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

A paucity of information is available concerning the use of levodopa and carbidopa during pregnancy. Particularly lacking is whether these agents cross the placenta and whether levodopa undergoes metabolism in the fetus. The present study carried out in aborted fetal tissues demonstrates that levodopa crosses the placental barrier and suggests that it may be metabolized in fetal tissues, including the brain and spinal cord. The possibility exists that early exposure to levodopa or dopamine may alter the normal neuronal development in the fetus, and caution in the use of levodopa during pregnancy should be observed.

The aim of the study was to find out whether the reserpine-induced rigidity is similar to that seen in parkinsonism. Simultaneous measurements of the muscle resistance of the hind foot to passive bending and stretching in the ankle joint, as well as of the electromyographic (EMG) activity of the gastrocnemius and tibialis anterior muscles of rats were carried out. Reserpine was injected in a dose of 10 mg/kg alone or with alpha-methyl-p-tyrosine (250 mg/kg) 1, 4 and 27.5 h before the measurements. Reserpine increased the muscle resistance of the rat's hind leg to passive movements. That effect was the strongest at 1-2 h after the injections, and diminished markedly afterwards. The rigidity was accompanied with an increase in the resting, as well as in the stretch-induced short- and long-latency EMG activity in the gastrocnemius muscle. However, the intensity of the latter symptom did not change for a long period of time, which seems to correlate with the striatal dopamine depletion. The results suggest that the reserpine-increased EMG activity is a good model of parkinsonian rigidity.

Electroconvulsive therapy (ECT) was given to 16 non-depressed, non-demented patients with advanced Parkinson's disease (PD). In all the patients an antiparkinsonian effect was seen, lasting for 18 months in one patient, 3-5 months in seven patients, and a few days to four weeks in eight patients. After ECT the levels of homovanillic acid and neuropeptide Y in cerebrospinal fluid (CSF) were significantly increased. The eight patients with long lasting motor improvement after ECT had significantly lower CSF-3-methoxy-4-hydroxyphenylglycol compared to the group with short lasting improvement. Five patients developed transitory mental confusion after ECT. In these patients, and in no others, a high albumin-ratio was found already before ECT was given - an indication of blood CSF barrier damage. Our results suggest that ECT is valuable in patients with drug refractory PD or PD with intolerance to antiparkinsonian drugs.

Antiglutamatergic acting substances are considered to be useful tools for the treatment of hypokinesia in animal models for Parkinson's disease (PD). Moreover, most known antiglutamatergic compounds act postsynaptically and are either toxic or weak with regard to their clinical potency. The antiepileptic drug "Lamotrigine (LTG)" inhibits presynaptic glutamate release and may therefore provide a novel approach for PD therapy. Encouraging results from a pilot project led us to establish a placebo controlled trial including 20 patients with PD. The substance was generally well tolerated. There was a significant difference in the investigator's overall assessment of efficacy (6/10 vs. 2/10 improvement; p < 0.05) and a tendency for LTG to exhibit a beneficial effect in some registration parameters, but no significant differences in motor response were found between the two groups. We failed to confirm that LTG mediates a strong antiparkinsonian effect in this small study, but to clearly demonstrate slight or moderate beneficial effects larger groups are required.

The neural mechanism of parkinsonian motor symptoms, i.e., rigidity, tremor and akinesia, which are the result of nigrostriatal dopamine deficiency, is interpreted from long-term observations on the effect of surgical and pharmacological treatment of the disease in relation to the neuropathological findings within the substantia nigra zona compacta (SNc). Rigidity, tremor and secondary akinesia start first with degeneration of the ventral tier of the SNc followed by spread of the pathology to the dorsal tier, which may produce primary akinesia. Later, locus ceruleus pathology will be added. Spread of pathology is extremely slow in the juvenile or early onset parkinsonism (JP) compared with that in Parkinson's disease (PD). This spreading of pathology from one functional system to another might be one of the key factors responsible for the progressive worsening of the disease, which is different in speed between JP and PD.

beta 2-Microglobulin (B2-MG) content was measured for the first time in the brain (caudate nucleus, putamen, and cerebral cortex) from control and parkinsonian patients by a highly sensitive sandwich enzyme immunoassay. The concentrations of B2-MG in dopaminergic striatal regions were significantly higher in parkinsonian patients than those in controls, whereas those in the cerebral cortex showed no significant difference between parkinsonian and control subjects. Tumor necrosis factor-alpha (TNF-alpha) concentrations were also increased in the striatum, confirming our previous findings, but not in the cerebral cortex. Since TNF-alpha may induce B2-MG expression, these results suggest that an immunological response may occur in the nigrostriatal dopaminergic regions in Parkinson's disease.

