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Biomedical subjects

M Cimino

Publications and source records attributed to M Cimino.

72 records · Page 4Linked to original sources
PubMed1985

Effects of ganglioside GM1 treatment on striatal glucose metabolism, blood flow, and protein phosphorylation of the rat.

Effects of ganglioside GM1 administration have been studied in unilaterally partially hemitransected rats on striatal energy metabolism, using the radioactive deoxyglucose (DG) technique, on striatal blood flow, using radiolabelled iodoantipyrine (IAP) as tracer, and on cyclic AMP (cAMP) and Ca2+ induced protein phosphorylation in striatal membranes (P2 fraction). Ganglioside GM1 treatment counteracted the imbalance in striatal energy metabolism, in striatal blood flow, as well as in protein phosphorylation found between the striata of the lesioned and unlesioned side, possibly due to excitatory effects on the lesioned side and inhibitory effects on the unlesioned side. In intact animals, GM1 treatment produced a reduction in cAMP and Ca2+ induced striatal protein phosphorylation. Facilitatory actions of the ganglioside GM1 dominate following a lesion, probably due to its possible function as a modulator of receptors for neuronotrophic factors, leading to restoration of metabolic rate and of cAMP and Ca2+ induced protein phosphorylation in the striatum of the lesioned side. The results emphasize that ganglioside GM1 treatment can restore the metabolism of a partially innervated striatum towards normal, as evaluated both at the level of the entire striatal structure by means of the DG and IAP techniques and at the molecular level by means of studies on the cAMP and Ca2+ induced protein phosphorylation.

Animals↗
PubMed1984

In vivo and in vitro evidence of dopaminergic system down regulation induced by chronic L-DOPA.

The biochemical modifications which occur in the dopaminergic system after chronic administration of L-DOPA are investigated. Levels of DA and of its metabolite 3-methoxytyramine (3-MT), an expression of the amount of DA released, were raised to the same extent in controls given a single dose of 1-DOPA and in chronically treated rats given 100 mg/kg of 1-DOPA plus 25 mg/kg of benserazide twice a day for 24 days. However, the reduction in neuronal function expressed by the decrease in 3-MT which follows treatment with DA agonists such as piribedil and apomorphine was less pronounced in the chronically L-DOPA treated rats. This suggests that such treatment causes a down regulation of DA receptors. These in vivo results were confirmed by in vitro analysis of DA receptor activity after chronic L-DOPA. Under these conditions there was a significant reduction in the number of [3H]-spiperone and [3H]-ADTN binding sites with no changes in their affinity. The in vivo and in vitro findings both suggest the involvement of a subsensitive compensatory mechanism or down regulation of dopaminergic neurons after chronic treatment with L-DOPA.

Animals↗
PubMed1984

Age-related modification of dopaminergic and beta-Adrenergic receptor system: restoration to normal activity by modifying membrane fluidity with S-adenosylmethionine.

Microviscosity of membranes prepared from striata and cortex of 3 or 30-month-old rats was measured by fluorescence polarization and electron spin resonance. The viscosity of the hydrophobic core of the lipid bilayer was significantly increased in striatal but not in cortical membranes of old rats. In old rats the incorporation of methyl groups into phosphatidylcholine was significantly lower than in young rats. beta-Adrenergic specific binding sites were reduced in striata, cortex and pineal gland of old rats. In the striata of these animals, [3H] spiperone specific binding sites and dopamine-stimulated adenylate cyclase were also low. A chronic treatment of old rats with S-adenosyl-L-methionine, the cofactor in phospholipid methylation, lowered microviscosity to normal values in striata but not in the cortex. In the same old rats, the beta-receptor in striata and pineal gland returned towards juvenile values; in the cortex, the modification was in the same direction but did not reach significance. Neither putative dopaminergic receptors nor the adenylate cyclase age-dependent decrease was modified by treatment with S-adenosyl-L-methionine.

Aging↗
PubMed1984

Biochemical effects of minaprine on striatal dopaminergic neurons in rats.

