Hirotaro Narabayashi

Tumor necrosis factor-α (TNF-α) increases both in the brain and in the cerebrospinal fluid from parkinsonian patients

Tumor necrosis factor-alpha (TNF-alpha), a glial-cell-related factor, was measured for the first time in the brain (striatum) and cerebrospinal fluid (CSF) from control and parkinsonian patients by a sensitive sandwich enzyme immunoassay. The concentrations of TNF-alpha in the brain and CSF were significantly higher in parkinsonian patients than those in controls. Since TNF-alpha is an important signal transducer of the immune system with cytotoxic and stimulator properties, these results suggest that an immune response may occur in the nigrostriatal dopaminergic regions in Parkinsons disease and that TNF-alpha may be related, at least in part, to the neuronal degeneration.

Interleukin (IL)-1β, IL-2, IL-4, IL-6 and transforming growth factor-α levels are elevated in ventricular cerebrospinal fluid in juvenile parkinsonism and Parkinson's disease ☆

Interleukin (IL)-1β, IL-2, IL-4, IL-6, epidermal growth factor (EGF), and transforming growth factor (TGF)-α were measured for the first time in ventricular cerebrospinal fluid (VCSF) from control non-parkinsonian patients, patients with juvenile parkinsonism (JP) and patients with Parkinsons disease (PD) by highly sensitive sandwich enzyme immunoassays. All cytokines were detectable in VCSF from control and parkinsonian patients, and the concentrations were much higher than those in lumbar CFS. The concentrations of IL-1β, IL-2, IL-4 and TGF-α in VCSF were higher in JP than those in controls (P < 0.05). In contrast, the concentrations of IL-2 and IL-6 in VCSF from patients with PD were higher than those from control patients (P < 0.05). These results agree with our previous reports, in which the cytokine levels were elevated in the striatal dopaminergic region of the brain from patients with PD. Since VCSF is produced in the ventricles, the alteration of cytokines in VCSF may reflect the changes of cytokines in the brain. Because cytokines play an important role as mitogens and neurotrophic factors in the brain, the increases in cytokines as a compensatory response may occur in the brain of patients of JP or PD during the progress of neurodegeneration. Increase in cytokines may contribute not only as a compensatory response but as a primary initiating trigger for the neurodegeneration.

Transforming growth factor-β1 levels are elevated in the striatum and in ventricular cerebrospinal fluid in Parkinson's disease

Transforming growth factor (TGF)-β1 content was measured for the first time in the brain (caudate nucleus, putamen, and cerebral cortex) and in ventricular cerebrospinal fluid (VCSF) from control and parkinsonian patients by a sandwich enzyme immunoassay. The concentrations of TGF-β1 were significantly higher in the dopaminergic striatal regions in parkinsonian patients than those in controls, but were not significantly different in the cerebral cortex between parkinsonian and control patients. Furthermore, the concentrations of TGF-β1 in VCSF were significantly higher in parkinsonian patients than those in non-parkinsonian control patients. Since TGF-β1 has potent regulatory activity on cell growth, these results suggest that TGF-β1 may have some significant modulatory role in the process of neurodegeneration in Parkinsons disease.

bcl-2 Protein is increased in the brain from parkinsonian patients

The proto-oncogene bcl-2 is involved in the regulation of cell death and may be able to block apoptosis in neurons through reduced generation of reactive oxygen species (ROS). The bcl-2 product was measured for the first time in brain (caudate nucleus, putamen and cerebral cortex), ventricular cerebrospinal fluid (VCSF), and lumber CSF (LCSF) from control and parkinsonian patients by highly sensitive two-site sandwich enzyme-linked immunosorbent assay (ELISA). The concentrations of bcl-2 in the nigrostriatal dopaminergic regions were significantly higher in parkinsonian patients than those in controls, whereas this product in cerebral cortex showed no significant difference between parkinsonian and control subjects. Neither VCSF nor LCSF from control or parkinsonian subjects contained the bcl-2 product in the detectable amount (< 5 U/ml). Since oxidative stress may be involved in neurogenerative disorders, accumulation of bcl-2 may reflect a mechanism for counterbalancing ROS-mediated damage, or it might represent the impairment of bcl-2-dependent protection from ROS in parkinsonian brain.

Biopterin in human brain and urine from controls and parkinsonian patients: Application of a new radioimmunoassay

Total biopterin concentrations in the post-mortem human brain (caudate nucleus) and in the urine of controls and parkinsonian patients were measured by a newly developed radioimmunoassay. There was good correlation between the total biopterin level and tyrosine hydroxylase activity in the human brain. Biopterin concentrations in the caudate nucleus were greatly reduced in parkinsonian patients. In contrast, the reduction of urinary biopterin in parkinsonian patients was slight and not statistically significant, as compared with normal controls.

