Regional brain kinetics of 6-fluoro-(β-11C)-L-dopa and (β-11C)-L-dopa following COMT inhibition. A study in vivo using positron emission tomography

Summary The regional brain kinetics of (content/r45512403483pk3m/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">-11C)-L-dopa and 6-fluoro-(content/r45512403483pk3m/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">-11C)-L-dopa was measured in six Rhesus monkeys using positron emission tomography (PET). Radioactivity accumulated specifically in the striatal region and the increase in L-dopa-derived radioactivity utilization with time was calculated using surrounding brain as a reference area, this being devoid of dopaminergic activity. The rate constant for selective striatal utilization i.e. grossly decarboxylation was 0.0110 ± 0.0007 (S.D) and 0.0057 ± 0.0006 min1 for (content/r45512403483pk3m/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">-11C)-L-dopa and 6-fluoro-(content/r45512403483pk3m/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">-11C)-L-dopa, respectively. After pre-treatment of the monkeys with the peripherally and centrally active catecholamine-O-methyl transferase (COMT) inhibitor Ro 40-7592 10 mg/kg, the decarboxylation rate remained unchanged (0.0112 ± 0.0015 min-1) for (content/r45512403483pk3m/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">11C)-L-dopa, whereas an increase in rate was measured for 6-fluoro-(content/r45512403483pk3m/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">-11C)L-dopa (0.0092 ± 0.0015 min–1). Differences in the distribution of radiolabelled metabolites i.e. the corresponding O-methyl-L-dopa in the reference area is most probably the reason for the difference in calculated decarboxylation rate seen between the radiotracers. The higher decarboxylation rate measured for 6-fluoro-(content/r45512403483pk3m/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">-11C)-L-dopa after blockade of COMT shows that the radiolabelled metabolites i.e. 6-fluoro-O-methyl-(content/r45512403483pk3m/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">-11C)-L-dopa significantly contributes to background radioactivity.     

The regional distribution of adenosine-regulating enzymes in the left and right ventricle walls of control and hypertrophic heart

Summary The transmural distribution of the adenosine-generating enzyme 5content/m36421tq26286362/xxlarge8242.gif" alt="prime" align="BASELINE" BORDER="0">-nucleotidase (5content/m36421tq26286362/xxlarge8242.gif" alt="prime" align="BASELINE" BORDER="0">N) and of the adenosine-degrading enzymes adenosine deaminase (ADA), AMP deaminase (AMP-D) and adenosine kinase (Ado-K) were determined across the walls of left and right ventricles of control and hypertrophic rat hearts.The enzyme distribution across the left ventricle wall (but not across the right wall) of normal hearts was not uniform: 5content/m36421tq26286362/xxlarge8242.gif" alt="prime" align="BASELINE" BORDER="0">N activity shows its highest levels in the subepicardial and in the subendocardial regions, whereas all the other enzyme activities show their lowest levels. A similar pattern of transmural distribution was also detected in other mammalian species (ox and pig).In the experimental cardiac hypertrophy, caused by two different types of chronic cardiac overload, the levels and the profiles of transmural distribution of 5content/m36421tq26286362/xxlarge8242.gif" alt="prime" align="BASELINE" BORDER="0">N and ADA enzyme activities may significantly change across the rat left ventricle wall.     

Spectrum of morphological appearance of amyloid deposits in Alzheimer's disease

Summary Immunocytochemical staining with monoclonal antibodies to the content/w0163080366r561t/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">-protein on tissue sections which have been pretreated with formic acid is not only a very specific but also a highly sensitive method for the detection of amyloid deposits in the brains of Alzheimer's disease victims. We report here a spectrum of morphological appearance of the brain amyloid deposits which are one of the main histopathological correlates of this disorder. Deposits of the content/w0163080366r561t/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">-protein are not only found in the well-known lesions [congophilic angiopathy and senile (neuritic) plaques] but are also seen under various morphological forms for which the word content/w0163080366r561t/xxlarge8220.gif" alt="ldquo" align="MIDDLE" BORDER="0">plaquescontent/w0163080366r561t/xxlarge8221.gif" alt="rdquo" align="MIDDLE" BORDER="0"> does not appear an appropriate term: amyloid fibrils are found as large areas of diffuse infiltration of the neuropil, as ribbon-like infiltration in the subpial layer of the cerebral cortex, as granular deposits in the white matter, as diffuse deposits in the molecular layer of the cerebellum and the basal ganglia and as star-shaped deposits in the cerebellar Purkinje cell layer. The morphology of these deposits seems to depend on the cyto-and fibroarchitectonics of the brain region in which they are found, on the amount of amyloid deposited, and also on the type of staining technique used. It is only under specific circumstances that the deposition of amyloid in the neuropil is accompanied by the formation of paired helical filaments in nerve cell processes and their parent perikarya. In conclusion, our studies suggest that the extent of brain amyloidosis in Alzheimer's disease is much wider than so far appreciated.Supported in part by grants 5-AGO-4220-05 and 5-HD-22634-02 from the National Institutes of Heath     

