Gian Luigi Piccinin

Effect of cytidine diphosphate choline (CDP-choline) on ischemia-induced alterations of brain lipid in the gerbil

Brain ischemia was produced in gerbils (Meriones unguiculatus) by the bilateral ligation of the carotid arteries. Definite changes in the energy status of brain demonstrated that carotid occlusion was effective. Five minutes before ligation, an intraventricular injection of either saline or cytidine diphosphate choline (CDP-choline, 0.6 μmol/brain, 3μl) was given to groups of animals. Control animals, with and without CDP-choline, together with the ischemic groups, were decapitated directly into liquid nitrogen; 10 min after arterial ligation. Brain free fatty acids, neutral lipids and phospholipids, which were labeled in vivo by the intraventricular injection of [1-14C] arachidonic acid (0.4–0.6 μCi, 6–9 nmol) 2 hr prior to ligation, were extracted, purified, and separated by thin-layer chromatographic procedures. The CDP-choline treatment noticeably corrected the increase of total and individual fatty acids due to ischemia and the increase of their radioactivity content. The changes in neutral lipids, particularly in the diacyl glycerol fraction, were also corrected by the injection of the nucleotide. CDP-choline partially reversed the decrease of brain phosphatidylcholine and of its labeling, which was due to ischemia. All the data indicate that the prior injection of CDP-choline stimulates the choline phosphotransferase reaction of brain towards synthesis of phosphatidylcholine and prevents the release of free fatty acids, particularly of arachidonic acid, associated with ischemia.

Frontal Lobe Dysfunction in Parkinson’s Disease: Prognostic Value for Dementia?

The purpose of this longitudinal study was to investigate if the presence of frontal motor deficits in parkinsonians without signs of global intellectual impairment may have a predictive value for the development of a progressive dementing process during the course of the illness. An examination of the higher level of motor organization, using skills thought to depend upon the integrity of the frontal regions, was performed by 30 parkinsonian patients who did not present any signs of general intellectual impairment. According to their performance, as compared with controls, they were divided into two subgroups: those with and those without frontal dysfunctions. After a mean period of 4 years, a second neuropsychological examination was carried out to assess any eventual change of mental status. The results suggest that frontal dysfunctions may be observed several years before the appearance of generalized intellectual impairment and may be considered one of the predictive factors for development of dementia in Parkinsons disease. Careful consideration of these defects during examination of motor abilities may be of value in the clinical management of parkinsonian patients.

The synthesis in vivo of choline and ethanolamine phosphoglycerides in different brain areas during aging.

The biosynthesis of choline and ethanolamine phosphoglycerides was tested in vivo in different brain areas of the rat during aging. Mixtures of [2−3H] glycerol and [Me-14C] choline or [2-3H] glycerol and [2-14H] ethanolamine were injected into lateral ventricle of the brain as lipid precursors and their incorporation into corresponding phospholipid was examined. A significant decrease of synthesis of both phosphoglycerides takes place in cerebral cortex and in the striatum, and is already apparent at 9 months of age with no further decrease or change therafter. No significant change takes place in the cerebellum. The unchanged absorption of injected water-soluble precursors, together with the lack of any significant change of phospholipid/protein ratio in all examined brain areas, suggests that the incorporation of both glycerol and nitrogen bases are affected by aging.

L-deprenyl therapy improves verbal memory in amnesic Alzheimer patients.

Altered monoaminergic neurotransmission could play an important role in the cognitive dysfunctions typical of dementia of the Alzheimer type (DAT). DAT is not, however, a homogenous phenomenon inasmuch as two forms are distinguishable: early onset (EO) and late onset (LO). Moreover, focal patterns of neuropsychological deterioration fall into various subgroups. According to our hypothesis, DAT patients, who at the onset of the disease mainly manifest memory disorders, also represent a specific subgroup characterized by impaired cortically projecting catecholaminergic pathways. In a 6-month randomized, double-blind, cross-over study versus placebo we analysed the influence of L-deprenyl on the verbal memory of 19 amnesic EO-DAT patients. Verbal memory was assessed by means of the Rey Auditory Verbal Learning Test. The results obtained show significantly better performances for L-deprenyl treated patients in learning and long-term memory skills. We suggest that L-deprenyl, through selective inhibition of MAO-B and by increasing the activity of the catecholaminergic systems, positively influences cognitive functions and behaviour founded on memory efficiency.

The metabolism of labelled choline in neuronal and glial cells of the rabbit in vivo.

