Characterization of the gamma-aminobutyric acid receptor system in human brain gliomas.

The properties of [3H]-gamma-aminobutyric acid [( 3H]GABA) binding were studied in biopsied specimens from normal human brain and from 18 cases of human brain gliomas, made up of 6 astrocytomas, 6 glioblastomas, 3 oligodendrogliomas, and 3 medulloblastomas. In fresh membranes obtained from normal gray and white matter one population of Na+-dependent GABA receptors was observed, while in the frozen Triton X-100-treated membranes two distinct populations of Na+-independent binding sites were detected. Specific GABA binding sites in brain gliomas were shown only in frozen Triton X-100-treated membranes. As in normal tissue, these receptors are Na+-independent and bind [3H]GABA with two distinct affinity components. The biochemical profiles of [3H]GABA binding to membranes obtained from different tumors of glial origin are quite similar and cannot be related to the degree of malignancy of the neoplasia.

Treatment of Parkinson's disease with proglumide, a CCK antagonist.

Proglumide, a cholecystokinin antagonist, did not improve Parkinson's disease in a preliminary drug treatment trial.

Distribution of a putative endogenous modulator of the GABAergic system in human brain.

Diazepam binding inhibitor (DBI) is a novel neuropeptide purified from rat, cow, and human brain that allosterically modulates GABAergic transmission by binding to benzodiazepine (BDZ)-recognition sites. Using a specific radioimmunoassay for human DBI, we investigated the distribution of this peptide in different brain areas. We characterized with high-pressure liquid chromatography the DBI immunoreactivity in brain tissue obtained by biopsy and autopsy; we detected one molecular species of DBI in both instances. The regional distribution of DBI in the human brain is similar to that observed in rat brain: high concentrations in cortical and limbic areas, cerebellum, and brainstem, and low concentrations in the basal ganglia. These data suggest a modulatory role for DBI in human brain.

Cerebrospinal fluid levels of diazepam-binding inhibitor in neurodegenerative disorders with dementia.

We investigated CSF levels of diazepam-binding inhibitor (DBI), a recently discovered neuropeptide that allosterically modulates GABAergic transmission, in various neurodegenerative disorders with dementia (28 patients with Parkinson's disease, 10 with Alzheimer's disease, 7 with Huntington's chorea). We applied a battery of neuropsychological tests to determine the degree of dementia and to exclude the presence of mood alterations. CSF DBI levels were elevated in parkinsonian subjects with dementia and in patients with Alzheimer's disease, but decreased in Huntington's chorea patients. We hypothesize that modifications of CSF DBI levels may be related to a functional or structural alteration of the GABAergic system.

Therapeutic experience with transdihydrolisuride in Huntington's disease.

Transdihydrolisuride is an ergot derivative with mixed agonist and antagonist effects on central dopamine receptors. We gave the drug orally (1 mg daily) to 10 patients with Huntington's disease. In seven patients, the chorea improved with no adverse effects during the study.

Cyclandelate versus flunarizine. A double-blind study in a selected group of patients with dementia.

A double-blind, double-dummy clinical trial was conducted in which the efficacy of cyclandelate 1600 mg daily was compared with that of flunarizine 10mg daily in 40 patients (25 men and 15 women) with dementia of cerebrovascular origin. Parameters were assessed before treatment, and after 45 and 90 days of therapy. At 90 days, significant improvements were observed in patients given cyclandelate in measurements of P100 latency in the left eye, neurological impairment, dementia scores, ischaemia scores, Gottfries mental deterioration scale, Hamilton depression scores, short term visual memory, long term memory, Bender-Gestalt test and Koh's blocks test. In flunarizine recipients, improvements were observed in neurological impairment, ischaemia scores, Gottfries scale and Hamilton depression scores. Patients treated with cyclandelate showed significantly greater ameliorations in symptoms as assessed by the ischaemia scale, evoked visual potential, visual memory and Koh's block test compared with those given flunarizine. However, in none of the parameters was flunarizine superior to cyclandelate.

Calmodulin content in human brain tumors.

Using a radioimmunoassay method, the particulate and soluble calmodulin levels were determined in biopsied specimens from normal human brain and from various human brain tumors. Both in normal and pathological tissues the major portion of calmodulin was revealed in the cytosol. The chromatographic elution profiles of calmodulin obtained from soluble and particulate fractions of the same specimen were identical, thus suggesting an identity of the supernatant and particulate form of calmodulin. In all the examined oncotypes, the calmodulin content was lower than in normal extracts and this biochemical feature could not have been correlated with the degree of malignancy of the neoplasia. Furthermore, the translocation of calmodulin from the particles to the cytoplasm, reported in other rapidly growing tumors, lacks in human cerebral ones. Our findings indicate that in human brain oncotypes the calmodulin distribution is quite different from that found in tumors taken from other tissues, where its level is increased and a positive correlation between calmodulin concentration and growth rate of neoplastic tissue has been revealed.

