Add time:07/20/2019         Source:sciencedirect.com

We have investigated the potential neurotoxicity of the catecholamine depleting agent 1,2,3,4-tetrahydro-2-methyl-4,6,7-isoquinolinetriol (TMIQ) in SH-SY5Y neuroblastoma cells. TMIQ induced a time and dose related inhibition of 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide; thiazoyl blue (MTT) reduction and an increase in lactate dehydrogenase release. After 72 h TMIQ (30 μM) significantly (P < 0.05) inhibited MTT reduction, and significantly increased LDH release. TMIQ cytotoxicity was not prevented by the inclusion of monoamine oxidase inhibitors (clorgyline or deprenyl), antioxidants (α-tocopherol or Trolox C) or the uptake1 inhibitor imipramine. TMIQ also induced a dose dependent stimulation of [3H]noradrenaline (NA) uptake, with maximum at 100 μM and EC50 of 8 μM. This stimulation of [3H]NA uptake was not prevented by the inhibition of protein kinase C, or activation of adenylate or guanylate cyclases. In addition, TMIQ significantly (P < 0.05) displaced [3H]nisoxetine binding from the uptake1 recognition site with a Ki of 71 ± 8 μM. However, as this interaction occurs at concentrations of TMIQ well above the EC50 for [3H]NA uptake, it is unlikely to explain TMIQ stimulated NA uptake. Furthermore, TMIQ inhibited potassium evoked [3H]NA release from SH-SY5Y cells, with an IC50 of 490 μM.Thus, TMIQ is cytotoxic to SH-SY5Y cells. However, the exact mechanism of toxicity requires further investigation, since it appears not to involve monoamine oxidase bioactivation, and is not mediated through membrane based free radical damage. Furthermore, although TMIQ inhibits mitochondrial Complex I (IC50 = 1.5 mM) with potency apparently greater than MPTP (2.7 mM), mitochondrial respiration was unaffected. The present studies suggest that the mechanism of toxicity differs from that causing depletion of catecholamines and inhibition of tyrosine hydroxylase by TMIQ described in previous studies.

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