The biochemical effects of minaprine, a new psychotropic drug, were investigated on striatal dopaminergic neurons in the rat. Minaprine did not displace [3H]spiperone in-vitro binding from striatal membranes but had clear effects on dopamine (DA) metabolites. Homovanillic acid (HVA) and dihydroxyphenylacetic acid (DOPAC) were significantly decreased in a dose-dependent manner after intraperitoneal administration of minaprine 30 min before killing. In rats injected with minaprine 15 mg kg-1 i.p. at different intervals, the decrease in striatal HVA and DOPAC was time-dependent and a concomitant rise in 3-methoxytyramine (3-MT) concentrations was observed. The maximum of these effects was reached 30 min after minaprine. When administered 5 min after a monoamineoxidase (MAO) inhibitor (pargyline, 100 mg kg-1 i.p.) and 30 min before killing, minaprine did not affect pargyline-induced changes in HVA, DOPAC and 3-MT levels. This together with other data suggests that minaprine affects DA metabolism by acting, at least partially, at presynaptic level through in-vivo inhibition of MAO 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↗
PubMed1983

Dopaminergic effects of buspirone, a novel anxiolytic agent.

The novel anxiolytic drug buspirone raised striatal levels of the dopamine metabolites homovanillic acid (HVA) and dihydroxyphenylacetic acid (DOPAC) 1 hr after oral administration. This effect was dose-dependent with a peak at 60 min. No changes were observed in the levels of 3-methoxytyramine (3MT), the extraneuronal metabolite of dopamine. Noradrenaline, serotonin and its metabolite 5-hydroxyindoleacetic acid (5HIAA) were not affected. Buspirone displaced [3H]spiroperidol from striatal binding sites, with an IC50 (1.8 x 10(-7) M), comparable to that of clozapine (IC50 = 1.4 x 10(-7) M) but considerably lower than that of haloperidol (4.7 x 10(-9) M). Buspirone was only a weak inhibitor of dopamine-stimulated adenyl cyclase. Buspirone was not active on the binding of trifluoperazine to calmodulin and did not modify calmodulin-induced activation of phosphodiesterase (PDE). Repeated administration of buspirone did not increase the number of DA receptors. These data show that, although buspirone has antidopaminergic activity, it can hardly be classified as a classic neuroleptic agent.

Animals↗
PubMed1983

Effects of systemic and intracerebroventricular domperidone treatment on striatal and hypothalamic dopaminergic neurons.

In this study we compared the effects of systemic administration of haloperidol (HAL), a typical dopaminergic antagonist and of domperidone (DOM), a dopamine (DA) receptor blocker which does not cross the blood brain barrier but has a potency similar to HAL at DA receptors, on hypothalamic and striatal DA system turnover (evaluated by means of HVA and DOPAC levels) and prolactin (PRL) secretion in male rats. In accordance with previous data, we found that HAL (1 mg/kg, i.p.) raised DOPAC and HVA levels whereas DOM (1 mg/kg, i.p.) did not alter DA turnover in striatum. Both DOM and HAL affected the hypothalamic DA system, increasing DOPAC levels in a pattern similar to that observed in PRL secretion. An intracerebroventricular (icv) injection of DOM and HAL (4 micrograms/10 microliters/rat) was then made to investigate its effect on DA turnover in this experimental condition at striatal and hypothalamic level. DOM stimulated DA turnover a little in the striatum though its action was delayed; no effects were seen on HVA and DOPAC concentrations in the hypothalamus at any of the tested times. On the other hand, an equal amount of HAL induced an increase in striatal HVA and DOPAC levels, with no significant effects on hypothalamic DA metabolites. These results show that systematically administered DOM and HAL may affect the hypothalamic tuberoinfundibular DA system, probably acting through PRL release. Furthermore DOM, even when injected icv, shows only weak antidopaminergic action on DA turnover in both central areas.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1980

Pharmacological regulation of calmodulin.