Diffuse type of senile plaques in the cerebellum of Alzheimer-type dementia demonstrated byβ protein immunostain

Summary We studied senile plaques (SP) in the cerebella of six autopsied subjects with Alzheimer-type dementia (ATD) and ten non-ATD autopsied subjects between the ages of 78 and 90. Neither SP nor amyloid angiopathy (AA) was observed in any of the non-ATD subjects. In the four of the six ATD subjects, diffuse plaques in the molecular layer were seen as ill-defined areas of fine fibrillar materials by content/xq44h662p9k23kp5/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0"> protein immunostaining with formic acid pretreatment, the modified Bielschowsky stain, and periodic acid-methenamine silver (PAM) stain. The plaques were not visible with Bodian, Congo red, or periodic acid-Schiff stains. Compact plaques in the Purkinje cell or in the granular cell layers were found in three of the six subjects. Their amyloid core was often surrounded by areolar amyloid deposits. AA was observed in three of the six subjects. The argyrophilia of the diffuse and compact plaques, demonstrated by the modified Bielschowsky and PAM stains, became undetectable when the sections were first treated with formic acid. Such treatment made the plaques immunoreactive with content/xq44h662p9k23kp5/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0"> protein antiserum. The findings suggested that cerebellar diffuse plaques and compact plaques consist mainly of an amyloid component, and are characteristic of ATD.     

The sodium channels of the neuroblastoma x glioma 108 CC 15 hybrid cell change their sensitivity for volatile and local anesthetics upon continuous passage

Summary We have studied the ion flux through the sodium channels of low passage number (<50p.) and high passage number (>150p.) neuroblastoma x glioma hybrid cells using [¹⁴C] guanidinium and specific neurotoxins to induce channel opening and closing. The sodium channels of low passage number hybrid cells could be opened by veratridine alone, suggesting the presence of voltage dependent channels in agreement with electrophysiological studies reported in the literature. The sodium channels of the high passage number hybrid cells, however, needed the synergistic action of veratridine and scorpion toxin for activation suggesting that these channels are content/tjgp7t4842138024/xxlarge8220.gif" alt="ldquo" align="MIDDLE" BORDER="0">silentcontent/tjgp7t4842138024/xxlarge8221.gif" alt="rdquo" align="MIDDLE" BORDER="0">. The [¹⁴C] guanidinium ion flux through the sodium channels of the high passage number hybrid cells was inhibited by significantly lower concentrations of the volatile anesthetics (halothane, isoflurane and enflurane) and the lcoal anesthetics (tetracaine and bupivacaine) than the comparable flux through the sodium channels of the low passage number hybrid cells.Dedicated to Prof. Dr. E. Wecker on the occasion of his 65th birthday.     

“Occult” hydrocephalus in children

The authors describe 32 children between 2 and 15 years of age who had hydrocephalus that was only clinically manifest late in life. The clinical picture of these children did not suggest an obvious increase in intracranial pressure; instead, the presenting signs were rather nonspecific and included macrocrania, mild psychomotor retardation, unsteady gait, increased muscle tone and deep tendon reflexes in the lower limbs, impaired ocular movement, epilepsy, and endocrine dysfunction. Their histories suggest the possible causes of the ventricular dilation in about one third of the cases were: perinatal hemorrhage, leptomeningitis, neurofibromatosis, and untreated aneurysm of the great vein of Galen. In 20 patients, however, no positive anamnestic findings were reported. CT scan revealed triventricular dilation in more than half of the cases; tetraventricular dilation was present in 6 patients, and biventricular dilation in the remaining subjects. All children underwent CSF shunting, which resulted in complete recovery in all but 2 cases. The most frequently recorded surgical complication was postoperative subdural effusion (7 subjects), which required surgical treatment in only 2 cases.Presented at the 15th Annual Scientific Meeting of the International Society for Pediatric Neurosurgery, New York, 1987     

Neuropeptides: Animal behaviour and human psychopathology

Summary Animal studies have demonstrated that neuropeptides modulate nervous system functions. It has been postulated that disturbances in neuropeptide systems may be aetiological factors in psychiatric and neurological disorders. Neuropeptides related to ACTH/MSH, including ORG 2766, increase motivation and attention and facilitate recovery processes after nerve damage. These peptides may be effective during the early stage of dementia. Vasopressin and related peptides improve memory processes in animals and humans. In addition, these peptides influence social behaviour, mood and addictive behaviour. The non-opioid content/tk77wk711g68650m/xxlarge947.gif" alt="gamma" align="MIDDLE" BORDER="0">-type endorphins have neurolepticlike activities in animals and antipsychotic effects in a category of schizophrenic patients. Peptides related to CCK have also been found to be effective in these patients. Some neuropeptides, e.g. TRH and PLG, have been reported to exert antidepressant effects. Further research may eventually produce neuropeptides with therapeutic action in psychiatric and neurological diseases.Parts of this article were presented on the occasion of the inauguration ceremony of the Department of Psychiatry of the University of Mainz on April 2 and 3, 1987     

