Journal of Neural Transmission - Parkinson's Disease and Dementia Section最新文献

It was shown in the present study that three antagonists of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) glutamate receptor, including 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline (NBQX), 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine (GYKI 52466) and 6-(1H-imidazole-1-yl)-7-nitro-2,3-(1H, 4H)-quinoxalinedione (YM90K), caused marked reversal of akinesia when administered into the entopeduncular nucleus of rats rendered parkinsonian by bilateral substantia nigra pars compacta lesion. These data suggest that centrally active AMPA antagonists may have therapeutic utility in the treatment of idiopathic Parkinson's disease.

Receptor binding studies on rat cortical membranes were used to characterize the NMDA receptor in aged rats (22 months) treated for 20 months with a memantine containing diet delivering 30 mg/kg/day in comparison to aged and young/adult rats treated with control-diet. Spatial memory impairing effects of (+)-MK-801 (0.16 mg/kg) in the radial maze was not altered within the course of memantine-treatment (up to 16 months). However, chronic memantine-treatment significantly increased the number of [3H]MK-801 binding sites and the affinity of [3H]glycine. A non-significant trend to such changes was also seen in aged-control rats. Glycine-dependent [3H]MK-801 binding (functional binding under non-equilibrium conditions at a fixed L-glutamate concentration) revealed that a decreased ability of glycine to stimulate channel opening in aged rats was partially attenuated by the long-term memantine treatment. Furthermore, an increased ability of spermidine to enhance [3H]MK-801 binding in aged-control rats was even more pronounced in the aged memantine-treated group. Together these findings may indicate that changes in functional receptor-channel properties during the process of aging occur prior to a detectable loss of binding sites and that memantine enhances an endogenous compensatory mechanism triggered by glutamatergic hypofunction which is suggested to take place in aging.

We studied changes in the concentrations of 5-hydroxytryptamine (5-HT), other indoleamines, and catecholamines in the cerebrospinal fluid (CSF) of freely-moving rats that had been administered citalopram, +/-1-[3- (Dimethylamino)propyl)-1-(4-fluorophenyl)-1, 3-dihydro-5-isobenzo-furancarbonitrile hydrobromide), a selective inhibitor of 5-HT uptake. In a microdialysis experiment, the intracerebral extracellular free 5-HT increased significantly, peaking 60 to 90 min after citalopram (30 mg/kg p.o.) was administered. The 5-HT concentrations in CSF from the cisterna magna increased significantly, reaching a maximum 6 hours after a single dose of citalopram (30 mg/kg p.o.) was given. Six hours after this dose, the CSF 5-HT concentration in the cisterna magna was significantly increased, and the 5-hydroxyindoleacetic acid (5-HIAA) concentration was significantly decreased. There were non-significant changes in the other indoleamines (tryptophan, 5-hydroxytryptophan, and kynurenine) and in the catecholamines (dopamine, homovanillic acid, normetanephrine, and 3-methoxy-4-hydroxyphenethyleneglycol). The 5-HT/tryptophan ratio was correlated significantly with the kynurenine/tryptophan ratio before treatment with citalopram (r = 0.81, p = 0.051), indicative that there is coordination of the serotonin and kynurenine pathways in normal rats. In the animals posttreatment there was no such correlation, suggesting that the changes in 5-HT are independent of the kynurenine system at least within the 6 hours postreatment. These CSF results appear to reflect selective inhibition of 5-HT uptake in brain tissues by citalopram that is not associated with changes in catecholamines.

The endogenous monoamine oxidase (MAO) inhibitory activity, termed tribulin, contains several components. We have previously identified one of them, isatin, which is a selective inhibitor of MAO B. In the present study we have purified several further components of human urinary tribulin which act as selective inhibitors of MAO A. They have been identified by gas chromatography-mass spectrometry (GC-MS) as ethyl indole-3-acetate (and/or methyl indole-3-propionate), methyl indole-3-acetate and ethyl 4-hydroxyphenylacetate. IC50 values for MAO A were found to be 44 microM (105 microM for methyl indole-3-propionate), 88 microM and 120 microM, respectively, whilst those for MAO B were each greater than 1 mM. The artificial formation of these esters was excluded by carrying the parent acids, from which they are presumably synthesized, through the purification procedure. As tribulin output is increased during stress or anxiety, these results point to a possible role for tryptamine and tyramine pathways in such disorders.

Combinations of dopaminergic agonists with glutamate receptor antagonists have been suggested to be a possible alternative treatment of Parkinson's disease. To gain further insights into this possibility, the antagonist of the competitive AMPA-type glutamate receptor NBQX and the ion-channel blocker of the NMDA glutamate receptor (+)-MK-801 in combination with the dopamine D1 receptor agonists: SKF 38393, SKF 82958 and dihydrexidine; the dopamine D2 receptor agonist bromocriptine and the dopamine-precursor L-DOPA were tested in rats pretreated with reserpine and alpha-methyl-p-tyrosine. MK-801 on its own induced locomotor behaviour and potentiated the antiakinetic effects of dihydrexidine and L-DOPA but not of the other dopamine agonists tested. NBQX neither on its own nor coadministered with the dopamine agonists tested had an antiakinetic effect. These results indicate that agents, blocking the ion-channel of the NMDA receptor, might be useful adjuvants to some but not all dopaminomimetics in therapy of Parkinson's disease. The same does not seem to be true for the AMPA-antagonist NBQX.

