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Biomedical subjects

G Toffano

Publications and source records attributed to G Toffano.

At least 37 records · Page 2Linked to original sources
PubMed1990

Cellular and synaptic alterations in the aging brain.

The morphological and functional impairments observed in the aging brain are discussed in the framework of theoretical concepts, such as the existence of different modalities of intercellular communication and of specific trophic features in the central nervous system. The relevance of changes at the cellular level (disappearance of neuronal cell bodies and proliferation of astroglial cells) and at the synaptic level (alterations in neurotransmitter and receptor levels) is discussed. Two, non-mutually exclusive hypotheses are advanced to explain the frequent absence of correlation between neuropathological findings and functional deficits in aged patients. According to the first, the physiological reshaping of brain circuits during aging may lead to "wrong" readjustments of neural networks (e.g. due to less effective endogenous and exogenous orienting signals) causing minor morphological alterations but marked functional deficits. The second hypothesis maintains that the absence of correlation between neuropathological and functional deficits is due to the impairment of restricted neuronal populations ("pacemaker and command neurons") which play a special role in the hierarchical organization of neuronal networks. These neurons (inter alia, peptidergic neurons) may also be involved in volume transmission (diffusion of electrical and chemical signals in the extracellular fluid to reach distant targets). Moreover, the relevance of glial cells, not only as regulators of the extracellular medium but also on the basis of their trophic links with neurons, is considered. Finally, the interplay between trophic factors and therapeutical experience for the maintenance and/or recovery of an impaired function in elderly patients is discussed.

Aging↗
PubMed1990

Quantitative autoradiographical analysis of the age-related modulation of central dopamine D1 and D2 receptors.

Quantitative autoradiography of [3H]SCH 23390 and [3H](-)-sulpiride binding was performed in the brain of rats of various ages (3, 11 and 24 months) in order to study the changes in D1 and D2 receptor density with age. Binding of [3H]SCH 23390 in the caudate-putamen decreased progressively and markedly at rostral levels in 11- and 24- compared with 3-month-old rats (max. decrease -63%) while at caudal levels significant decrease was observed only in 24-month-old rats. [3H](-)-Sulpiride binding progressively decreased during aging in the caudate-putamen at rostral levels and the decrease was more pronounced laterally (-70% at 24 months), while at caudal levels no significant decrease was observed. D1 and D2 binding sites also decreased in the nucleus accumbens and olfactory tubercle of aged rats, while in the substantia nigra only the D1 receptors appeared to be modified with aging. No change was found in the entopeduncular nucleus, amygdala, frontoparietal, suprarinal-prefrontal and anterior cingulate cortex. The results indicate that the age-associated decrease of D1 and D2 receptors is not widespread, being confined to dopaminergic areas with high density of dopamine receptors.

Aging↗
PubMed1990

Excitatory amino acid receptor agonists stimulate membrane inositol phospholipid hydrolysis and increase cytoplasmic free Ca2+ in primary cultures of retinal neurons.

A variety of neurotransmitters are believed to elicit effects through receptor-stimulated inositol phospholipid metabolism. It appears that most major types of retinal neurons receive a direct glutamatergic input. The aim of the present studies was to characterize excitatory amino acid (EAA) receptor-mediated breakdown of inositol phospholipids and changes in Ca2+ homeostasis in primary avian retinal cell cultures. Cell monolayers, prepared from 8-day-old chick embryo neural retina, were labelled with [3H]inositol for 48 h, and used after 7 days in vitro. Kainic acid stimulated the accumulation of inositol phosphates in a time- and dose-dependent manner (ED50 = 30 microM). The EAA receptor agonists glutamate, N-methyl-D-aspartate (NMDA), ibotenate and quisqualate were all active, with the rank order: glutamate greater than kainate greater than NMDA much greater than ibotenate approximately quisqualate. External Ca2+ was required for these effects. Agonist actions were inhibited by type-specific antagonists, and also Mg2+ in the case of glutamate and NMDA. Glutamate, NMDA and kainate also elevated cytosolic free Ca2+ in individual retinal cells loaded with the Ca2(+)-sensitive dye Fura-2, as assessed by digital fluorescence ratio imaging microscopy. The agonist-induced increases in [Ca2+]i were largely dependent on extracellular Ca2+, independent of membrane depolarization and were blocked by Mg2+ for glutamate and NMDA. These results demonstrate that vertebrate retinal cells possess EAA receptors coupled to intracellular signal transduction pathways.

Amino Acids↗
PubMed1990

Regulation of the synthesis and metabolism of striatal dopamine after disruption of nerve conduction in the medial forebrain bundle.

