Lack of involvement of glutamate‐induced excitotoxicity in MPP⁺ toxicity in striatal dopaminergic terminals: possible involvement of ascorbate

Abstract

1 The present study concerns the possible relationship between glutamate excitotoxicity and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/1-methyl-4-phenylpyridinium (MPTP/MPP + ) neurotoxicity on striatal dopaminergic terminals. 2 MPP + neurotoxicity has been studied by means of two MPP + perfusions separated by 24 h. After the second MPP + 1 mM perfusion, dopamine extracellular output, measured by microdialysis, was considered to be an index of the dopaminergic neurone damage produced by the ®rst MPP + 1 mM perfusion. 3 High concentration (10 mM) of glutamate uptake inhibitor L-trans-pyrrolidine-2,4-dicarboxylic acid (PDC) stimulated basal release of dopamine and protected against the neurotoxic eect of MPP + . 4 PDC 10 mM perfusion produced an increase in the extracellular output of glutamate and aspartate, and a decrease in that of ascorbate. 5 The protective eect against MPP + toxicity observed with PDC 10 mM was completely abolished when this glutamate uptake inhibitor was co-perfused with ascorbate 0.5 mM. 6 These results suggest that glutamate-induced neurotoxicity is not involved in MPP + toxicity. The protective eect found with the glutamate uptake inhibitor could be due to a decrease in extracellular ascorbate levels.

Nigrostriatal dopaminergic neurotoxicity of L-cysteine after stereotaxic administration into the substantia nigra of rats: Potential implications for MPTP-induced neurotoxicity and parkinson’s disease

“…CySH and CysGly are then translocated into neurons to provide intraneuronal CySH, the rate limiting precursor for intraneuronal GSH synthesis (Bannai, 1984;Sagara et al, 1993;Dringen et al, 1999). Thus, the release of glial GSH and its degradation by 7-GT/DP as a MPP+-induced energy impairment subsides may be the source of elevated extracellular Glu (Carboni et al, 1990;Matarredona et al, 1997) and CySH (Han et al, 1999) together with Gly. During this period of recovering but still impaired neuronal ATP production, transiently elevated extracellular levels of Glu and more prolonged elevation of extracellular CySH, both formed by the 7-GT/DP-mediated degradation of GSH which continues to be released from glia (Han et al, 1999), should continue NMDA/AMPA receptor activation.…”

“…Thus, when MPP--perfusions are discontinued and the dopaminergic energy impairment begins to subside, increasing ATP production should initiate repolarization of the neuronal membrane and reuptake of newly released DA (Cao et al, 1990). However, as extracellular levels of DA begin to decline when MPP + perfusions are discontinued, presumably reflecting initiation of its reuptake, extracellular levels of Glu begin to increase (Carboniet al, 1990;Matarredona et al, 1997). Unless very high concentrations of MPP + are perfused (Carboni et al, 1990), this delayed elevation of extracellular Glu is relatively small and brief (ca.…”

“…Microdialysis experiments demonstrate that during MPP + perfusion into the rat striatum a massive instantaneous release of DA occurs (Rollema et al, 1986) but extracellular Glu remains at or close to basal levels (Carboni et al, 1990;Matarredona et al, 1997). This suggests that MPP + does not significantly impair the energy status of glutamatergic neurons but evokes a dopaminergic energy impairment of a magnitude that profoundly depolarizes the neuronal membrane (Chiueh and Huang, 1991) thus mediating a massive release of DA.…”

“…Unless very high concentrations of MPP + are perfused (Carboni et al, 1990), this delayed elevation of extracellular Glu is relatively small and brief (ca. 30 min) (Matarredona et al, 1997). Because MPP + is not a glutamatergic neurotoxin (Matarredona et al, 1997) and extracellular Glu levels increase only when MPP + perfusions are discontinued raises an important question concerning the source of this EAA.…”

“…30 min) (Matarredona et al, 1997). Because MPP + is not a glutamatergic neurotoxin (Matarredona et al, 1997) and extracellular Glu levels increase only when MPP + perfusions are discontinued raises an important question concerning the source of this EAA. Furthermore, the delayed elevation of extracellular Glu is only brief yet several hours are required before signs of neuronal injury develop following MPTP/MPP + administration (Kohutnicka et al, 1998).…”