We studied the usefulness of measuring volumes of the hippocampus, amygdala and frontal lobes with coronal magnetic resonance imaging (MRI) scans in the diagnosis of early Alzheimer's disease (AD). We examined 32 patients diagnosed according to the NINCDS-ADRDA criteria of probable AD and 16 age-matched healthy cognitively normal controls. The AD patients had mild dementia with a mean score of 22.8 in the Mini-Mental Status Examination (MMSE). We used a 1.5 T magnetic resonance imager and normalized the volumes for brain area. The AD patients had significantly smaller volumes of the right and the left hippocampus (-38%) (ANOVA, p < 0.0001) and the left frontal lobe (-16%, p < 0.05) compared to controls. The reductions in volumes of the right frontal lobe (-13%), the right amygdala (-14%) or the left amygdala (-18%) were not statistically significant. In the discriminant function analysis which included the volumes of the hippocampus, amygdala, and the frontal lobes and age, the volumes of the left and right hippocampus, the left and right frontal lobe, and the right amygdala entered the model and we could correctly classify 92% of the subjects into AD and control groups (Chi-square 42.6, df 5, p < 0.001). By using the volumes of the hippocampus, the frontal lobes or the amygdala on their alone, the correct classification was achieved in 88%, 65% and 58% of the subjects, respectively. In addition, in AD patients the volumes of the left hippocampus correlated significantly with the MMSE score and with immediate and delayed verbal memory; the smaller the volume the more impaired was their performance. Our data indicate that measurements of volumes of the hippocampus might be useful in diagnosis of early AD.

The present study investigated the effect of d-cycloserine, a partial agonist at the glycine binding site on NMDA receptor complex, on the performance of scopolamine-treated adult rats in a water maze task assessing spatial learning and in a delayed non-matching to position task assessing working memory in a spatial context. In the spatial learning task, scopolamine (0.4 mg/kg, i.p.) impaired acquisition (increased escape latency and distance) and increased swimming speed of rats. D-cycloserine (1.0 mg/kg, i.p.) reversed the deficits in acquisition performance but not the increases in behavioral activity. In the working memory task, scopolamine (0.2 mg/kg, i.p.) produced deficits on nonmnemonic rather than on mnemonic performance factors; scopolamine delay-independently decreased the percent correct responses and reduced behavioral activity of rats. D-cycloserine (1.0, 3.0 and 10 mg/kg, i.p.) did not reverse these performance deficits. When administered alone, the moderate to higher doses of d-cycloserine had no effects on working memory but the lower dose produced slight deficits in mnemonic performance factors; the 1.0 mg/kg dose delay-dependently decreased the percent correct responses without affecting behavioral activity of rats. In the water maze task, d-cycloserine had no effects on acquisition performance or behavioral activity of rats. These results suggest that acute, systemic administration of d-cycloserine does not improve spatial learning or working memory. However, at appropriate doses this agent may be efficacious in disease states of central cholinergic hypofunction since 1.0 mg/kg d-cycloserine was able to reverse the scopolamine-induced deficits in acquisition.

The expression of proenkephalin (PENK), prodynorphin (PDYN) and c-fos genes was studied in the striatum of C57B1/6 mice treated with 1-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine (MPTP), which are used as a rodent model of Parkinson's disease (PD). Two weeks after systemic administration of MPTP (2 x 40 mg/kg, s.c. 18h apart), the lesion of the substantia nigra (SN) could be visualised by loss of the nigral tyrosine hydroxylase (TH) mRNA hybridization signal and by a 91% decrease in striatal dopamine levels. The levels of PENK and PDYN mRNAs were not significantly changed in the striatum of the lesioned mice, as compared to non-treated controls. The induction of the immediate early gene c-fos by the dopamine D2 receptor antagonist haloperidol was not altered, while the selective D1 receptor agonist SKF 38393 failed to induce c-fos in the striatum of MPTP-treated mice. These results are in contrast to the data concerning rats with the 6-hydroxydopamine (6-OHDA) lesion of the SN, which serve as another rodent model of PD. In the striata of 6-OHDA-lesioned rats, PENK gene is upregulated, PDYN gene is down-regulated and the induction of c-fos gene by D2 receptor antagonists is abolished, whereas selective D1 receptor agonists induce c-fos gene, which does not occur in non-lesioned rats. We presume that the lack of influence of the MPTP lesion in mice on the striatal gene expression was mainly caused by insufficient dopamine depletion in the striatum, which could not be increased in this model. The importance of the changes observed in 6-OHDA-lesioned rats has been discussed in the context of the mouse and primate MPTP models of PD.

The relationship between event-related potentials (ERPs) and cognitive functioning was studied in patients with Parkinson's Disease (PD) but without dementia. Auditory and visual stimuli were used; 30 subjects participated in the auditory study and 20 in the visual study. Patient groups did not differ with respect to gender, age, education, illness duration, and level of cognitive functioning. Visual stimuli were 2.3 cpd sinusoidal grating patterns randomly presented in an oddball paradigm (oblique vs. vertical spatial orientation). Auditory stimuli were tones presented at 70 dB SPL at a rate of 1.1/second, also using the oddball paradigm (1.5K vs. 1K tones). All patients were given neuropsychological tests to measure verbal fluency, memory, visual spatial perception, and abstract reasoning. P300 and N200 abnormalities correlated with a number of these measures, such that longer ERP latencies were related to lower scores on tests of cognitive functioning. Patterns of results suggest that auditory and visual ERPs correlate with different subsets of neuropsychological functions in nondemented PD patients and that N200 may provide a new metric for clinical use.

The behavioral effects of cabergoline, pergolide and bromocriptine were investigated in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned parkinsonian cynomolgus monkeys with attention to the induction of hyperactivity, as evidenced by irritability, excitability and aggressiveness. All three drugs improved the parkinsonism in a dose-dependent fashion following a single injection. Among the three dopamine (DA) receptor agonists used, the antiparkinsonian effect of pergolide was the strongest and had an immediate effect, while cabergoline showed the longest duration of the antiparkinsonian effect and was least potent in inducing hyperactivity.