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M J Hurley

Publications and source records attributed to M J Hurley.

At least 19 recordsLinked to original sources
PubMed2006

What has been learnt from study of dopamine receptors in Parkinson's disease?

Since the introduction of dopamine replacement therapy using L-3,4-dihydroxyphenyalanine (L-DOPA) to treat Parkinson's disease and the recognition of the problems associated with L-DOPA use, numerous studies have investigated dopamine receptor regulation and function in Parkinson's disease. These studies have provided insight into the pathological process of the disorder and the molecular consequences of chronic dopaminergic treatment, but they have been less successful in identifying new pharmacological targets or treatment regimes that are as effective as L-DOPA at alleviating the symptoms of Parkinson's disease. This review will present a summary of the reported changes in dopamine receptor regulation and function that occur in Parkinson's disease and will discuss their contribution to the current pharmacological management of Parkinson's disease.

Animals↗
PubMed2005

Immunoautoradiographic analysis of NMDA receptor subunits and associated postsynaptic density proteins in the brain of dyskinetic MPTP-treated common marmosets.

l-3,4-dihydroxyphenylalanine methyl ester (l-DOPA)-induced dyskinesia in Parkinson's disease may result from aberrant glutamatergic stimulation of the striatum due to synaptic plasticity in the motor cortex or striatum as a consequence of adaptation of striatal output pathways. This might result from changes in NMDA receptor subunit or NMDA receptor associated postsynaptic density (PSD) scaffold protein expression. Using immunoautoradiography the expression levels of NR1 and NR2B subunits of the NMDA receptor and the postsynaptic density scaffold proteins, PSD-95, PSD-93, and neurofilament light (NFL) were examined in normal common marmosets (Callithrix jacchus) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned animals that exhibited high or low levels of l-DOPA-induced dyskinesia. Brains from MPTP-lesioned animals that were not primed for l-DOPA-induced dyskinesia were not included in this study. No alterations in the NR1 NMDA receptor subunit were observed. The NR2B NMDA receptor subunit was increased in caudal caudate nucleus and putamen, hippocampus, cingulate motor area (CMA), supplementary motor area (SMA) and dorsal primary motor cortex (dMI) of highly dyskinetic MPTP-lesioned marmosets, but not in animals with low levels of dyskinesia. PSD-93 was decreased in the globus pallidus of marmosets with high and low levels of dyskinesia and increased in the CMA, SMA and dMI of highly dyskinetic marmosets. PSD-95 was increased in the SMA of highly dyskinetic marmosets, but not in animals with low dyskinesia. NFL expression was elevated in the SMA and dorsal and ventral MI of highly dyskinetic marmosets. These results suggest that l-DOPA treatment of MPTP-lesioned marmosets can affect glutamatergic systems and indicate that altered NMDA receptor function may relate to dyskinesia.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2003

Expression of cannabinoid CB1 receptor mRNA in basal ganglia of normal and parkinsonian human brain.

Reverse transcription polymerase chain reaction (RT-PCR) was used to examine the expression of the cannabinoid CB(1) receptor mRNA in post-mortem brain tissue obtained from normal subjects and patients dying with Parkinson's disease. CB(1) receptor mRNA was detected in striatal (nucleus accumbens, caudate nucleus and putamen) and extrastriatal (globus pallidus, substantia nigra) brain regions. In parkinsonian tissue the level of CB(1) receptor mRNA was decreased in the caudate nucleus, anterior dorsal putamen and external segment of the globus pallidus, but remained unchanged in the other brain areas examined. These results show that CB(1) receptor mRNA expression was altered in Parkinson's disease (though the effects of drug treatment can not be ruled out) and indicate that cannabinoid CB(1) receptor mRNA expression was affected by alterations in dopaminergic systems.

Actins↗
PubMed2001

Dopamine D(1) receptor expression in human basal ganglia and changes in Parkinson's disease.