Alpidem, a novel anxiolytic drug. A double-blind, placebo-controlled study in anxious outpatients.

The anxiolytic activity of alpidem (150 mg/day) and its effects on psychomotor performances were compared with placebo in 60 outpatients. The trial was a double-blind, parallel group, and the two treatments were administered orally in three divided doses for 3 weeks. Eighteen male and 42 female patients (mean age, 39.6 years) suffering from generalized anxiety or adjustment disorder with anxious mood of at least 1-month duration entered the trial at the end of a 1-week placebo run-in period designed to exclude early placebo responders. Efficacy was assessed with the Hamilton rating scale for anxiety (HRSA), the state-trait anxiety inventory (STAI x 1: anxiety as state), a visual analogue scale (VAS), and clinical global impression (CGI). Psychomotor performance was assessed by the digit symbol substitution test (DSST). Alpidem was significantly more effective than placebo in decreasing the severity of anxiety, both in the physician's judgment [total HRSA (p = 0.007), psychic symptoms (p = 0.0040), somatic symptoms (p = 0.0002)] and in the patients' evaluation [STAI x 1 (p = 0.0001) and VAS (p = 0.0003)]. Psychomotor performance was improved by both treatments; there was no difference between results with alpidem and placebo at the DSST (p = 0.2801), but the improvement was almost twofold on alpidem. Side effects were negligible with both treatments and the efficacy index, obtained from the CGI, was significantly better with alpidem than with placebo after day 7 (at least p less than 0.03).

Effects of alpidem in anxious elderly outpatients: a double-blind, placebo-controlled trial.

The efficacy and safety of alpidem, a new anxiolytic imidazopyridine, were compared with those of placebo in anxious elderly patients (65-80 years) by means of a randomized, double-blind, parallel group study. Following a 7-day "placebo run-in," 40 anxious patients were randomized to receive either alpidem or placebo. Daily doses ranging from 75 to 150 mg (25-50 mg t.i.d.) were administered for 3 weeks. Hamilton Rating Scale for Anxiety (HRSA), State Trait Anxiety Inventory (STAI-X1), Visual Analogue Scale (VAS), and Clinical Global Impression (CGI) were used on days 0, 3, 7, 14, and 21 for assessing efficacy. Psychomotor and mnesic performances were evaluated at the same time by means of the Digit Symbol Substitution Test (DSST), the Grünberger's test for fine motor coordination, and the Hawie's test for immediate memory. Possible adverse events were also recorded during the five visits. The anxiolytic efficacy of alpidem was significantly (p < 0.01) superior to that of placebo in all the rating scales adopted. The anxiolytic action was clearly evident from day 7. For most of the patients the active dose was 25 mg t.i.d. No relevant adverse effects were observed in both groups. No impairment of psychomotor and mnesic performances could be observed in the alpidem group. Alpidem is a new interesting anxiolytic drug for anxious elderly patients because it appears remarkably safe and, at effective doses, it does not impair psychomotor performances and cognitive functions.

Listeria rhombencephalitis: report of two cases with early diagnosis and favourable outcome.

We present 2 cases of Listeria monocytogenes rhombencephalitis (L-RE), both affecting previously healthy adult men. Each of them developed a diphasic syndrome first characterized by fever, nausea and headache, followed, in a second phase, by severe brain stem dysfunction at the level of the pons, with meningism, multiple cranial nerve palsies, ataxia, and, in one case, seizures. The early examination of the cerebrospinal fluid (CSF) demonstrated the presence of Gram-positive bacilli whose typical characteristics were compatible with those of Listeria, allowing for immediate administration of a specific therapy. Neuroimaging techniques (either CT or MRI) did not provide any evidence of brain stem involvement, and they did not positively contribute to the diagnostic process. The immediate use of a specific antibiotic therapy led to a favourable clinical outcome for both patients.

Benzodiazepine receptors and diazepam-binding inhibitor in human cerebral tumors.

Benzodiazepines can regulate neoplastic growth and immune response through specific peripheral benzodiazepine receptors. We investigated the presence of peripheral and classic central benzodiazepine receptors as well as diazepam-binding inhibitor, an endogenous ligand of both types of receptors, in different human cerebral tumors. Peripheral benzodiazepine receptors were present in all the tumor types studied, whereas central benzodiazepine receptors and diazepam-binding inhibitor were detectable in astrocytomas and glioblastomas and undetectable in meningiomas, neurinomas, and metastases. The role of diazepam-binding inhibitor and of the different benzodiazepine receptors in neoplastic cells is still to be defined.

Proglumide, a cholecystokinin receptor antagonist, reduces neuroleptic action in Huntington's chorea.

In a pilot study, proglumide, a cholecystokinin receptor antagonist, was administered to 8 patients affected from Huntington's chorea under long-term haloperidol treatment. The effectiveness of haloperidol on chronic symptomatology was reduced by the concomitant administration of proglumide; the latter drug, when administered alone, did not modify the severity of chorea compared to placebo. Possible explanations of these results are discussed, stressing the modulatory role of CCK not only on the dopaminergic, but also on the GABAergic system.

