reduced in vivo radical formation, with reduction of dopamine catabolism. (R)-Salsolinol and the isoquinolinium ion reduced in vitro hydroxyl radical production from dopamine autoxidation. On the other hand, 40 microM N-methyl-(R)-salsolinol increased the hydroxyl radical level in the striatum, and the radical production by its autoxidation was confirmed in vitro. N-Methyl-(R)-salsolinol affected neither in vivo dopamine catabolism nor in vitro production of hydroxyl radicals from dopamine. These results show that (R)-salsolinol and N-methyl-(R)-salsolinol may be neuroprotective and neurotoxic, respectively, and thus might be in the pathogenesis of Parkinson's disease.