1. After physical (knife-cut) or chemically-mediated (tetrodotoxin 300 nM, 1.5 microliters; 1.0 microliters min-1) interruption of nerve conduction in the nigrostriatal tract, there was a marked increase in the synthesis and metabolism of dopamine in the isolated dopaminergic nerve terminals of the striatum. The effect peaked at 4 h post-transection, at which time 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were increased by 300% and 700% respectively (DOPAC: 27 +/- 13 vs 80 +/- 17 nmol g-1; HVA: 6.66 +/- 3.57 vs 54 +/- 18 nmol g-1). The increases in dopamine content and metabolism are secondary to an increase in the rate of synthesis on the lesioned side, versus the intact, control side. 2. In both experimental situations, haloperidol (1.0 mg kg-1, i.p.) retained its known ability to induce a significant increase in DOPAC and HVA in the striatum, despite the interruption of nerve conduction in the nigrostriatal tract. 3. Six days after cutting the left nigrostriatal tract, dopamine in the left striatum was reduced to less than 5% of the control value, and DOPAC and HVA were not detectable. In the denervated, left striatum, the synthesis of dopamine (from injected L-DOPA), and its metabolism to DOPAC and HVA, occurred to the same degree as in the intact right side. In these DOPA-treated rats, haloperidol (1.0 mg kg-1, i.p.) caused a further increase in DOPAC and HVA in the intact striatum, but not in the denervated striatum. 4. Under non-stressful conditions, using a combination of anaesthetic treatments, electrical stimulation (400 muA, 0.4 ins, 15 Hz, 15 min) of the nigrostriatal tract did not increase DOPAC or HVA in the striatum on the stimulated side. 5. It is concluded (a) that there is a significant presynaptic, and/or local circuit mechanism capable of activating the synthesis and metabolism of dopamine in the isolated, striatal, dopaminergic nerve terminals. Furthermore, haloperidol can act directly on the striatal, dopaminergic nerve terminal, to cause an increase in the synthesis and metabolism of striatal dopamine. (b) After degeneration of the striatal dopaminergic nerves, the denervated striatum retains the ability to synthesize (from L-DOPA) and metabolize dopamine, to the same degree as the intact, innervated, contralateral striatum. (c) When stress is minimized, and release of dopamine is induced by electrical stimulation of the medial forebrain bundle, the catabolism of dopamine (to DOPAC and HVA) during the release-uptake cycle may not be a significant factor under physiological conditions. (d) When dopamine synthesis is increased in the striatum, the normal blood concentration of tyrosine is adequate to sustain the increased synthesis, and precursor availability is not a limiting factor. (e) These results suggest that some of the basic concepts about the neurochemical/neurophysiological regulation of monoaminergic neurones may require further reevaluation.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1990

Parenteral administration of GM1 ganglioside to presenile Alzheimer patients.

The pharmacokinetic parameters of GM1 ganglioside were examined in 16 patients (mean age 64 +/- 5 years) with Alzheimer's disease. The ganglioside was given intramuscularly and subcutaneously. The maximum GM1 blood level was reached after 48-72 h, the subcutaneous route leading to the highest blood levels, but the individual variability was relatively large. When 100 mg GM1 ganglioside was given daily for a week, maximum serum values of 15 to 20 mumol/l were found in 3 patients. The elimination half-life from serum was 60-75 h.

Aged↗
PubMed1990

Monosialoganglioside effects following cerebral ischemia: relationship with anti-neuronotoxic and pro-neuronotrophic effects.

Increasing evidence is available indicating that systemically administered GM1 is able to provide for functional recovery in different experimental models of CNS injury, including cerebral ischemia. Current evidence indicates that the GM1 effects are associated, in the acute phase, with attenuation of secondary neuronal damage due to its capability to antagonize excitatory amino acid-related neurotoxicity in vivo as in vitro. Furthermore, the ganglioside is able to facilitate occurrence of long-term reparative processes, an effect most likely reflecting the potentiation of the action of neuronotrophic factors. This bifaceted action of GM1 makes the ganglioside ideally suited for clinical treatment of patients afflicted by cerebrovascular insufficiencies.

Animals↗
PubMed1990

New perspectives in the treatment of hypoxic and ischemic brain damage: effect of gangliosides.

Aircrews operating at high G forces and altitudes may be exposed to both physiological and physical stresses capable of inducing brain hypoxia. A potential therapeutic tool for the treatment of flight personnel, monosialoganglioside (GM1) has been found to reduce deficits and enhance repair following CNS injury. A survey of experimental evidence concerning the effects of GM1 in the acute phase of CNS injury supports its proposed application for aerospace medicine.

