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Biomedical subjects

G Toffano

Publications and source records attributed to G Toffano.

At least 109 records · Page 6Linked to original sources
PubMed1984

Effects of gangliosides on the functional recovery of damaged brain.

The effect of GM1 ganglioside on the recovery of dopaminergic nigro-striatal neurons was studied in rats after unilateral hemitransection. GM1 treatment favoured the collateral sprouting of dopaminergic axons in the striatum as indicated by the induced increase of tyrosine hydroxylase (TH) activity and immunofluorescence. Concomitantly GM1 partially prevented the decrease of TH activity caused by the hemitransection in the substantia nigra ipsilateral to the lesion. A significant increase of TH immunoreactivity was also detected in the substantia nigra: GM1 prevented the disappearance of TH-positive cell bodies and increased the formation of TH-positive collaterals and dendrites with respect to the saline treatment. The addition of GM1 to embryonic dissociated mesencephalic cell cultures stimulates the expression of dopaminergic characteristics as suggested by the increase of 3H-DA uptake.

Animals↗
PubMed1984

Synergistic effect of phosphatidylserine with gamma-aminobutyric acid in antagonizing the isoniazid-induced convulsions in mice.

The influence of phosphatidylserine (PS) on the isoniazid-induced convulsions has been studied in mice. Sonicated dispersions of this phospholipid given intravenously do not show anticonvulsant activity but they do so when gamma-aminobutyric acid (GABA) is simultaneously injected. GABA alone is inactive. The synergism between PS and GABA is influenced by the structure of the phospholipid liposomes. In contrast to multilamellar vesicles, oligolamellar vesicles are active. Under these conditions the effect shows head group specificity, in that the neutral phosphatidylcholine (PC) or the acidic phosphatidylinositol (PI) are inactive, either in the presence or in the absence of GABA. Lysophosphatidylserine (lysoPS), the deacylated PS derivative, shows increased efficacy as an isoniazid antagonist in the presence of GABA, and has anticonvulsant activity also in the absence of GABA. Other lysophospholipids are inactive. It is suggested that PS, after its metabolic conversion to lysoPS, enhances the anticonvulsant effect of GABA.

Animals↗
PubMed1984

Modulation of lysophosphatidylserine-dependent histamine release.

Apomorphine (2-30 microM) inhibits lysophosphatidyl-serine-dependent histamine release in rat and mouse peritoneal mast cells. The drug-induced inhibition is influenced by the concentration of lysophosphatidylserine. Log concentration-response curves show a surmountable type of antagonism between the two compounds.

Animals↗
PubMed1984

Local effects of lysophosphatidylserine in rats.

To study the inflammatory properties of lysophosphatidylserine (a phospholipid acting as a histamine releaser), rats were subjected to local treatment with this compound. In the paw a rapid and dose-dependent edematous reaction occurred within 30-60 min (ED50 2.5 micrograms/rat). The effect was dependent on the intact configuration of serine head group since lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidic acid and N-acetimidyl-lysophosphatidylserine were uneffective. Indomethacin produced a weak inhibition but chlorpheniramine and cyproheptadine inhibited 50 and 70%, respectively. Consistently, the histamine stores of the paw were found to be decreased at the end of the lysophosphatidylserine effect. Increase in vascular permeability was observed also after the injection of lysophosphatidylserine into the dorsal skin and pleural cavity although the phospholipid was less effective in these regions. The fluid extravasation in the pleural cavity was 75% prevented by cyproheptadine. Parallel in vitro experiments showed that the effect of lysophosphatidylserine on isolated pleural and peritoneal mast cells is increased when a leukocyte lysate was also added. After centrifugation the activity was retained in the insoluble fraction. It is concluded that lysophosphatidylserine, injected locally, elicits an inflammatory reaction mediated by the components of mast cell granulus. The response may be amplified by the migration of other inflammatory cells into the exudate.

Animals↗
PubMed1984

Different responses of rodent mast cells to lysophosphatidylserine.