The expression of the human dopamine D(1) receptor was examined by reverse transcription polymerase chain reaction (RT-PCR) and radioligand binding using [(3)H]-SCH23390 in post-mortem brain tissue that was obtained from normal subjects and patients dying with Parkinson's disease who were receiving treatment with dopaminergic drugs. D(1) receptor mRNA and specific [(3)H]-SCH23390 binding sites were found in both striatal (nucleus accumbens, caudate nucleus and putamen) and extrastriatal (globus pallidus and substantia nigra) brain regions. In parkinsonian brain, D(1) receptor mRNA was increased in the nucleus accumbens, while a decrease was detected in the substantia nigra pars compacta. No change in D(1) mRNA levels was found in the other brain areas examined. An increase in the density of specific [(3)H]-SCH23390 binding sites was found in the anterior putamen and a decrease in the external segment of the globus pallidus, no changes were detected elsewhere. This study demonstrates that regulation of D(1) receptor expression in the brain of patients dying with Parkinson's disease that were treated with L-DOPA is confined to small alterations in restricted brain regions.

Aged↗
PubMed2001

Cultured human foetal cerebral cortex, transfected with tyrosine hydroxylase cDNA, as a source of neural transplant material.

Obtaining an adequate supply of foetal dopaminergic tissue to treat Parkinson's disease by neural transplantation can be difficult. In this study primary cultures of human foetal cerebral cortex cells were transfected, using cationic lipids, with a eukaryotic expression vector (pCIneo-THI) containing the cDNA for human tyrosine hydroxylase isoform I (TH). Cortical cells from human (10-14 week) foetuses were cultured for 11 days in vitro and transfected twice with pCIneo-THI during this time. The double transfection process resulted in 3-4% of the cells becoming TH positive. When grafted into the striatum of 6-OHDA lesioned rats the transfected foetal cerebral cortex cells reduced amphetamine-induced circling behaviour by 75%, while grafts of untransfected cells had no significant effect on turning. TH transfected foetal cerebral cortex cells may therefore be a useful alternative supply of tissue for use in neural transplants to treat Parkinson's disease.

Adrenergic Agents↗
PubMed2001

Thermal inactivation kinetics of bovine cathepsin D.

Cathepsin D, the principal indigenous acid proteinase in bovine milk, is a lysosomal proteinase, which exists in milk in four forms, including the inactive zymogen procathepsin D. The thermal inactivation kinetics of bovine cathepsin D, isolated from spleen and milk, were studied under isothermal conditions, using a specific HPLC assay to determine residual activity. Inactivation of the blood enzyme preparation followed first order kinetics, with z-values in phosphate buffer (pH 6.7) and skimmed milk of 6.5 and 7.6 degrees C, respectively, the enzyme being far more stable in the latter environment. Inactivation kinetics of the enzyme purified from milk were more complex, and could be best approximated by a double exponential model. Again, stability was higher in milk than in buffer. The double exponential model may indicate differing heat stabilities of isoforms of the enzyme, or stabilization of the enzyme by some milk constituent. It is clear that the enzyme can survive, at least partially, processes such as heating at 55 degrees C for 30 min during manufacture of high-cook cheese varieties (45% survival), and HTST pasteurization (8% survival), and thus may contribute to proteolysis in a range of dairy products.

Animals↗
PubMed2000

Adenosine A(2A) receptor mRNA expression in Parkinson's disease.

The expression of the human adenosine A(2A) receptor was examined by reverse transcription polymerase chain reaction in post-mortem human brain tissue that was obtained from normal subjects and patients who died with Parkinson's disease. Adenosine A(2A) receptor mRNA was detected in both striatal (nucleus accumbens, caudate nucleus and putamen) and extrastriatal (globus pallidus and substantia nigra) brain regions. A significant decrease in the level of adenosine A(2A) receptor mRNA was found in the anterior and posterior caudate nucleus and anterior dorsal putamen, whereas a significant increase was observed in the substantia nigra pars reticulata of Parkinsonian brain when compared to age-matched controls. No change in adenosine A(2A) receptor mRNA levels was seen in any other brain region examined. This study demonstrates that A(2A) receptor mRNA expression is altered in the basal ganglia of patients who died with Parkinson's disease and who were receiving treatment with dopaminergic drugs. The adenosine A(2A) receptor appears subject to regulation by dopaminergic systems in human brain, though these data do not permit a distinction to be made between the effects of neuronal degeneration or drug treatment. The adenosine A(2A) receptor may therefore form a target for the treatment of basal ganglia disease.

Aged↗
PubMed1996

Dopamine D3 receptors are not involved in the induction of c-fos mRNA by neuroleptic drugs: comparison of the dopamine D3 receptor antagonist GR103691 with typical and atypical neuroleptics.