Animals↗
PubMed1990

Hypoxic-ischemic damage and the neuroprotective effects of GM1 ganglioside.

In vitro studies have shown that monosialoganglioside GM1 reduces excitatory amino acid-related neurotoxicity by limiting the downstream consequences of abusive excitatory amino acid receptor stimulation. Systemic administration of GM1 appears to be efficacious in reducing acute neuronal damage and in facilitating medium- and long-term functional recovery after brain injury. We propose that GM1 protective effects in the acute injury phase results from attenuation of excitotoxicity, whereas the functional recovery seen at longer term could reflect GM1 potentiation of neuronotrophic factors. The potential therapeutic efficacy of GM1 administration in humans is suggested by clinical studies demonstrating improved neurologic outcome in stroke patients.

Amino Acids↗
PubMed1989

Transient forebrain ischemia produces multiple deficits in dopamine D1 transmission in the lateral neostriatum of the rat.

Striatal dopamine D1 transmission was studied in rats 7 days after transient (30 min) forebrain ischemia using the 4-vessel occlusion model. The striatal distribution of dopamine D1 ([3H]SCH 23390 binding sites) and D2 ([3H]sulpiride binding sites) receptors as well as the distribution of adenylate cyclase ( [3H]forskolin binding sites) and of the intracytoplasmic dopamine and cAMP-regulated phosphoprotein DARPP-32 related to D1 transmission were analyzed. While the distribution of D2 receptors was unaffected 7 days after the ischemic insult, all the other markers showed a patchy disappearance in the dorsolateral part of the neostriatum. These findings underline the existence of selective multiple deficits in D1 transmission after transient forebrain ischemia in rat striatum.

Animals↗
PubMed1989

Internalization of phosphatidylserine by adherent and non-adherent rat mononuclear cells.

Energy-dependent, protein-mediated incorporation of radiolabeled phosphatidylserine vesicles is observed in casein-elicited rat peritoneal cells. Cell fractionation and a comparison with other phospholipids demonstrate the selective interaction of phosphatidylserine with the mononuclear fraction of these cells. During 60 min of incubation, unchanged phosphatidylserine accumulates in the cells whereas lysophosphatidylserine is released in the medium. When adherence is used to fractionate the mononuclear cells, phosphatidylserine uptake is detected in the macrophage-enriched fraction (adherent cells) and in the lymphocyte-enriched fraction (non-adherent cells). Evidence of stereoselective uptake and of phosphatidylserine internalization in both cells is obtained by the use of phosphatidyl-D-serine and by digestion of the extracellular phospholipid with phospholipase A2. Only in lymphocytes is the uptake of phospholipid substantially inhibited by cytochalasin B, metabolic poisons and a low incubation temperature (17 degrees C). Phosphatidylserine deacylation-reacylation is instead detected in both cells. It is concluded that lymphocytes actively concur in the uptake of phosphatidylserine by rat mononuclear cells.

Animals↗
PubMed1989

Complete spinal cord transection at different postnatal ages: recovery of motor coordination correlated with spinal cord catecholamines.

The ability of rats that are cordotomized at different times between postnatal day (PN) 0-28, to recover four-limb motor coordination, varies as a function of the time of cordotomy. The rats were evaluated at 37 independent observers for four-limb coordination, scored on a scale of 10 (best) to 0 (worst). The rank order of recovery from best to worst is: PN7 greater than PN0 greater than PN14 greater than PN21 greater than PN28. The hindlimbs are active only when they receive proprioceptive sensation from contact with a surface. They appear completely paralyzed when, for example, the rats are challenged to climb an inclined surface of spaced metal bars (Fig. 4). The content of both dopamine (DA) and norepinephrine (NE) in the adult spinal cord rostral to the transection, also varied as a function of transection time. DA was present in the lumbar (that is, caudal to the transection) region of the cord in the PN0, PN7 and PN14 groups, with the highest concentration in the PN7 group. NE was not present in the lumbar region in any of the experimental groups. It is concluded that rats can recover a substantial degree of four limb motor activity after cordotomy, provided the cord is transected before the fourteenth postnatal day. Moreover, this recovery of motor coordination, apparently correlates closely with the presence of DA in the lumbar region of the cord. Whether there is a causal relationships between recovery of motor coordination and the content of DA in the lumbar cord is not known.

Animals↗
PubMed1989

Chronic phosphatidylserine treatment improves spatial memory and passive avoidance in aged rats.