The lysophosphatidylserine-induced activation of mast cells has been studied in preparations obtained from different rodents. In mouse and gerbil peritoneal mast cells lysophosphatidylserine behaves as an agonist, inducing noncytotoxic histamine release at 0.2-8 microM. In rat peritoneal and pleural mast cells lysophosphatidylserine is ineffective, but the histamine-releasing activity becomes manifest upon the addition of suboptimal concentrations of other mast cell activators. The common structure-activity relationship shows the link between these effects of lysophosphatidylserine but the calcium requirement indicates differences in the mechanism of action. Histamine release in mouse mast cells is independent of external calcium. Thus, lysophosphatidylserine induces mobilization of endogenous calcium stores in these cells. By contrast, histamine release in gerbil and rat mast cells is dependent on the addition of external calcium indicating that the phospholipid promotes calcium influx. While in gerbil mast cells calcium influx is promoted by lysophosphatidylserine alone, in rat it requires the combined action of the phospholipid and other mast cell agonists. Differently from lysophosphatidylserine, compound 48/80 elicits histamine release in rat and gerbil mast cells. Mouse mast cells are unaffected. Thus, gerbil mast cells are the only preparation in which the action of these two agonists can be observed simultaneously.

Animals↗
PubMed1984

Lysophosphatidylserine as histamine releaser in mice and rats.

Lysophosphatidylserine is a specific inducer of histamine release in isolated mast cells. To determine whether a similar effect is manifest in vivo, the phospholipid was injected (1-5 mg/kg i.v.) into mice and rats. A dose-dependent rise in blood histamine was observed in both animals. The several-fold increase in blood histamine occurred in the first minutes and was followed by a slower decline toward normal values. A second dose of lysophosphatidylserine was without effect. Systemic manifestations (depression, hypothermia, hypotension) were associated with the increased blood histamine level. When the tissue histamine stores accessible to lysophosphatidylserine were previously decreased by repeated phospholipid injections, no systemic symptoms occurred. Mobilization of carbohydrate reserves was also manifest during the action of lysophosphatidylserine. Prior treatment with compound 48/80 induced sustained refractoriness to lysophosphatidylserine. Structure-activity relationship demonstrated that the property to induce histamine release was linked to the structure of serine head group. Thus, other natural phospholipids or lysophospholipids were inactive. It is concluded that in analogy with the effect seen in vitro lysophosphatidylserine produces in vivo release of mast cell histamine.

Adrenalectomy↗
PubMed1984

Depletion and recovery of neuronal monoamine storage in rats of different ages treated with reserpine.

The effect of reserpine on dopamine, noradrenaline, adrenaline and serotonin concentrations in different brain regions, and the recovery of normal levels of these monoamines after such treatment were studied in rats aged 5, 15 and 27 months. In a preliminary experiment we found that distribution of the drug was not altered in the aged rats. Then we observed that a single dose of reserpine (5 mg/kg IP) had a similar depleting effect on all the brain monoamines, in all the brain regions considered in all three age groups. The curves expressing recovery of monoamine storage in all the nerve terminals, several days after treatment, were superimposable. These results suggest that in the rat, age does not influence the effect of reserpine on the storage mechanism of brain monoamines. Moreover, as restoration of this mechanism depends on the synthesis of new vesicles, the similarity in the rates of recovery in adult, old and very old rats indicated indirectly that synthesis of these neuronal organelles is not affected by aging.

Aging↗
PubMed1984

Effects of phosphatidylserine on avoidance relearning in rats (preliminary observations).

During six learning sessions in a shuttle-box avoidance situation, male Sprague-Dawley rats show two kinds of learning efficiency which allow for dividing them in the subgroups of high-responding (HR) and low-responding (LR) animals. The effect of phosphatidylserine, a pharmacologically active phospholipid obtained from bovine brain, has been studied on the relearning phase of these two populations of rats. Chronic administration of phosphatidylserine (15 mg/kg i.p. for 30 days) significantly increased the avoidance performances of LR animals, without changing those of HR rats. The results obtained suggest that the different behavioral response to the phosphatidylserine treatment may depend on the pre-drug baseline of avoidance learning capability and on the effect that the drug exerts on some brain neurotransmitter metabolism.

Animals↗
PubMed1984

Promotion of neuritogenesis in mouse neuroblastoma cells by exogenous gangliosides. Relationship between the effect and the cell association of ganglioside GM1.