The effect of acute and chronic administration of dopamine receptor antagonists on the expression of mRNA encoding the cellular immediate-early gene c-fos was investigated in rat brain by in situ hybridization using 35S-labelled oligonucleotide probes. The selective dopamine D3 receptor antagonist GR103691 had no effect on the level of c-fos mRNA after acute or chronic treatment. Acute treatment with haloperidol increased the level of c-fos mRNA in the caudate-putamen, nucleus accumbens shell and core, olfactory tubercle and parietal cortex. After chronic treatment with haloperidol increases in the level of c-fos mRNA in the caudate-putamen and nucleus accumbens core were no longer observed. The increase in the level of c-fos mRNA in the nucleus accumbens shell was attenuated but still significantly elevated above the level measured in vehicle-treated animals. In the olfactory tubercle, parietal cortex, frontal cortex and cingulate cortex the level of c-fos mRNA was decreased after chronic haloperidol treatment. Acute sulpiride treatment reduced the level of c-fos mRNA in the olfactory tubercle, parietal cortex and cingulate cortex. After chronic treatment with sulpiride the level of c-fos mRNA was reduced in the dorsal caudate-putamen only. Acute clozapine treatment increased the level of c-fos mRNA in the nucleus accumbens shell and islands of Calleja. After chronic treatment with clozapine the level of c-fos mRNA remained elevated in the islands of Calleja but not in the nucleus accumbens shell. These results indicate that acute and chronic blockade of dopamine D3 receptors does not cause induction of c-fos transcription in limbic, striatal or cortical regions of rat brain. This study also demonstrated that acute blockade of dopamine receptors with haloperidol, sulpiride and clozapine induced different regionally specific patterns of c-fos expression which were altered after chronic blockade.

Animals↗
PubMed1996

Neural toxicity of retroviruses.

Recombinant retroviruses containing the cDNA for human tyrosine hydroxylase-1 and Escherichia coli lacZ gene were used to infect primary foetal ventral mesencephalon and cortical cultures from rat brain. Severe neuronal toxicity resulted 3-4 days after infection, glial cells seemed to be much more resistant. The toxicity was likely to have resulted from an agent present within the virus-containing medium itself, rather than from the retrovirus itself. The results of this study indicate that retroviruses are not suitable vectors for the introduction of tyrosine hydroxylase into primary neuronal cultures.

Animals↗
PubMed1996

D3 receptor expression within the basal ganglia is not affected by Parkinson's disease.

Quantitative receptor autoradiography and in situ hybridization were used to investigate the expression of dopamine D3 receptors in sections of human brain containing limbic (nucleus accumbens) and striatal (caudate nucleus, putamen) regions. High levels of dopamine D3 receptor mRNA and specific [3H](+/-)7-hydroxy-N,N-di-N-propyl-2-aminotetralin ([3H]7-OH-DPAT) binding sites were detected in the nucleus accumbens with lower levels in the caudate nucleus and putamen. No difference in D3 receptor expression was observed between normal and parkinsonian brain. These results indicate that D3 receptor expression is not altered in Parkinson's disease. In addition, they suggest that dopamine release in striatal and limbic areas is not necessary for maintenance of D3 receptor expression.

Aged↗
PubMed1996

Dopamine D3 receptors in the basal ganglia of the common marmoset and following MPTP and L-DOPA treatment.

The distribution of the dopamine D3 receptor was studied by receptor autoradiography using [3H]7-OH-DPAT in striatal and extrastriatal brain regions of the common marmoset (Callithrix jacchus). Saturation studies demonstrated that [3H]7-OH-DPAT bound with similar affinity to different regions of marmoset brain. In normal marmosets, specific [3H]7-OH-DPAT binding was found in both striatal and extrastriatal regions. Very high levels of specific [3H]7-OH-DPAT binding were detected in the islands of Calleja and nucleus accumbens but in addition high levels of binding were detected in rostral caudate nucleus and putamen. In common marmosets treated with the selective nigral neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), the levels of specific [3H]7-OH-DPAT binding in striatal and extrastriatal regions were not different to those in normal animals. Chronic treatment of MPTP-treated marmosets with L-DOPA/ carbidopa did not alter the levels of specific [3H]7-OH-DPAT binding in any brain region. These results demonstrate that in common marmosets D3 receptors are located in both striatal and limbic regions. The receptor density is not altered by dopaminergic denervation or by chronic L-DOPA administration. The D3 receptor may, therefore, be important in both the therapeutic and adverse effects of drugs used to treat Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1996

Effect of chronic treatment with typical and atypical neuroleptics on the expression of dopamine D2 and D3 receptors in rat brain.

