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Biomedical subjects

J P Bennett

Publications and source records attributed to J P Bennett.

At least 73 records · Page 4Linked to original sources
PubMed1995

NMDA receptor blockade increases in vivo striatal dopamine synthesis and release in rats and mice with incomplete, dopamine-depleting, nigrostriatal lesions.

The role of excitatory amino acids (EAAs) in the regulation of striatal dopamine (DA) synthesis and release in rats and mice with incomplete DA-depleting lesions of the nigrostriatal system was investigated using in vivo microdialysis in rats and estimates of striatal in vivo tyrosine hydroxylase activity in mice. Dopaminergic nigrostriatal input to the striatum was partially lesioned in rats with stereotactic perinigral 6-hydroxydopamine injections and in C57BL mice with systemic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment. In rats, addition of the NMDA receptor antagonist 2-amino-5-phosphonopentanoic acid (AP-5, 10 mM) to dialysate increased local striatal DA release and synthesis. In 6-hydroxydopamine partially lesioned rats, the effects of AP-5 on DA release were significantly diminished, and AP-5 had no significant effect on DA synthesis. Perfusion with the non-NMDA receptor antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX, 1 mM) alone increased DA synthesis slightly, whereas DNQX + AP-5 (10 mM) increased DA synthesis to levels comparable with those observed with AP-5 alone. Local striatal DA synthesis was also increased by addition of the NMDA receptor antagonist (+/-)-3-(2-carboxypiperizin-4-yl)propyl-1-phosphonic acid (CPP, 1 mM) to the perfusion buffer. Local inhibition of nitric oxide synthase with nitro-L-arginine (10 mM) perfused through the striatal microdialysis probe did not alter DA synthesis, suggesting that the effects observed with NMDA receptor blockade are not mediated by nitric oxide. In unlesioned mice, none of the systemically injected EAA receptor antagonists altered striatal DA synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Reduction of MPP(+)-induced hydroxyl radical formation and nigrostriatal MPTP toxicity by inhibiting nitric oxide synthase.

N-Methyl, 4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces experimental parkinsonism after oxidation to N-methylpyridinium ion (MPP+), accumulation in dopamine neurons and concentration in mitochondria. Inhibition by MPP+ of mitochondrial electron transport impairs respiratory function, but the molecular mechanisms of cell death are not clear. We tested the hypothesis that locally produced nitric oxide is a key component in MPTP toxicity by providing a necessary intermediate in the production of hydroxyl free radicals. Inhibition of nitric oxide synthase reduced MPP(+)-induced hydroxyl radical formation in striatum and MPTP toxicity to nigrostriatal dopamine terminals, but did not interfere with inhibition of complex-I activity. Nitric oxide appears to be necessary for hydroxyl free radical generation in MPP+ toxicity and may play a role in neuronal degeneration in Parkinson's disease.

Amino Acid Oxidoreductases↗
PubMed1994

L-dopa increases nigral production of hydroxyl radicals in vivo: potential L-dopa toxicity?

Dopamine (DA) deficiency in Parkinson's disease is commonly treated with L-dihydroxyphenylalanine (L-dopa), the amino acid precursor to DA. L-dopa is neurotoxic in vitro and impairs survival of metabolically stressed neurons in vivo. We examined with microdialysis of substantia nigra in awake rats the local production of hydroxyl (OH) radicals before and after systemic L-dopa. We found a dose-dependent increase in OH radical output which paralleled the rate of dopa catabolism, was not blocked by deprenyl, and was increased further by acute inhibition of mitochondrial complex I activity. Following high L-dopa doses, catabolism of dopa-derived DA can exceed capacity of nigral mechanisms to reduce formation of or detoxify free radicals.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1994

Suppression of dyskinesias in advanced Parkinson's disease: moderate daily clozapine doses provide long-term dyskinesia reduction.

Dyskinesias commonly appear during L-dihydroxyphenylalanine (L-DOPA) therapy of advanced Parkinson's disease (PD) and can occur in both dose-related and dose-independent patterns. Clozapine exerts a dose-related suppression of L-DOPA-induced dyskinesias by shifting the i.v. L-DOPA dose-response curve for production of dyskinesias without altering relief of parkinsonism. We report our outpatient experience with 13 patients on daily clozapine therapy (maximum dose 400 mg/day), followed for 3-21 months (median 10). Beneficial effects of clozapine, determined from twice-weekly diaries, included increased "on time" and decreased "off time" and time "on with dyskinesia." Improvements were statistically apparent by 75 mg/day and remained so through 200 mg/day. Sedation was a common problem, reflected by increased time "asleep" which was significant by 50 mg/day. Sedation was dose limiting in most patients. Orthostatic hypotension and sialorrhea were variably present. No patients had seizures, bone marrow toxicity, or detectable loss of efficacy of clozapine with chronic use. We conclude that clozapine is an effective agent for suppression of dyskinesias in PD with an effective daily dose for most patients of 100-200 mg/day.