Abstract— Adult rabbits were injected intraventricularly with [14C]ethanolamine and the incorporation of the base into the phosphatidylethanolamine and ethanolamine plasmalogen (and their water‐soluble precursors) of isolated neuronal and glial cells was investigated. All the radioactivity was incorporated into the base moiety of the ethanolamine lipids for the time intervals examined in both types of cells. In neurons, maximum labelling of the two ethanolamine lipids occurred at 7 h after administration, whereas the highest specific radioactivity for glial phosphatidylethanolamine and ethanolamine plasmalogen was reached at 20 and 36 h, respectively. The two lipids had a faster turnover in neurons than in glia, and in both populations incorporated the base at a faster rate than did whole brain tissue. The maximum incorporation rates for phosphorylethanolamine and CDP‐ethanolamine were reached in both types of cell at about 6 h after administration but the content of radioactivity per unit protein for phosphorylethanolamine was much higher in glial than in neuronal cells. It is concluded that the site of most active synthesis of ethanolamine phospholipids in vivo is the neuronal cell, with a possible transfer of intact lipid molecule to the glial compartment.

Characteristic Clinical Aspects of Parkinson Patients with Intellectual Impairment

The present study is based on the hypothesis that Parkinsons disease is not a single homogeneous entity and that parkinsonians with intellectual impairment are a distinct subgroup of the parkinsonian population. An assessment of cognitive functions was performed on 70 patients with Parkinsons disease and on 90 control patients. Analysis of their performances led to the division of parkinsonians into two subgroups: with and without neuropsychological impairment. Investigation of the clinical characteristics of the two subgroups showed that parkinsonians who are mentally impaired differ from other parkinsonians in that they present a more marked severity of the extrapyramidal syndrome with predominant bradykinesia and an earlier deteriorating response to levodopa treatment.

Neuropsychological Follow-Up of Parkinsonian Patients with and without Cognitive Impairment

In order to evaluate possible progression in the severity of their cognitive impairment, 34 parkinsonians with intellectual impairment were followed longitudinally for 7 years. Each patient was matched for age, sex, severity and duration of illness, and pharmacological treatment, with a parkinsonian patient without cognitive impairment. Results suggest that cognitive deficits are not static but rather there is a progression in the severity. Furthermore, patients suffering from severe dementia are more likely to die during the follow-up period. The prognosis of Parkinsons disease seems to be changed substantially by the occurrence of dementia. The natural history of parkinsonian dementia does not seem to differ from the history of other forms of dementia with a progressively disabling course leading to a complete loss of autonomy.

Effect of various drugs producing convulsive seizures on rat brain glycerolipid metabolism.

Convulsive seizures were elicited in the rat by the injection of several different drugs (pyridoxal phosphate, bicuculline, penicillin and ouabain). Glycerolipid metabolism was studied after the intraventricular injection of [2-3H]glycerol, which was incorporated into rat brain glycerides. The percentage of total lipid label found in each lipid class (phosphatidylethanolamine, PE; phosphatidylcholine, PC; phosphatidylserine, PS; phosphatidic acid, PA; phosphatidylinositol, PI; diacylglycerol (+ monoacylglycerol), DG and triacylglycerol, TG) depended on the time elapsed from the injection of the labeled precursor. The percent of total lipid radioactivity as PE and PC increased with time (3–60 min), whereas the opposite was true for the radioactivity of DG and PA. The radioactivity of other lipid classes did not appreciabily vary between 3 and 60 min from the injection of the labeled glycerol. The intraventricular administration of pyridoxal phosphate together with labeled glycerol decreased the percent of lipid radioactivity as PE and increased that as DG. This ‘lipid effect’ was detected also after the administration of other convulsants, such as ouabain and penicillin. The intraperitoneal administration of bicuculline affected lipid metabolism in cerebellum.

The transport of cytidine into rat brain in vivo, and its conversion into cytidine metabolites

Double-labeled cytidine, with a3H/14C isotope ratio of 20.00, has been intraventricularly injected into the brain of young rats, and its fate followed up to 90 min from administration together with the time-course of labeling. The injected nucleoside enters the brain as an intact molecule and is immediately utilized without prior degradation. Cytidine is actively converted into uridine and CMP, the latter being then transformed by a stepwise mechanism into CDP and CTP, and finally into CDP-choline and CDP-ethanolamine. The results indicate that administered cytidine represents a compound likely to enter metabolic events, which lead to CDP-choline and CDP-ethanolamine synthesis, and presumably to phospholipid production.

Cerebellar metabolism of phosphatidylcholine and its hydrosoluble precursors during bicuculline-induced convulsive seizures

The cerebellar incorporation of labeled choline into phosphatidylcholine (PC) and its hydrosoluble choline-containing precursors has been examined during the course of bicuculline-induced convulsive seizures. The labeling of phosphocholine and of PC diminished in these conditions whereas that of cytidine-5′-diphosphate choline (CDP-choline) was practically unaffected. Moreover, the cerebellar pools of phosphocholine and CDP-choline increased by 75–100% after 6 min of convulsions; these compounds were formed from lipid through the action of phospholipases or through the reverse action of choline phosphotransferase. From the data reported in this paper it should also be inferred that the cytidylyltransferase reaction was activated. It is therefore concluded that the cerebellar metabolism of PC and its precursors was affected in various ways by the bicuculline-induced convulsive seizures.