A number of psychotropic drugs, particularly the phenothiazines and related antipsychotic compounds, inhibit a variety of calmodulin-dependent enzymes. The mechanism by which these compounds inhibit the activity of calmodulin is through a selective calcium-dependent binding to this protein. With the notable exception of certain stereoisomers, compounds that are clinically effective antipsychotic agents showed the greatest degree of binding to calmodulin. Other classes of pharmacological agents, including aminergic agonists and antagonists, and nonspecific central nervous system depressants and stimulants, showed little or no binding to calmodulin. In fact, the specificity with which antipsychotic drugs bind to calmodulin suggests the possibility of screening for new and clinically more effective antipsychotic agents based on their selective binding to calmodulin. Certain neuropeptides that produce behavioral effects in animals also were found to inhibit the activity of calmodulin, suggesting that there may be endogenous psychotogens or antipsychotic peptides that interact with calmodulin. Although under ordinary conditions the binding of antipsychotics to calmodulin is reversible, the binding of phenothiazine antipsychotics to calmodulin can be made irreversible either photochemically by ultraviolet irradiation, or enzymatically by a hydrogen peroxide-peroxidase system. Such a labeling technique should prove to be a useful tool to study the localization and turnover of calmodulin. These results indicate that several of the diverse biochemical actions of antipsychotic agents can be explained by a common mechanism, namely, by their binding to and inhibition of calmodulin, and raise the possibility that calmodulin may serve as one of the cellular receptors for certain antipsychotic compounds. However, further studies must be completed before we can state with any degree of certainty that these in vitro biochemical findings can explain the pharmacological and clinical actions of the antipsychotics.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1980

Acute and chronic effects of psychoactive drugs on adrenergic receptors and calmodulin.

The effects that psychoactive compounds have on those biochemical mechanisms of brain that influence the metabolism of cyclic nucleotides depend on whether the drugs are administered acutely or chronically. For example, antipsychotic agents acutely block the action of catecholamines on the adrenergic receptor-adenylate cyclase complex, thereby preventing the catecholamine-induced rise in cyclic AMP. But with long-term treatment, which might correspond more closely to the manner in which they are used clinically, the drugs appear to produce a compensatory increase in these catecholaminergic receptors. Repeated stimulation of adrenergic receptors with compounds that block the uptake of catecholamines, such as the antidepressants, produces a decrease in the number of these receptors and a concomitant subsensitivity to the effects of catecholamines on the formation of cyclic AMP. This is in contrast to their acute actions which result in a potentiation of the action of catecholamines. In addition to their effects on catecholamine receptors, clinically-effective antipsychotic drugs also bind to an endogenous calcium-dependent protein termed calmodulin, which is found in high concentrations in the CNS. This binding of antipsychotics to calmodulin can explain several of their biochemical actions and suggests that some of the pharmacological and perhaps clinical effects of these drugs may also be explained by a common mechanism. In fact, the specificity with which antipsychotic drugs bind to calmodulin suggests the possibility of searching for new and clinically more effective antipsychotic agents based on their selective binding to calmodulin.

Adenosine Triphosphatases↗
PubMed1975

Interaction of nerve growth factor with tubulin. Studies on binding and induced polymerization.

The interaction of the nerve growth factor with the neurotubule protein has been studied with the aim of elucidating the nature of the large complexes that they form when incubated together and the factors and control this event. The results show that the binding of nerve growth factor to tubulin is followed by the formation of large structures that, in certain experimental conditions, accelerate the rate of tubulin polymerization to form microtubules or catalyze their assembly in conditions where this process does not occur spontaneously. The formation of large nerve growth factor-tubulin complexes starts to occur only at a molar ratio of 1.0-1.5 NaCL or GTP strongly inhibit this proceed without a detectable effect on NGF binding. Two hypotheses are postulated explain these findings. Firstly, that tubulin has two sites with different affinity for nerve growth factor and the polymerization occurs only when the second NGF molecule has interacted with the microtubule protein. Alternatively, free tubulin in solution is the polymerization by hindering site of tubulin-factor complexes present in solution at a 1.1 molar ratio. In both cases, GTP, Na-+ or H-+ will affect the formation of large unsoluble, tubulin-NGF complexes, by changing their conformation or by decreasing electrostatic interactions.

