ABSTRACT
The possible protection against the toxicity of 1-methyl-4-phenylpyridinium (MPP(+)) afforded by inhibitors of nitric oxide synthase (NOS) and the antagonist of N-methyl-D-aspartate receptor function, MK-801, was studied in a brain-slice superfusion system. Significant decreases in levels of dopamine and its metabolites 3,4-dihyroxyphenylacetic acid (DOPAC) and homovanillic acid were observed following incubation of slices with 25 microM MPP(+). The activity of intracellular lactate dehydrogenase (LDH), a marker of cell viability, was also significantly decreased. These effects were attenuated by preincubation with I mM 7-nitroindazole (7NI), a selective inhibitor of the neuronal isoform of nitric oxide synthase (NOS). In contrast, the nonspecific NOS inhibitor N(omega)-nitro-L-arginine, also at 1 mM, had no effect on levels of dopamine metabolites but did show a small attenuation of the levels of dopamine. 7NI alone caused some increase in levels of dopamine and a decrease in the metabolite DOPAC, which is consistent with it also acting as an inhibitor of monoamine oxidase-B. MK-801 afforded no significant protection of aminergic cells, although changes in LDH activity suggested that there may have been some protection of non-aminergic neurons affected by this, relatively high concentration of MPP(+).
Subject(s)
1-Methyl-4-phenylpyridinium/antagonists & inhibitors , 1-Methyl-4-phenylpyridinium/poisoning , Enzyme Inhibitors/pharmacology , Nitric Oxide Synthase/antagonists & inhibitors , 3,4-Dihydroxyphenylacetic Acid/metabolism , Animals , Brain/drug effects , Brain/metabolism , Dizocilpine Maleate/pharmacology , Excitatory Amino Acid Antagonists/pharmacology , Female , Homovanillic Acid/metabolism , In Vitro Techniques , Indazoles/pharmacology , L-Lactate Dehydrogenase/metabolism , Nitric Oxide Synthase Type I , Nitroarginine/pharmacology , Rats , Rats, WistarABSTRACT
Taurine is a sulphur-containing beta-amino acid found in high (millimolar) concentrations in excitable tissues such as brain and heart. Its suggested roles include osmoregulator, thermoregulator, neuromodulator, and potential neurotransmitter. This amino acid has also been shown to be released in large concentrations during ischaemia and excitotoxin-induced neuronal damage. Here we report a protective effect of taurine against MPP(+)-induced neurotoxicity in coronal slices from rat brain. Significant protective effects were observed at taurine concentrations of 20 and 1 mM, suggesting a potential role for taurine in cases of neuronal insult. Studies with the synthetic taurine analogues taurine phosphonate, guanidinoethane sulphonate, and trimethyltaurine suggested the observed effect to be mediated via an extracellular mechanism. The use of GABA receptor ligands muscimol and bicuculline indicated the effect to be mediated through activation of GABA(A) receptors.
Subject(s)
1-Methyl-4-phenylpyridinium/pharmacology , Neurotoxins/pharmacology , Receptors, GABA-A/physiology , Taurine/pharmacology , Animals , Bicuculline/pharmacology , Drug Combinations , Female , GABA Agonists/pharmacology , GABA Antagonists/pharmacology , In Vitro Techniques , Ligands , Muscimol/pharmacology , Rats , Rats, Wistar , Receptors, GABA-A/metabolism , Taurine/analogs & derivativesABSTRACT
Tyrosine Hydroxylase is the rate-limiting enzyme in the synthesis of dopamine, and as such, it is widely used as a marker of dopaminergic cells. Within the basal ganglia, the dopaminergic cells are located in the substantia nigra pars compacta, and project to the striatum. It is this pathway which degenerates during Parkinson's disease. The data presented here illustrate examples of tyrosine-hydroxylase immunoreactive cells in striatum following intrastriatal injection with the neurotoxin MPP+. We further show by electron microscopy that these cells are, in fact, neurons and that they possess ultrastructural features of interneurons.