Aged↗
PubMed1994

Effects of prenatal cocaine exposure upon postnatal development of neostriatal dopaminergic function.

Pregnant rats were injected twice daily with 20 mg/kg cocaine (or saline) from gestational day 10 to parturition. Brains from offspring were examined with quantitative receptor autoradiography [D1 receptor (D1R), D2 receptor (D2R) and dopamine transporter (DAT)] and quantitative in situ hybridization [D1R mRNA, D2R mRNA, preproenkephalin (PPE) mRNA] for markers of neostriatal dopaminergic function. Prenatal cocaine exposure did not alter postnatal development of striatal D1R sites, but D1R mRNA levels were reduced by a third at days 14 and 35. D2R sites were increased over control in lateral striatum by day 6, and remained elevated through postnatal day 35. Total D2R mRNA was increased over control in both medial and lateral striatum at 7 and 14 days but was equal to control at 35 days. Prenatal cocaine exposure increased DAT density at postnatal days 1 through 5, but reduced it at days 14 and 35; PPE mRNA expression was reduced at days 7, 14 and 35. Many of these results are similar to those found in experimental animals and humans following cocaine withdrawal.

Animals↗
PubMed1994

Magnetic resonance imaging of neuronal grafts in the primate.

This preliminary study demonstrates the vital role that magnetic resonance imaging plays in the study of neuronal grafts in a nonhuman primate model of Huntington's disease. MRI scans were used to accurately locate and stereotactically lesion the anterior putamen of an adult rhesus monkey, thereby mimicking the anatomical and biochemical changes in Huntington's disease. Follow-up scans were utilized to confirm correct placement of the lesion and to stereotactically implant primate fetal neuronal tissue precisely into the lesion. Additionally, MRI appeared capable of imaging the fetal striatal grafts in rhesus monkeys. While the precise cellular composition of growing grafts was not identifiable on MRI scans, differentiation between normal, lesioned, and engrafted tissue was possible. Correlation of the magnetic resonance images of the grafted regions with actual graft tissue in perfused sections of the brain was shown. The use of magnetic resonance imaging, as indicated in these neuronal implantation studies, allows for a wide variety of future research possibilities where noninvasive and precise localization of the graft is mandated.

Animals↗
PubMed1994

Regulation by D2 dopamine receptors of in vivo dopamine synthesis in striata of rats and mice with experimental parkinsonism.

The effects of D2 dopamine (DA) receptor antagonism or stimulation by systemic haloperidol or quinpirole, respectively, on in vivo DA synthesis in 6-hydroxydopamine (6-OHDA)-lesioned rats and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated black mice were assessed by measuring the rate of dihydroxyphenylalanine (DOPA) accumulation following acute inhibition of L-aromatic amino acid decarboxylase with NSD-1015. 6-OHDA and MPTP caused partial lesions of nigrostriatal input to the striatum. Dopamine synthetic capacity was preserved relative to the severity of nigrostriatal lesion over a broad range of DA depletions. An exponential increase in fractional DA synthesis (the ratio DOPA/DA) was observed with increasing DA depletion, suggesting an elevation of the DA synthetic capacity per surviving DA terminal. In both lesioned rats and mice, haloperidol caused a significant increase in fractional DA synthesis above that induced by the lesion alone, while quinpirole significantly depressed fractional DA synthesis. Our results provide evidence that nigrostriatal terminals acquire increased DA synthetic capacity as nigrostriatal lesions exceed 90%, but that the increase in fractional DA synthesis observed in partially lesioned animals is not due to a loss of autoreceptor function. Pharmacological strategies to stimulate DA synthesis and release in moderately advanced Parkinson's disease should be pursued.

Animals↗
PubMed1994

Distribution of mRNA for the GABA transporter GAT-1 in the rat brain: evidence that GABA uptake is not limited to presynaptic neurons.

Cells containing mRNA for the gamma-aminobutyric acid (GABA) transporter GAT-1 were identified in rat brain by in situ hybridisation. They were found in most of the known locations of GABAergic neurons, as defined by the distribution of mRNA for glutamic acid decarboxylase, the synthetic enzyme for GABA. Within the cerebellum there was substantial labelling of basket and stellate cells in the molecular layer, and of Golgi cells but no others in the granule cell layer. Many Purkinje cells were unlabelled while others, particularly in the hemispheres, were moderately labelled. Many of the Purkinje cells negative for GAT-1 mRNA had adjacent intensely labelled small cells whose size and position corresponded to Bergmann glia. Numerical comparison of cells labelling for GAT-1 mRNA and the mRNAs for the two known isoforms of glutamic acid decarboxylase were made on serial sections of cerebral cortex. Cells positive for GAT-1 mRNA were more numerous, indicating that expression of the transporter is not just limited to GABAergic cells and we suggest that it may also be expressed postsynaptically by some non-GABAergic neurons.