Ganglioside GM1 promoted neuritogenesis of neuroblastoma cells, neuro-2a clone, in monolayer culture. GM1 bound to neuro-2a cells in three distinct forms, one removable by treatment with serum-containing solutions, one serum-resistant and labile to trypsin treatment, and one resistant to serum and trypsin treatments. The proportions among the three forms of cell-associated GM1 varied in relation to duration of exposure to ganglioside, ganglioside concentration in the medium, and number of cells in culture. The form removable by serum was predominant at the initial stages of association and at the highest ganglioside concentrations (over 10(-6)M); the trypsin-labile and -stable forms tended to increase with increasing cell number and decreasing ganglioside concentration. The neuritogenic effect of GM1 was higher when neuro-2a cells were incubated for 24 h in the presence of GM1 and fetal calf serum. Under this condition the percentage of neurite-bearing cells increased from 11% of control to 62% at the optimal ganglioside concentration of 10-4M. The effect was still present, although to a lower extent (from 11% to 28% of neurite-bearing cells), when cells were first exposed for only 2 h to GM1, then washed and incubated for 24 h in the presence of fetal calf serum. The trypsin-labile and -stable forms of cell-associated GM1 had a fundamental role in the effect, whereas the form removable by serum was not involved. The preparation of GM1 used was extremely pure (99%) and, in particular, had a peptide contamination, if any, less than 1:20,000-1:50,000.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Effect of GM1 ganglioside treatment on the recovery of dopaminergic nigro-striatal neurons after different types of lesion.

The effect of GM1 ganglioside treatment on the recovery of biochemical and behavioral parameters which define the activity of nigro-striatal dopaminergic systems has been investigated in rats after different types of lesion. GM1 favours the recovery of tyrosine-hydroxylase activity, of the number and affinity of 3H-N-n-propyl-norapomorphine binding sites in the striatum of the lesioned side and reduces the apomorphine-induced rotational behavior after mechanical (i.e. unilateral hemitransection) but not after chemical (i.e. 6-OHDA injected in the substantia nigra) lesion. The source of regrowing dopaminergic nerve terminals in the striatum after hemitransection is mainly a response of intact remaining axons of the ipsilateral side. Moreover the contralateral nigro-striatal systems seems to play, through intrathalamic connections, an important role in regulating the GM1-induced increase of the tyrosine-hydroxylase activity.

Animals↗
PubMed1984

Studies on aging processes.

By means of computer assisted morphometry and microdensitometry it has been possible to characterize aging processes in transmitter identified neurons demonstrated at the presynaptic level by immunocytochemistry and at the postsynaptic level by receptor autoradiography. Three-month- and 24-month-old rats were used in the present study. It was discovered that the DA neurons innervating the striatum and nucleus accumbens underwent degeneration in the aging brain both at the pre- and post-synaptic level, while the DA synapses within the tuberculum olfactorium remained intact. In this quantitative receptor autoradiographical analysis 3H-spiperone and 3H-N-propyl-norapomorphine were used as radioligands for DA receptors. In comparison with the aging induced changes in DA receptors in the striatum and in the nucleus accumbens the alpha 2- and the beta-adrenergic receptors appeared to be more resistant to the aging process. In the analysis of the opiate receptors of the aging brain it could be demonstrated by quantitative receptor autoradiography using both radioligands for the mu-type (3H-etorphin) and delta-type (3H-d-ala2-d-leu5-enkephalin) of opiate receptors that there is a marked and widespread disappearance of both types of opiate receptors in the aging brain. It must be emphasized that no correlation exists in the degeneration pattern of the mu- and delta-type of opioid receptors indicating that they may represent two separate entities with separate trophic regulation. In contrast, it was discovered in the quantitative receptor autoradiographical analysis that 3H-flunitrazepam binding was increased in many areas of the aging brain compared with the adult rat brain. These results underline the heterogeneity in the degenerative patterns which take place in transmitter receptors in relation to aging. Thus, these results indicate that the simple replacement therapy in aged patients may not give optimal results. As a matter of fact, such treatments can lead to a further unbalance between the various types of transmitter identified neurons building up the neuronal networks of the brain, which are undergoing degeneration.

Aging↗
PubMed1984

Further studies on the effects of the GM1 ganglioside on the degenerative and regenerative features of mesostriatal dopamine neurons.

