Comparison of cytotoxicity of a quaternary pyridinium metabolite of haloperidol (HP⁺) with neurotoxinN-methyl-4-phenylpyridinium (MMP⁺) towards cultured dopaminergic neuroblastoma cells

Abstract

Haloperidol has recently been found to be metabolized to its pyridinium ion (HP⁺). This conversion of haloperidol to HP⁺ appears to be similar to the activation of the dopaminergic neurotoxinN-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toN-methyl-4-phenyl pyridinium ion (MPP⁺). MPP⁺ is responsible for the damage of striatal dopaminergic neurons induced by MPTP in humans and animals. It seemed sensible to investigate whether or not HP⁺ might be toxic towards dopaminergic neurons and perhaps associated with some of the residual motofunction side effects of haloperidol. We therefore investigated the neurotoxicity of HP⁺ toward cultured human dopamine neuroblastoma cells (SH-SY5Y) and compared it with that of MPP⁺. HP⁺ reduced the viability as measured by MTT and [³H]thymidine incorporation methods in SH-SY5Y cells. Cell membrane integrity is reduced by the treatment of HP⁺ as measured by intracellular LDH levels. The toxicity was concentration and time dependent. Interestingly, HP⁺ appeared to be more toxic than MPP⁺ towards the SH-SY5Y cells in early phase in cultures. The toxicity of MPP⁺ appear to be progressive and subsequently become more than HP⁺ with prolonged cultivation. In contrary to MPP⁺, the toxic effect of HP⁺ towards a dopamine transporter transfected SK-N-MC cell line is not different from its wild type. This indicates that dopamine uptake system is probably not involved in the cytotoxicity caused by HP⁺.