The effect of chronic treatment (21 days) with typical and atypical neuroleptics on the expression of striatal and limbic D2 and D3 dopamine receptors was investigated in rat brain by in situ hybridization and receptor autoradiography. Haloperidol and sulpiride increased D2 receptor expression in striatal and limbic areas. In contrast, clozapine had no effect on D2 receptor expression. Haloperidol decreased D3 receptor expression in limbic areas, with the exception of the islands of Calleja where an increase occurred. Sulpiride and clozapine increased D3 receptor expression in limbic and striatal regions but decreased D3 receptor expression in the islands of Calleja. This study demonstrates that chronic treatment with typical and atypical neuroleptics produces different regionally specific changes in limbic and striatal D2 and D3 receptor expression. The alterations in dopamine receptor expression were different for each drug, but a distinction between the effects of atypical and typical neuroleptics could be made. Comparison of mRNA levels in animals which were not withdrawn from drug treatment with those that were withdrawn, demonstrated that some changes in receptor expression occurred during drug treatment, whilst others only manifested when drug treatment had ceased. The different regulation of dopamine D2 and D3 receptor expression by typical and atypical neuroleptics may have relevance to the ability of these drugs to cause extrapyramidal side-effects.

Animals↗
PubMed1979

Filtration characteristics of the polyester fiber micropore blood transfusion filter.

The filtration characteristics of a new polyester fiber (Fenwal II) micropore blood transfusion filter were investigated. Filtration of stored human whole blood and packed cells resulted in return of screen filtration pressure (SFP) of the blood to normal. Increased filter weights verified removal of large amounts of debris and microaggregates from the blood. Filtration of large quantities of blood accomplished at very high flow rates did not adversely affect the composition of the filtered blood. We conclude that the polyester fiber (Fenwal II) micropore blood transfusion filter is effective in removing microaggregates from stored whole blood and packed cells. It has a high volume capacity, allows rapid flow, and is reliable during pressure transfusion.

Blood Banks↗
PubMed1977

Polyurethane foam (Bentley) micropore blood transfusion filter: filtration characteristics.

Stored human blood of varying age was passed through polyurethane foam (Bentley) micropore blood transfusion filters. Passage through these filters resulted in decreased screen filtration pressure (SFP) of the blood and increased filter weights. Numerous microaggregates were removed and SFP returned to normal after filtration. Occlusion of the filter occurred after passage of only 2 units of whole blood. On the basis of this research, we conclude that polyurethane foam (Bentley) micropore blood transfusion filters are effective in removal of microaggregates from stored human blood. Because the filtering capacity is not great, it is recommended that when these filters are used during transfusion a new filter be used for each unit of blood administered.

Blood Preservation↗
PubMed1977

Lead actions on sodium-plus-potassium-activated adenosinetriphosphatase from electroplax, rat brain, and rat kidney.

Inorganic lead ion, in micromolar concentrations, reversibly inhibits the sodium-plus-potassium-activated adenosinetriphosphatase (ATPase) and potassium-activated p-nitrophenylphosphatase (NPPase) activities of microsomal fractions from electric organ, rat kidney, and rat brain. In the presence of 3 mM MgC12 and 3 mM ATP, the concentrations of PbC12 producing half-maximal inhibition of the ATPase from these tissues are 4 X 10(-6) M, 20 X 10(-6) M, and 55 X 10(-6) M, respectively. The corresponding values for inhibition of the NPPase are 10(-6) M, 53 X 10(-6) M, and 22 X 10(-6) M. PbC12 also stimulates the phosphorylation by [gamma-32P]ATP of a microsomal protein from all three tissues in the absence of added sodium ion. This reaction was extensively studied with electroplax microsomes. In common with the well-known Na+-dependent phosphorylation of (Na+ + K+)-ATPase, the Pb2 -dependent reaction is inhibited by ouabain, specific for ATP, dependent on Mg2+, and yields and acid-stable phosphoprotein with a molecular weight of 98,000 in sodium dodecylsulfate. The Pb2+-dependent phosphoprotein, however, is not sensitive to K+. These observations are pertinent to the biochemistry and toxicity of inorganic lead in tissues and to the molecular mechanism of the cation transport enzyme.

4-Nitrophenylphosphatase↗