By means of computer assisted morphometry and microdensitometry the effects of chronic GM-1 ganglioside treatment have been further evaluated on the degenerative and regenerative features of mesostriatal DA neurons in the rat brain. In this study mainly a rostrocaudal morphometrical analysis was performed in the substantia nigra of the lesioned side. The specificity of the action of the GM-1 ganglioside on the substantia nigra DA cells was evaluated by a comparison with antiinflammatory drugs such as betametazon and acetylsalicylic acid. In the rostrocaudal analysis it was demonstrated that chronic GM-1 treatment preferentially protected the caudally located dopamine nerve cells from degeneration after partial hemitransection, while instead this chronic GM-1 treatment increased tyrosine hydroxylase immunoreactivity mainly within the rostrally located DA nerve cells present close to the site of the lesion. Furthermore, the specificity of the GM-1 action was demonstrated by the absence of protective effects of chronic treatment with betametazon and acetylsalicylic acid on the dopamine nerve cells of the lesioned side. These results open up the possibility that chronic GM-1 treatment, by exerting a stimulatory metabolic action on the DA nerve cells located close to the lesion, can enhance the production of neurotrophic factors in these cells, which in turn can diffuse out to increase the survival of the less severely lesioned DA nerve cells located in the caudal part of the substantia nigra. These results indicate that chronic GM-1 treatment may be beneficial in the treatment of neurons undergoing degeneration, which takes place e.g. in Parkinson's disease and after mechanical injury to the brain due to accidents or neurosurgical operations.

Animals↗
PubMed1983

Chronic ganglioside treatment counteracts the biochemical signs of dopamine receptor supersensitivity induced by chronic haloperidol treatment.

Chronic ganglioside treatment (10 mg/kg, i.p.) using the molecular species with only one neuroaminic acid residue (GM1) given together with haloperidol (0.3 and 5 mg/kg, i.p.) once daily in male rats, counteracted the haloperidol-induced increase in the number of [3H]spiperone binding sites in striatal membranes when the low dose of haloperidol, but not the high dose, was administered. The present results therefore indicate that chronic GM1 treatment can partially counteract the increase in the number of dopamine receptors having a high affinity for neuroleptics (D2 type) induced by chronic haloperidol treatment in striatal membranes, and therefore may also partially counteract the development of neuroleptic-induced dopamine receptor supersensitivity.

Animals↗
PubMed1983

Calmodulin content in different brain areas of aging rats.

An age-related decrease of calmodulin content was detected in the striatum, cerebral cortex and cerebellum of 3-, 22- and 30-month-old rats. This age-related decrease of calmodulin level occurred both in the supernatant and in the pellet fraction of high speed centrifuged tissues. However, the rates of age-dependent calmodulin loss in the pellet and supernatant fraction were differentiated according to the cerebral region considered, suggesting a different brain area sensitivity to the aging process.

Age Factors↗
PubMed1983

Biochemical changes of rat brain membranes with aging.

Modification of membrane composition and enzymatic activities both in total brain homogenate and purified synaptic plasma membrane of 3 and 24 month old rats has been investigated. Protein, cholesterol and phospholipid content and (Na+, K+)ATPase and 2',3' cyclic nucleotide phosphohydrolase activities were determined. The major changes occurred in the whole homogenate where a general increase in total protein and cholesterol content with age and a significant increase of the cholesterol/phospholipids molar ratio has been detected. In S.P.M. aging process induced a decrease of protein, cholesterol and phospholipids content associated with an increased membrane viscosity and a decrease of delta E. These data are consistent with a change in the structural organization and in the distribution pattern of different cell population in the aging brain. A possible artifactual effect of freezing on the reported parameter is also discussed.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗
PubMed1983

Phospholipid methylation increases [3H]diazepam and [3H]GABA binding in membrane preparations of rat cerebellum.

The effect of phospholipid methylation on both [3H]diazepam and [3H]GABA ( [3H]gamma-aminobutyric acid) binding to crude synaptic plasma membrane from rat cerebellum has been studied. S-Adenosylmethionine (SAM) stimulates [3H]methyl group incorporation into membrane phospholipids and enhances [3H]diazepam binding by increasing the apparent Bmax. Conversely, inhibition of [3H]methyl group transfer from [3H]SAM to phospholipids by preincubation with SAM at 0 degrees C or with SAH abolishes the increase of binding. After preincubation with SAM, analysis of the GABA binding reveals the presence of binding sites with high affinity, a property absent in control membranes preincubated without SAM. Among the neurotransmitter bindings tested, only those of GABA and benzodiazepine in the cerebellum and beta-adrenergic ligands in the cerebral cortex are enhanced upon stimulation of phospholipid methyltransferase activity. [3H]Dihydromorphine, [3H]dihydro-alpha-ergokryptine and [3H]spiroperidol bindings are not affected by SAM. The present data suggest an involvement of phospholipid methylation in regulation of both [3H]GABA and [3H]-diazepam binding.

Animals↗