Animals↗
PubMed1993

NMDA receptors increase OH radicals in vivo by using nitric oxide synthase and protein kinase C.

Prolonged activation of brain N-methyl-D-aspartic acid (NMDA) receptors increases intraneuronal (Ca2+) and nitric oxide (NO) synthesis, and may be responsible for neuronal death in acute brain insults and chronic neurodegenerative diseases. NO can be converted in vitro to toxic hydroxyl (OH) radical. Using microdialysis of striatum in awake animals, we found that local NMDA receptor activation increased outflow of OH radicals four-fold. NMDA-stimulated OH production was blocked by inhibitors of nitric oxide synthase (NOS) and protein kinase C (PKC). NMDA receptor-mediated neuronal death may derive from NOS- and PKC-dependent synthesis of OH radicals.

Alkaloids↗
PubMed1993

Degeneration of long-term fetal neostriatal allografts in the rhesus monkey: an electron microscopic study.

Primate fetal neostriatal neurons were implanted into the ibotenic acid-lesioned primate striatum and the animals were allowed to survive for 8 months. Light microscopic examination of the transplanted tissue demonstrated that the grafts were between 1.0 and 1.5 mm in diameter. The transplants were highly gliotic, but contained both normal appearing and degenerating neurons. At the electron microscopic level, the transplanted neurons displayed ultrastructural features identical to those of medium spiny, medium aspiny, and large aspiny striatal neurons. However, the majority of the grafted neurons showed evidence of degeneration. The grafts' neuropil demonstrated numerous glial processes, as well as mature axodendritic and axospinous synapses. Although this study was limited to only two graft recipients, the degenerative changes seen in the long-term primate allografts suggest that extension of these techniques into the clinical setting may be premature at the present time.

Animals↗
PubMed1993

Using computer algebra to determine rate constants in biochemistry.

In earlier work we have described how computer algebra may be used to derive composite rate laws for complete systems of equations, using the mathematical technique of Gröbner Bases (Bennett, Davenport and Sauro, 1988). Such composite rate laws may then be fitted to experimental data to yield estimates of kinetic parameters. Recently we have been investigating the practical application of this methodology to the estimation of kinetic parameters for the closed two enzyme system of aspartate aminotransferase (AAT) and malate dehydrogenase (MDH) (Fisher 1990a; Fisher 1990b; Bennett and Fisher, 1990): aspartate + alpha-ketoglutamate <--> glutamate + oxaloacetate; oxaloacetate + NADH <--> malate + NAD. In this paper we present a fuller (although not yet complete) analysis of the system. We show how symbolic estimates of the error behaviour of the parameters can be made, and used to identify those which are of kinetic significance. Finally we consider how metabolic control analysis can be applied directly to such a system.

Aspartate Aminotransferases↗
PubMed1993

Degranulation of individual mast cells in response to Ca2+ and guanine nucleotides: an all-or-none event.

Widespread experience indicates that application of suboptimal concentrations of stimulating ligands (secretagogues) to secretory cells elicits submaximal extents of secretion. Similarly, for permeabilized secretory cells, the extent of secretion is related to the concentration of applied intracellular effectors. We investigated the relationship between the extent of secretion from mast cells (assessed as the release of hexosaminidase) and the degranulation (exocytosis) responses of individual cells. For permeabilized mast cells stimulated by the effector combination Ca2+ plus GTP-gamma-S and for intact cells stimulated by the Ca2+ ionophore ionomycin, we found that exocytosis has the characteristics of an all-or-none process at the level of the individual cells. With a suboptimal stimulus, the population comprised only totally degranulated cells and fully replete cells. In contrast, a suboptimal concentration of compound 48/80 applied to intact cells induced a partial degree of degranulation. This was determined by observing the morphological changes accompanying degranulation by light and electron microscopy and also as a reduction in the intensity of light scattered at 90 degrees, indicative of a change in the cell-refractive index. These results may be explained by the existence of a threshold sensitivity to the combined effectors that is set at the level of individual cells and not at the granule level. We used flow cytometry to establish the relationship between the extent of degranulation in individual rat peritoneal mast cells and the extent of secretion in the population (measured as the percentage release of total hexosaminidase). For comparison, secretion was also elicited by applying the Ca2+ ionophore ionomycin or compound 48/80 to intact cells. For permeabilized cells and also for intact cells stimulated with the ionophore, levels of stimulation that generate partial secretion gave rise to bimodal frequency distributions of 90 degrees light scatter. In contrast, a partial stimulus to secretion by compound 48/80 resulted in a single population of partially degranulated cells, the degree of degranulation varying across the cell population. The difference between the all-or-none responses of the permeabilized or ionophore-treated cells and the graded responses of cells activated by compound 48/80 is likely to stem from differences in the effective calcium stimulus. Whereas cell stimulated with receptor-directed agonists can undergo transient and localized Ca2+ changes, a homogeneous and persistent stimulus is sensed at every potential exocytotic site in the permeabilized cells.