Naloxone is unable to stimulate ACTH/cortisol secretion in patients with de novo Parkinson's disease, suggesting a reduced endogenous opioid control of the hypothalamic-pituitary-adrenal axis in parkinsonian patients. In the present study we examined whether Parkinson's disease also impairs the secretion of LH, which is under the inhibitory control of different opioid peptides than ACTH/cortisol. In addition, we examined whether a chronic dopaminergic therapy for at least one year with levodopa (450 mg/day) plus benserazide (112.5 mg/day) in 3 divided oral doses/day of Madopar modifies the ACTH/cortisol and/or the LH response to naloxone (4 mg as an i.v. bolus plus 10 mg infused in 2 hours). Ten parkinsonian patients (aged 52-62 years) and 8 normal controls (50-60 years) were tested with naloxone and in a different occasion with normal saline. The parkinsonian patients were tested both before and after dopaminergic treatment. Tests started at 09.00 h and lasted 2.5 hours. Basal ACTH/cortisol and LH levels were similar in all groups. During saline tests, ACTH/cortisol levels showed a slight physiological decline in all groups, whereas LH levels remained constant. Naloxone administration significantly increased the plasma levels of ACTH/cortisol and LH in the normal controls, but not in the parkinsonian patients before the dopaminergic treatment. In contrast, dopaminergic therapy restored significant ACTH/cortisol and LH responses to naloxone in parkinsonian patients. In fact, after levodopa plus benserazide, naloxone-induced ACTH, cortisol and LH increments in parkinsonian patients were significantly higher than before therapy and were indistinguishable from those observed in the normal controls. These data suggest that in men Parkinson's-related dopaminergic alterations may underlie the defective endogenous opioid control of ACTH/cortisol and LH secretion.

Mice treated with reserpine (5 mg/kg IP), 24 h beforehand, were completely akinetic. Fluent locomotion was reinstated with the D1-selective agonist SKF 38393 (3-30 mg/kg IP), the D2-selective agonist RU 24213 (0.5-5 mg/kg SC) and the mixed D1/D2 agonist apomorphine (0.025-0.5 mg/kg SC). Clonidine (0.03125-1 mg/kg IP) caused a dose-dependent sedation in dopamine-intact mice, but had no effect by itself on the locomotor activity of monoamine-depleted mice. In drug interaction experiments, clonidine did not modify the motor stimulant action of SKF 38393, but greatly enhanced the motor responses to RU 24213 and apomorphine. These results support the hypothesis that alpha-adrenoceptor agonists facilitate dopamine D2 but not dopamine D1 motor responding in the reserpine-treated mouse model of Parkinson's disease.

A characteristic feature of both Parkinson's disease (idiopathic paralysis agitans) and normal aging is loss of pigmented neurons in the substantia nigra. This has been found to correlate with the accumulation of neuromelanin and with oxidative stress in this brain region, but a clear association between these factors has not been established. Based on our recent demonstration that neuromelanin is a true melanin, containing bound metal ions in situ, we present a general model for its accumulation in vivo and the hypotheses (1) that it has a cytoprotective function in the sequestration of redox-active metal ions under normal conditions but (2) that it has a cytotoxic role in the pathogenesis of Parkinson's disease. Thus, neuromelanin accumulates normally through the autooxidation of catecholamines and serves tightly to bind redox-active metal ions, processes which would accelerate under conditions of intracellular or extracellular oxidative stress. Based on the known properties of melanin, however, neuromelanin also has the potential for exacerbating oxidative stress, eg by generating H2O2 when it is intact or by releasing redox-active metal ions if it loses its integrity; these reactions also would modulate the reactivity of the neuromelanin. By overwhelming intracellular antioxidative defense mechanisms, such a positive-feedback cycle could turn a condition of chronic or repeated oxidative stress in vulnerable neurons into an acute crisis, leading to cellular death. If the cumulative stress in duration and/or degree is severe enough, neuronal depletion could be sufficient to cause Parkinson's disease during life. One possible trigger for this cascade is suggested by the increased nigral iron contents in postmortem parkinsonian brains and the correlation of this disease with urban living where exposure to heavy metal ions is high: the saturation of neuromelanin with redox-active metal ions. Parkinson's disease therefore may be a form of accelerated aging in the substantia nigra associated with environmental toxins in which neuromelanin has a central, active role.

Mutations in the beta-amyloid precursor protein gene on chromosome 21 were shown to cause a small proportion of Alzheimer's disease. We studied the occurrence of the point mutations in exon 17 of the beta-amyloid precursor protein gene in a sample of Finnish familial Alzheimer patients and nondemented controls using polymerase chain reaction and a single strand conformation polymorphism technique. In addition, mutations in familial Alzheimer's disease patients were studied by sequencing the amplified products. Interestingly, two probable polymerase chain reaction errors were detected in codons 717 and 693 of the exon 17. However, no mutations in the exon 17 were confirmed adding the study to the body of literature that mutations in the exon 17 are a rare cause of familial Alzheimer's disease.