The effects of some neurotoxins on tetrahydrobiopterin metabolism

Previous studies in man have shown that following dosing with L--3,4-dihydroxyphenylalanine (L-DOPA) and cotrimoxazole, plasma biopterins were raised. By analogy with dihydropteridine reductase deficient children in whom plasma biopterins are greatly elevated and the observations that these preparations were dihydropteridine reductase inhibitors, it was assumed that these raised plasma levels were due to increased efflux from tissues which resulted in tissue depletion of biopterins. In some human disease states such as senile dementia of the Alzheimer type lowered plasma biopterins were observed; by analogy with tetrahydrobiopterin synthesis deficient children these reduced plasma biopterins were attributed to lowered tetrahydrobiopterin synthesis and concomitant low tissue biopterin levels. Because of ethical considerations it was not possible to measure directly the tissue biopterins changes in either case. The Wistar rat was used as a model for human tetrahydrobiopterin metabolism, since tissues not normally accessible for study in humans, such as the brain and liver, could be examined for their effects on tetrahydrobiopterin metabolism after administration of the various agents. Plasma total biopterins in normal conditions were found to be much higher than in healthy humans. The elevation of plasma total biopterins concentration following the administration of dihydropteridine reductase inhibitors to humans, such as L-DOPA and cotrimoxazole was not observed in the rat. However, the administration of inhibitors of de novo tetrahydrobiopterin biosynthesis, such as diaminohydroxypyrimidine (DAHP) and bromocriptine was shown to decrease plasma biopterins concentration. In general, hepatic biopterins were decreased after administration of both dihydropteridine reductase inhibitors and de novo biosynthesis inhibitors. Drugs which are direct (bromocriptine) or indirect (L-DOPA and Sinemet Plus) agonists at dopamine receptors were investigated and were shown to decrease hepatic total biopterins concentration, but had no effect on brain biopterins. Bromocriptine was demonstrated as a potent inhibitor of de novo tetrahydrobiopterin biosynthesis in vivo and in vitro. Cotrimoxazole decreased brain tetrahydrobiopterin concentration. DAHP was effective in causing hyperphenylalaninaemia due to tetrahydrobiopterin deficiency in the rat. p-hydroxyphenylacetate was shown to be an effective inhibitor of dihydropteridine reductase in vivo. Phenylacetate administration had no observable effect on tetrahydrobiopterin metabolism, but did cause tyrosinaemia. It is proposed that scopolamine reduces tetrahydrobiopterin turnover. Lead and aluminium exposure caused deranged tetrahydrobiopterin metabolism. Aluminium, but not lead decreased brain choline acetyltransferase activity. Phenylalanine loading in normal human subjects was followed by an elevation in plasma biopterins which was not observed after tyrosine loading. Plasma N : B ratios correlated well with VEP latencies after tyrosine loading, but not after phenylalanine loading in healthy subjects. The use of derived pterin measurements as an indicator of tetrahydrobiopterin turnover or tetrahydrofolate status is discussed in the text.

Beta frequency neuronal network activity in the primary motor cortex

In this study I investigated the mechanisms of neuronal network oscillatory activity in rat M1 using pharmacological manipulations and electrical stimulation protocols, employing the in vitro brain slice technique in rat and magnetoencephalography (MEG) in man. Co-application of kainic acid and carbachol generated in vitro beta oscillatory activity in all layers in M1. Analyses indicated that oscillations originated from deep layers and indicated significant involvement of GABAA receptors and gap junctions. A modulatory role of GABAB, NMDA, and dopamine receptors was also evident. Intracellular recordings from fast-spiking (FS) GABAergic inhibitory cells revealed phase-locked action potentials (APs) on every beta cycle. Glutamatergic excitatory regular-spiking (RS) and intrinsically-bursting (IB) cells both received phase locked inhibitory postsynaptic potentials, but did not fire APs on every cycle, suggesting the dynamic involvement of different pools of neurones in the overall population oscillations. Stimulation evoked activity at high frequency (HFS; 125Hz) evoked gamma oscillations and reduced ongoing beta activity. 20Hz stimulation promoted theta or gamma oscillations whilst 4Hz stimulation enhanced beta power at theta frequency. I also investigated the modulation of pathological slow wave (theta and beta) oscillatory activity using magnetoencephalography. Abnormal activity was suppressed by sub-sedative doses of GABAA receptor modulator zolpidem and the observed desynchronising effect correlated well with improved sensorimotor function. These studies indicate a fundamental role for inhibitory neuronal networks in the patterning beta activity and suggest that cortical HFS in PD re-patterns abnormally enhanced M1 network activity by modulating the activity of FS cells. Furthermore, pathological oscillation may be common to many neuropathologies and may be an important future therapeutic target.