Animals↗
PubMedDate not supplied

Levels of NGF, p75NGFR and ChAT immunoreactivity in brain of adult and aged microencephalic rats.

Methylazoxymethanol (MAM)-induced microencephalic aged animals with reduced cortical mass and unmodified basal nucleus were used to study the relationship between cells that produce and cells that utilize NGF. Total cortical ChAT activity of MAM 2, 19 and 27 month old animals was reduced compared to their age-matched controls. To verify whether the reduction of enzyme activity can be ascribed to changes in or ablation of projecting neurons, we carried out immunohistochemical analysis of ChAT and low affinity NGF receptor (p75NGFR) in the basal nucleus of control and MAM-treated animals. ChAT and p75NGFR immunostaining of basal forebrain cholinergic neurons showed morphological changes in MAM animals, as revealed by cellular atrophy, reduced dendritic arborization and decreased staining intensity. In the cerebral cortex of microencephalic animals, reduced levels of NGF compared to controls were observed at all examined ages. These results suggest that MAM treatment induces long-lasting ablation of cortical NGF-synthesizing cells leading to reduced trophic support to basal forebrain cholinergic neurons, which might be responsible for the cellular atrophy observed in the basal nucleus.

Aging↗
PubMedDate not supplied

In situ hybridization histochemistry as a tool to study gene expression and its regulation in the central nervous system.

The recent application of in situ hybridization histochemistry to neuroanatomy, neuroendocrinology, and neuropharmacology has permitted explorations into the regulation of gene expression in the central nervous system (CNS) at the level of single neurons. Although cDNAs were the first probes to be used in hybridization studies, cRNAs and synthetic oligonucleotides have been recently employed because of the many advantages these single-stranded probes offer compared to the cDNAs. Using synthetic oligonucleotides, we described the distribution of the calmodulin mRNA and the regulation of proenkephalin mRNA in the rat brain. The results reported show the specificity of the hybridization and that the levels of calmodulin mRNA are more abundant in the cerebral cortex than in the striatum. Furthermore, we demonstrated that the administration of 6-hydroxydopamine in early postnatal life induces an increase in the expression of striatal proenkephalin mRNA measured at postnatal day 32.

Amino Acid Sequence↗
PubMedDate not supplied

Prenatal exposure to ethanol causes differential effects in nerve growth factor and its receptor in the basal forebrain of preweaning and adult rats.

In this study we investigated nerve growth factor (NGF) levels in the cortex and hippocampus of the offspring of pregnant female Sprague-Dawley rats receiving a single intragastric administration of acute ethanol on the 15th day of gestation and compared them with a control group of rats that received an injection of sucrose. We also examined the distribution of the low-affinity NGF receptor, p75NGFR, on NGF-responsive neurons that are localized in the septum and the nucleus of Meynert, which receive the respective trophic support from the hippocampus and the cortex. In the ethanol-treated group, the results show that at post-natal age 15 days, the NGF septohippocampal pathways were markedly affected. At day 15, the NGF level was significantly higher in the offspring of ethanol-treated rats. By day 40, NGF values in both groups decreased to similar levels. At day 60, however, the NGF level in the ethanol-treated animals decreased to a significantly lower value than that of the control group, which remained essentially unchanged. In parallel, at day 60 the numbers of septal cholinergic neurons expressing p75NGFR were also significantly lower in ethanol-treated rats than in control animals. Because ethanol is known to induce neurological disorders, as well as deficits in cell proliferation and differentiation, the results suggest that one cause of the deleterious effects induced by ethanol is the low availability of NGF during certain stages of postnatal brain development.

Animals↗