Animals↗
PubMed1993

Suppression of dyskinesias in advanced Parkinson's disease. I. Continuous intravenous levodopa shifts dose response for production of dyskinesias but not for relief of parkinsonism in patients with advanced Parkinson's disease.

We characterized the clinical dose-response curves for relief of parkinsonism and production of dyskinesias as a function of plasma levodopa and 3-O-methyldopa levels in six patients with advanced Parkinson's disease (PD) and fluctuating responses to oral levodopa/carbidopa. Dose response to ramped intravenous levodopa infusion was measured after overnight drug withdrawal on two occasions: first after chronic, intermittent oral levodopa/carbidopa, and second after 3 to 5 days of continuous intravenous levodopa. Continuous intravenous levodopa shifted the dyskinesia dose-response curve to the right, reduced maximum dyskinesia activity, but did not significantly alter dose response for relief of parkinsonism. Improvement in dyskinesia was apparent by the second day of continuous levodopa, during which ratios of plasma dopa/3-O-methyldopa remained constant. Our results support the hypothesis that relief of parkinsonism and production of dyskinesia by levodopa occur by separate mechanisms.

Aged↗
PubMed1993

Suppression of dyskinesias in advanced Parkinson's disease. II. Increasing daily clozapine doses suppress dyskinesias and improve parkinsonism symptoms.

We gave increasing daily doses of clozapine to six patients with advanced Parkinson's disease (PD) and levodopa-induced dyskinesias. Clozapine reduced the daily dyskinesia time five-fold, increased "on" time eight-fold, and doubled the serum [DOPA] producing half-maximal dyskinesia. Parkinsonism scores after overnight DOPA withdrawal improved with increasing daily clozapine intake, and there was no clozapine dose-related shift in levodopa dose response for relief of parkinsonism. Patients experienced sedation, sialorrhea, and orthostatic hypotension. Clozapine appears to be an effective agent for suppression of levodopa-induced dyskinesias in PD.

Aged↗
PubMed1992

A postsynaptic GABA transporter in rat spinal motor neurones.

The plasma membrane uptake system for gamma-amino butyric acid (GABA) is conventionally assumed to be presynaptic, so that after release GABA could be taken up and incorporated into synaptic vesicles for re-use. Using in situ hybridization histochemistry we find that rat spinal motor neurones express GAT-1, a transporter protein for GABA, but that they do not express glutamic acid decarboxylase, the synthetic enzyme for GABA. We conclude that the uptake system is located postsynaptically in these cells. Our observation may explain previous reports where GABA has been detected immunocytochemically in motor neurones.

Animals↗
PubMed1992

Simultaneous microdialysis in striatum and substantia nigra suggests that the nigra is a major site of action of L-dihydroxyphenylalanine in the "hemiparkinsonian" rat.

L-DOPA is frequently used to relieve symptoms of Parkinson's disease (PD), but its use in patients with more advanced PD is complicated by on-off phenomena. We used simultaneous microdialysis of striatum and ipsilateral substantia nigra to characterize changes in extracellular fluid (ecf) levels of dopamine (DA) following systemic treatment with L-DOPA (25 mg/kg as methylester) in awake, normal rats and those with partial (less than 99%) or complete (greater than 99%) DA depleting unilateral lesions of the nigrostriatal pathway (nsp). In normal rats, nigral ecf DA rose 17-fold above baseline after L-DOPA, compared to a 2.6-fold increase in normal striata. Striatal ecf DA rose equally after L-DOPA in all three groups, whereas peak nigral ecf DA in completely lesioned rats was three times that in normal or partially lesioned animals. Peak nigral ecf DA in completely lesioned rats exceeded striatal ecf DA in all groups by almost 2-fold. Activity after L-DOPA was biphasic ("hyperkinetic/bradykinetic") in completely lesioned but not in normal or partially lesioned animals, and the reduced activity occurred 2.5-4 h after L-DOPA at a time when both nigral and striatal ecf DA levels were still elevated. L-DOPA-induced increases in activity were predictable by greater elevations in nigral compared to striatal ecf DA in animals with complete lesions of the nigrostriatal pathway. Post-DOPA reduced activity might result from desensitization of synaptic events mediated by DA receptors; this may underlie DOPA-related on-off phenomena in patients with advanced PD.

Animals↗