β-Methyl-15-p-iodophenylpentadecanoic acid metabolism and kinetics in the isolated rat heart

The use of 15-p-iodophenyl-content/n1660k166543322t/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">-methyl-pentadecanoic acid (content/n1660k166543322t/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">Me-IPPA) as an indicator of long chain fatty acid (LCFA) utilization in nuclear medicine studies was evaluated in the isolated, perfused, working rat heart. Time courses of radioctivity (residue curves) were obtained following bolus injections of both content/n1660k166543322t/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">Me-IPPA and its straight chain counterpart 15-p-iodophenyl-pentadecanoic acid (IPPA). IPPA kinetics clearly indicated flow independent impairment of fatty acid oxidation caused by the carnitine palmitoyltransferase I inhibitor 2[5(4-chlorophenyl)pentyl]oxirane-2-carboxylate (POCA). In contrast, content/n1660k166543322t/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">Me-IPPA kinetics were insenstive to changes in fatty acid oxidation rate and net utilization of long chain fatty acid. Analysis of radiolabeled species in coronary effluent and heart homogenates showed the methylated fatty acid to be readily incorporated into complex lipids but a poor substrate for oxidation. POCA did not significatly alter metabolism of the tracer, suggesting that the tracer is poorly metabolized beyond content/n1660k166543322t/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">Me-IPPA-CoA in the oxidative pathway.     

The reduction of water intake in rats caused by a low dose of apomorphine is unaltered by α-methyl-p-tyrosine: are autoreceptors not involved?

Summary Low doses of the dopamine (DA) agonist apomorphine (APO) induces a behavioural syndrome characterized by reduced spontaneous activity, reduced food and water intake and induction of yawning and penile erections. Traditionally these effects of APO have been considered to be caused by a preferential stimulation of DA autoreceptors, causing a decreased amount of transmitter at the postsynaptic receptors. If this is so, it could be hypothesized that 1) the same behavioural effects should be obtained if DA transmission is decreased by some other means, for example by synthesis inhibition, and that 2) the response to APO should be altered if DA transmission is already lowered.It was found that high doses of content/w8x5867877j7152h/xxlarge945.gif" alt="agr" align="BASELINE" BORDER="0">-methyl-p-tyrosine (content/w8x5867877j7152h/xxlarge945.gif" alt="agr" align="BASELINE" BORDER="0">-MPT; 50–200 mg/ kg) did not reduce water intake in thirsty rats, which low doses of APO do. It was further found that pretreatment with content/w8x5867877j7152h/xxlarge945.gif" alt="agr" align="BASELINE" BORDER="0">-MPT did not alter the response to APO. These results are difficult to reconcile with the DA autoreceptor hypothesis claiming that behavioural effects of low doses of APO are caused by a decreased release of DA. An alternative interpretation is that low doses of APO stimulates a certain population of sensitive postsynaptic D-2 receptors.     

Preponderance of β- over α-adrenoceptors in mediating the positive inotropic effect of phenylephrine in the ferret ventricular myocardium

Summary [³H]prazosin bound to the membrane fraction derived from the ferret ventricular muscle with high affinity in a saturable manner (K _d = 0.25 nmol/l and B _max = 27 fmol/mg protein in the right ventricle). [³H]CGP-12177, a content/q36337836672084r/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">-adrenoceptor ligand, bound to the membrane fraction with a _{K d} value of 0.29 nmol/l and a B _max of 42 fmol/mg protein. In the isolated ferret papillary muscle driven at 1 Hz at 37°C, phenylephrine elicited a concentration-dependent positive intropic effect. The maximal effect of phenylephrine was comparable to that of isoprenaline. Prazosin (0.3 content/q36337836672084r/xxlarge956.gif" alt="mgr" align="MIDDLE" BORDER="0">ol/l) shifted the concentration-response curve for phenylephrine slightly but significantly to the right, the maximal response being unaffected. In contrast, bupranolol (0.3 gmol/l) shifted the curve for phenylephrine markedly downwards: the maximal response was depressed significantly to 40% and the curve became less steep. In the presence of prazosin and bupranolol the curve was shifted to the right, being essentially parallel to the control curve. These results indicate that in the ferret ventricular myocardium both content/q36337836672084r/xxlarge945.gif" alt="agr" align="BASELINE" BORDER="0">- and content/q36337836672084r/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">-adrenoceptors mediate the positive inotropic effect of phenylephrine. The extent of contribution of the two classes of adrenoceptor is quite different from that in other mammalian species. In the ferret heart, content/q36337836672084r/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">-adrenoceptors predominate over content/q36337836672084r/xxlarge945.gif" alt="agr" align="BASELINE" BORDER="0">-adrenoceptors in mediating the positive inotropic effect of phenylephrine, although the number of content/q36337836672084r/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">-adrenoceptors is not especially high when compared with other species. Send offprint requests to M. Endoh at the above address