Dopamine mediates striatal malonate toxicity via dopamine transporter‐dependent generation of reactive oxygen species and D2 but not D1 receptor activation

Abstract

Intrastriatal injection of the reversible succinate dehydrogenase inhibitor malonate results in both chemically induced hypoxia and striatal lesions that are similar to those seen in Huntington's disease and cerebral ischaemia. The mechanisms leading to neuronal death involve secondary excitotoxicity, the release of dopamine from nigrostriatal ®bres and the generation of reactive oxygen species (ROS) including nitric oxide (NO) and hydroxyl radicals. Here, we further investigated the contribution and mechanism of dopamine on malonate-induced striatal lesions. Prior lesions of the nigrostriatal pathway with 6-OHDA or the depletion of striatal dopamine stores by pretreatment with reserpine, an inhibitor or the vesicular monoamine transporter type-2 (VMAT2), in combination with a-methyl-p-tyrosine resulted in a signi®cant reduction of malonate-induced striatal lesion volumes. This was paralleled by block or reduction of the malonate-induced generation of ROS, as measured by the conversions of salicylate to 2,3-dihydroxybenzoic acid (2,3-DHBA) using microdialysis. Systemic or intrastriatal application of L-DOPA or dopamine, respectively, reconstituted malonate toxicity and the generation of ROS in 6-OHDA-lesioned rats. Block of the dopamine transporter by GBR12909 did not result in a reduction of malonate-induced dopamine release, but signi®cantly reduced the generation of hydroxyl radicals. The D2 receptor agonist lisuride and the mixed D1 and D2 receptor agonist apomorphine, but not the D1 receptor agonist SKF38393, partially restored malonate toxicity in 6-OHDAlesioned rats without increasing the generation of ROS. In line with these results sulpiride, an inhibitor of D2 receptors, reduced the malonate-induced lesion volume, whereas SCH23390, an inhbitor of D1 receptors, was ineffective. Our data suggest that malonate-induced dopamine toxicity to energetically impaired neurons is mediated by two independent pathways: (i) dopamine transporter uptake-dependent, dopamine receptor-independent generation of ROS, and (ii) excessive stimulation of D2 receptors.

DJ‐1 modulates the p38 mitogen‐activated protein kinase pathway through physical interaction with apoptosis signal‐regulating kinase 1

“…Several studies have proposed that dopaminergic neuronal death is increased via the activation of the ASK1 signaling pathway [Cassarino et al, 2000;Saporito et al, 2000;Chun et al, 2001;Xia et al, 2001;Ouyang and Shen, 2006;Pan et al, 2007]. These observations indicate that ASK1 may exert an important effect in the mediation of dopaminergic neuronal death, and that the blockage of ASK1 signaling via specific inhibitors may prevent or effectively retard the progression of PD and other neurodegenerative diseases.…”

Neuroprotective Effects of Synaptic Modulation in Huntington's Disease R6/2 Mice

“…In addition, the dopamine antagonist tetrabenezine ameliorated the observed motor deficits and reduced striatal neuron loss in these YAC128 mice. Depletion of striatal dopamine stores using reserpine, in combination with ␣-methyl-para-tyrosine, has also been reported to significantly reduce malonate-induced striatal lesions (Xia et al, 2001). This was accompanied by a reduction in malonateinduced generation of reactive oxygen species.…”

Studies on striatal neurotoxicity caused by the 3,4-methylenedioxymethamphetamine/ malonate combination: implications for serotonin/dopamine interactions

“…Although it has been suggested that DA may only result in little toxicity, as long as neurones do not show an energy compromise, DA may be toxic to neurones when energy impairments or a pro-oxidant environment accompanies its release (Moy et al, 2000;Xia et al, 2001;Jones et al, 2005). This possibility is in agreement with the fact that MDMA, despite releasing large amounts of DA, is not toxic when directly perfused into the brain (Esteban et al, 2001), but becomes toxic when combined with the energy inhibitor malonate (Nixdorf et al, 2001).…”

“…Generation of reactive oxygen species (ROS) is also a key feature of malonate-induced neurotoxicity (Fernandez-Gomez et al, 2005), an effect that depends to a great extent on DA (Bowyer et al, 1996;Reynolds et al, 1998;Ferger et al, 1999;Maragos et al, 1999;Moy et al, 2000;Xia et al, 2001;Maragos et al, 2004).…”