Phenylethanolamine N-methyltransferase and other enzymes of catecholamine metabolism in human brain

The activities of tyrosine hydroxylase (TH), DOPA decarboxylase (DDC), dopamine beta-hydroxylase (DBH), phenylethanolamine N-methyltransferase (PNMT), and monoamine oxidase (MAO) with serotonin and phenylethylamine as substrates were measured in catecholaminergic regions of human brain from 10 controls and 3 patients with Parkinsonism. PNMT activity was detected in hypothalamus, thalamus and cerebellar nucleus of the control human brain, and was reduced in hypothalamus of Parkinsonian cases. Type A (with serotonin as substrate) and type B (with phenylethylamine as substrate) MAO activities were high in all brain regions with little individual variations in controls and Parkinsonian cases. TH activity was high in the controls and was markedly decreased, in substantia nigra, caudate nucleus, putamen and in pallidum, in all three cases of Parkinsonism. DDC activity in these regions was also decreased in 2 patients. However, one Parkinsonian case had only decreased TH and normal DDC activities. DBH activity in hypothalamus was also reduced in the Parkinsonian cases.

The soluble form of Fas molecule is elevated in parkinsonian brain tissues

Fas is an apoptosis-signaling receptor molecule on the surface of a number of cell types. The soluble form of Fas (sFas) was measured for the first time in brain (caudate nucleus, putamen and cerebral cortex), ventricular cerebrospinal fluid (VCSF), and lumbar CSF (LCSF) from control and parkinsonian patients by a highly sensitive two-site sandwich enzyme-linked immunosorbent assay (ELISA). The concentrations of sFas in nigro-striatal dopaminergic regions were significantly higher in parkinsonian patients than those in controls, whereas this product in cerebral cortex showed no significant difference between parkinsonian and control subjects. Neither VCSF nor LCSF contained the sFas molecule in the detectable amounts (< 16 pg/ml). These results suggest that the presence of sFas possibly leads to cell death/neurodegeneration in parkinsonian brain.

Disorder in reciprocal innervation upon initiation of voluntary movement in patients with Parkinson's disease

SummaryReciprocal innervation of the soleus motoneurones upon initiation of voluntary ankle dorsiflexion was investigated in eight patients with Parkinsons disease. H-reflex and visually guided step tracking methods were used for testing moto-neurone excitability and for controlling the timing of movement initiation, respectively. While reciprocal inhibition appeared almost simultaneously with the agonist electromyographic (EMG) onset in normal subjects (Kagamihara and Tanaka 1985), facilitation appeared in the majority of patients under the same onset condition. It increased slowly, reaching a maximum at about 100 ms after the EMG onset. It then subsided slowly at around 200–300 ms, and was replaced thereafter by an inhibitory effect. No coactivation of the soleus muscle was detected electromyographically. The facilitation between the EMG onset and the onset of mechanical contraction was attributed to the direct effect of the descending command from the brain, suggesting a certain disorder in controlling the system for reciprocal innervation.

Pergolide in the Treatment of Parkinson’s Disease

Three trials evaluated the efficacy and safety of pergolide.Eighty-six de novo patients and 314 patients already receiving levodopa were enrolled in an open-label study. Of the de novo patients, 47.5% showed a marked or moderate improvement and 32% showed a mild improvement. In the levodopa add-on group, 53.8% showed marked or moderate improvement and 36.3% showed mild improvement. In a short-term, double-blind study, the efficacy of pergolide was compared with that of bromocriptine. One hundred seventy-two patients were randomized to receive pergolide, and 173 were randomized to receive bromocriptine. In de novo patients, bromocriptine (n equals 49) and pergolide (n equals 49) demonstrated similar efficacy. However, significantly more levodopa-treated patients in the pergolide group, compared with the bromocriptine group, demonstrated marked or moderate improvements in several items of the rating scale score. In a long-term study, 151 of 314 patients receiving pergolide in combination with levodopa remained in the study for 3 years, and 127 for 4 years, and in these patients the initial improvement was maintained. In 18 of 62 de novo patients, the initial improvement was maintained for up to 3 years. These trials indicate that pergolide has efficacy in patients with Parkinsons disease, either as monotherapy or in combination with levodopa. NEUROLOGY 1995;45(suppl 3): S13-S21

Homospecific activity (activity per enzyme protein) of tyrosine hydroxylase increases in parkinsonian brain

Tyrosine hydroxylase (TH) contents in the caudate nucleus, putamen, and substantia nigra from control and parkinsonism brains were measured for the first time by a sandwich enzyme immunoassay. Both the TH protein content and TH activity (Vmax) were decreased in parallel in the parkinsonian brains as compared with those of the control brains. In contrast, TH “homospecific activity” (activity per enzyme protein) was significantly increased in the parkinsonian brains. The results indicate that the decrease of TH activity in parkinsonian brains is due to the decrease of TH protein content as a result of cell death. The increase in the “homospecific activity” of residual TH in parkinsonian brain suggests such molecular changes in TH molecules as result in a compensatory increase in TH activity.