Learning/memory deficits in senescent animals are widely used as a tool to evaluate the therapeutic potential of agents for treatment of age-associated cognitive dysfunction. As assessed in the Morris water maze test, aged (21-24 months) rats showed a variable loss of spatial memory. Aged non-impaired rats performed as well as young subjects, while aged impaired rats exhibited a severe and persistent place-navigation deficit. Passive avoidance retention was similarly affected in the two aged subpopulations. Chronic oral administration of phosphatidylserine (50 mg/kg/day for up to 12 weeks), a pharmacologically active phospholipid, was found to improve both the spatial memory and the passive avoidance retention of aged impaired rats. Results are discussed with reference to the phosphatidylserine-induced improvement of age-associated deterioration of brain functions in rats.

Aging↗
PubMed1989

Incorporation of exogenous ganglioside GM1 into neuroblastoma membranes: inhibition by calcium ion and dependence upon membrane protein.

Since exogenous gangliosides are known to promote neuritogenesis, the incorporation of exogenous GM1 into neuroblastoma membranes was examined. Neuro-2A cells, synchronized in the G1/G0 phase, were suspended in HEPES buffered saline containing 10(-4) M [3H]GM1, and membrane incorporation was measured as radioactivity remaining with the cell pellet following incubation with serum-containing medium and trypsin. Calcium ion (0.01 to 10 mM) reduced incorporation of exogenous GM1, due to its interaction with GM1 micelles in solution. When cells were treated with proteases prior to incubation with GM1, the inhibitory effect of Ca2+ was lost and total incorporation into membranes was lowered by approximately one order of magnitude. Pretreatment of cells with 0.05% trypsin resulted in an inhibition of GM1 incorporation within 5 minutes. When trypsinized cells were resuspended in complete growth medium, the cells recovered the ability to incorporate GM1 with time, and this paralleled labeling of cellular protein with [3H]leucine. The role of membrane protein in the incorporation of exogenous GM1 could not be explained by the lytic release of cytosolic transfer proteins nor the artifactual coating of the cell surface by serum proteins. These results suggest that the incorporation of exogenous gangliosides into cellular membrane lipid bilayers cannot be fully explained by considerations of lipophilicity alone, and leads us to propose that initial recognition by membrane protein(s) is necessary.

Animals↗
PubMed1989

Ganglioside function in the development and repair of the nervous system. From basic science to clinical application.

Gangliosides play important roles in the normal physiological operations of the nervous system, in particular that of the brain. Changes in ganglioside composition occur in the mammalian brain not only during development, but also in aging and in several neuropathological situations. Gangliosides may modulate the ability of the brain to modify its response to cues or signals from the microenvironment. For example, cultured neurons are known to respond to exogenous ganglioside with changes characteristic of cell differentiation. Gangliosides can amplify the responses of neurons to extrinsic protein factors (neuronotrophic factors) that are normal constituents of the neuron's environment. The systemic administration of monosialoganglioside also potentiates trophic actions in vivo and improves neural responses following various types of injury to the adult mammalian central nervous system. The possible molecular mechanism(s) underlying the ganglioside effects may reflect an action in modulating ligand-receptor linked transfer of information across the plasma membrane of the cell.

Animals↗
PubMed1989

Basic fibroblast growth factor promotes the survival and development of mesencephalic neurons in culture.

Neuronotrophic effects of basic fibroblast growth factor (bFGF) have been reported for some central nervous system neurons. Here we report that also rat mesencephalic neurons are responsive to bFGF. bFGF produces a significant increase in the number of neurite-bearing cells, as well as in the degree of their fiber network. The present findings also provide the first evidence that bFGF can affect, in a concentration-dependent manner, at least two defined CNS neuronal populations, i.e., dopaminergic and gabaergic neurons. This effect was quantified by assessing the specific [3H]dopamine and [gamma-14C]aminobutyric acid uptakes with time in culture. Stimulation of uptake was more pronounced for dopaminergic neurons, suggesting a relative specificity in the actions of bFGF. These effects of bFGF were completely blocked by affinity-purified polyclonal antibodies. The possibility that bFGF plays a key role in normal nervous system development or function is discussed.

Animals↗
PubMed1989

Effects of intraventricularly applied gangliosides and N-acetylneuraminic acid on acquisition and retention performance of a brightness discrimination task in rats.

The effects of intraventricularly applied gangliosides (about 90 to 120 nmoles/10 microliters) and N-acetylneuraminic acid (800 nmoles/10 microliters) on acquisition and retention of a brightness discrimination task were studied in rats. Single injection of GT1b and N-acetylneuraminic acid improved the retention performance. GM1 showed an enhancing effect on both acquisition and retention, while GD1a and GD1b exerted no influence on the behavioral parameters tested. The findings presented show how memory may be improved by exogenous application of substances commonly occurring in the mammalian body.

Animals↗