Glial brain tumors lack microvascular adrenergic receptors.

In human and animal brain microvessels beta-adrenergic receptors have been identified which are suggested to subserve the regulation of capillary function in both physiological and pathological conditions. Brain tumors are supplied by vessels that differ from those supplying normal cerebral tissue in various structural and functional parameters. In order to study the characteristics of brain tumor microcirculation, we have investigated the presence of beta-adrenergic receptors in capillaries isolated from different types of neoplasms using the specific radioligand 125I-iodocyanopindolol (ICYP). The microvessels were isolated and prepared by albumin flotation and glass bead filtration from normal and pathological tissues. No ICYP-specific binding was detected in the microvessels of tumors of glial origin, while capillaries obtained from meningiomas and neurinomas showed, like the normal brain, a specific binding of the radioligand. The data indicate that the regulation of capillary function in glial tumors differs from that of normal cerebral tissue and extraparenchymal tumors, thus indicating an impaired control of the vascular permeability.

Decreased density of benzodiazepine receptors in lymphocytes of anxious patients: reversal after chronic diazepam treatment.

Peripheral-type benzodiazepine receptors were measured in human circulating lymphocytes using 3H-PK 11195 as specific ligand. In a group of outpatients with anxiety disorders a significant decrease of receptor density (-37%) was found compared with age-matched controls. In these patients long-term diazepam treatment restored binding density to normal levels: the effect persisted after drug withdrawal. Acute i.v. diazepam administration did not change receptor density. The observed receptor changes could reflect a down-regulation phenomenon and indicate that lymphocyte function reflect central nervous events.

Different patterns of CSF neurotransmitter metabolism in patients with left or right hemispheric stroke.

In 30 ischemic stroke patients, divided into 2 groups depending on the side of their hemispheric cerebral lesion, the authors evaluated the levels of CSF homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA). The changes of these metabolites in CSF samples collected 3, 14 and 25 days after stroke have been correlated to the clinical course. In both groups, which were similar in respect to the localization of the infarcted area and to the volume of the lesion, the levels of HVA and 5-HIAA increased in the first 2-3 days and gradually declined to normal values in the following 3 weeks, in parallel with the regression of neurological deficits. The increase of HVA and 5-HIAA was statistically significant only in left hemisphere-injured patients. A linear regression analysis between the clinical score values and the CSF levels of the two metabolites at different time-points of observation revealed a significant correlation only for the HVA in the left-lesioned patients.

Glutamate uptake is decreased in platelets from Alzheimer's disease patients.

Because excitotoxicity may be involved in neurodegeneration in Alzheimer's disease, we investigated possible modifications of platelet glutamate uptake in AD patients. High-affinity glutamate uptake was studied in platelets from 35 Alzheimer's disease patients, 10 multi-infarct dementia patients, and 35 age-matched normal controls; it was decreased by 40% in platelets from Alzheimer's disease patients compared with controls and with multi-infarct dementia patients. Platelet glutamate uptake could be used as peripheral marker of glutamatergic involvement and as adjunctive diagnostic tool in Alzheimer's disease patients.

Decrease in phorbol ester receptors in human brain tumors.

We have characterized the specific binding of [3H]-phorbol-12,13-dibutyrate in the white and gray matter of normal human brain and in cerebral tumors as an index of the availability of protein kinase C enzyme molecules. White matter has less than 50% phorbol-ester-binding capacity in comparison to gray matter. The binding is lower in tumors of glial origin when compared with normal white matter. Tumors of nonglial origin such as neurinoma and meningioma have a lower binding capacity than glial tumors. Metastatic tissues have the lowest binding capacity. The analysis of binding parameters in tumors and in the corresponding normal peritumoral tissues confirms the decreased binding capacity of neoplastic tissues in comparison to tissues not undergoing malignant transformation. These data suggest that brain glial tumors have a low availability of protein kinase C enzyme molecules and point to the potential involvement of this system in malignant transformation of human brain cells.

Physiologic study of the subthalamic volume.

Deep brain stimulation (DBS) obtains good control of advanced PD symptoms. Chronic stimulation of Stn may alleviate rigidity, dyskinesia and tremor. Anatomical and functional intraoperative mapping are mandatory to obtain careful target localisation. Per-operative macrostimulation was carried out in 22 patients undergoing bilateral DBS in Stn; a volume 6 mm above to 4 mm below Stn was explored. Positive, collateral and adverse effects were recorded every 2 mm. Results obtained during acute stimulation were correlated to anatomical data from stereotactic atlases. Our findings suggest a volume, encompassing the zona incerta, Forel's fields and the lowermost part of anterior thalamus, functionally homogeneous to Stn. In fact, the stimulation of this volume obtains reduction of PD symptoms comparable to Stn.