4 research outputs found
Recommended from our members
MPP +-induced increases in extracellular potassium ion activity in rat striatal slices suggest that consequences of MPP + neurotoxicity are spread beyond dopaminergic terminals
MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) produces symptoms similar to idiopathic Parkinson's disease in primates. A metabolite of MPTP, MPP
+ (1-methyl-4-phenylpyridinium), is actively accumulated by dopaminergic (DA) terminals and selectively destroys nigrostriatal DA neurons. The mechanism of this effect remains unknown but reports that MPP
+ inhibits electron transport in isolated mitochondria and increases oxidation of cytochrome
b in striatal slices suggest that depression of ATP production is involved. To relate metabolic effects of MPP
+ with tissue electrophysiology, extracellular potassium ion activity [K
+]
0 was measured by microelectrodes simultaneous to optical monitoring of reduction/oxidation (redox) activity of cytochrome
b during superfusion of MPP
+ onto rat striatal and hippocampal slices. MPP
+ increased oxidation of cytochrome
b and increased [K
+]
0 in slices of striatum. These increases were greater than expected from a selective effect of MPP
+ on DA terminals which likely comprise no more than 3% of the total striatal mass. These effects of MPP
+ were slowed by a dopamine uptake inhibitor (mazindol) and did not occur in hippocampal slices. These findings indicate that MPP
+ influences ion transport as well as metabolic activity and that these actions require the presence of functioning DA terminals. However, the large amplitudes of the MPP
+-induced changes suggest that consequences of MPP
+-neurotoxity are not ultimately confined to DA terminals. Two hypothesis are proposed: that energy failure in DA terminals results in leakage of neurotoxic substances or metabolites altering membrane conductance properties of adjacent cells and thereby placing additional demand upon ion transport pumps and mitochondrial oxidative phosphorylation; or that there is secondary uptake of MPP
+ leading to mitochondrial inhibition in cells neighboring DA terminals
Recommended from our members
1-Methyl-4-phenylpyridinium (MPP+) increases oxidation of Cytochrome- b in rat striatal slices
Effects of 1-methyl-4-phenylpyridinium, (the active metabolite of the neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), on reduction/oxidation activity of mitochondrial cytochromes were studied in rat striatal slices using scanning spectrophotometry. The objective was to test the hypothesis that the neurotoxin alters electron transport in the mitochondrial respiratory chain. Incubation of rat striatal slices with MPP+ (1 μM) produced a time-dependent oxidation of Cytochrome-
b in a manner consistent with the concept of a block in electron transport in the intramitochondrial respiratory chain between nicotinamide adenine dinucleotide (NAD) and Cytochrome-
b. This effect of MPP+ was decreased by co-incubation with a potent dopamine uptake inhibitor (mazindol), or when studied in a tissue with low dopaminergic innervation (hippocampus). The amplitude of Cytochrome-
b oxidation was greater than that expected from a selective effect of MPP+ on dopaminergic neurons suggesting that neighboring cells are influenced secondary to the MPP+ effect on dopaminergic terminals
Recommended from our members
MPP +-induced pathophysiology demonstrates advantages of neurotoxicology studies in brain slices
Since MPTP and its metabolite MPP
+ produce nigrostriatal lesions and symptoms similar to Parkinson's disease, recent studies have aimed toward defining their selectivity and neurotoxic mechanisms. In mitochondria in vitro, MPP
+ blocked electron transport and decreased oxygen consumption. However, these effects were not selective to striatal mitochondria or even to mitochondria from brain, they required concentrations of MPP
+ much greater than those found in vivo, and physiological actions could not be related to intramitochondrial changes. Lower doses of MPP
+ did produce highly selective degeneration of dopaminergic (DA) neurons in cell cultures. We report here that MPP
+ provoked large (80%) oxidations of cytochrome
b and large K
o
+ increments (approximately 30 mM) in rat striatal slices. These effects were slowed by mazindol, which inhibits DA uptake, and were markedly attenuated in rat hippocampal slices which have little DA input. Since DA terminals comprise only 2–4% of the striatal mass, the large MPP
+-induced changes suggest that while MPP
+ neurotoxicity in brain requires the presence of functioning DA terminals, effects are not confined to these terminals. Such studies illustrate the complexity of MPP
+ neurotoxicity and demonstrate the importance of investigations in models such as brain slices with an extracellular space and intercellular relationships as in intact brain
Recommended from our members
Mechanisms of MPP+ Neurotoxicity: Oxyradical and Mitochondrial Inhibition Hypotheses
Recent studies demonstrate that 1-methyl-4-phenylpyridinium (MPP+) is selectively toxic to dopaminergic (DA) neurons. Investigations suggest that this selectivity results primarily from the affinity of MPP+ for the dopamine reuptake system which results in preferential accumulation of the toxin within the terminals of the nigrostriatal dopaminergic (DA) system (Javitch and Snyder, 1985;Pileblad and Carlssen, 1985; Mayer et al. 1986)