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Biomedical subjects

M Miele

Publications and source records attributed to M Miele.

At least 55 records · Page 3Linked to original sources
PubMed1994

The physiologically induced release of ascorbate in rat brain is dependent on impulse traffic, calcium influx and glutamate uptake.

Extracellular brain ascorbate fluctuates with neuronal activity. There is previous evidence that the release of ascorbate is triggered by the re-uptake of neuronally released glutamate. This hypothesis predicts that drugs which block the release and re-uptake of glutamate will also block the release of ascorbate. In the present experiments we have used a novel dialysis electrode which allows continuous monitoring of physiologically induced ascorbate release from the striatum in freely moving rats. An infusion of the enzyme ascorbic acid oxidase abolished the increase in oxidation current in response to tail-pinch, which identified it as an ascorbate current. Perfusion with tetrodotoxin reduced the response to 25% and with CdCl2 to 4% of control. Perfusion with the uptake blocker L-trans-pyrrolidine-2,4-di-carboxylate reduced the response to 24% of control. A neuroprotective function for this coupling of ascorbate and glutamate release is discussed.

Animals↗
PubMed1993

Correlation between 1-methyl-4-phenylpyridinium ion (MPP+) levels, ascorbic acid oxidation and glutathione levels in the striatal synaptosomes of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated rat.

In 6-month-old male Wistar rats, levels of dopamine (DA), dihydroxyphenylacetic acid (DOPAC), ascorbic acid (AA), dehydroascorbic acid (DHAA), uric acid, glutathione (GSH) and 1-methyl-4-phenylpyridinium ion (MPP+) were determined by HPLC in the crude striatal synaptosomal fraction after single injections of MPTP 35 mg/kg i.p. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced a 32.5% death rate within 15 min to 10 h. Groups of surviving rats were sacrificed 1, 3, 8 and 24 h after MPTP. MPTP significantly increased levels of DHAA and uric acid and decreased levels of DOPAC and GSH. Individual synaptosomal levels of MPP+ were correlated inversely with DOPAC (r = -0.601, P < 0.002) and GSH levels (r = -0.496, P < 0.02) and directly with levels of uric acid (r = +0.627, P < 0.001); these latter, in turn, were correlated with DHAA (r = +0.418, P < 0.05) and GSH levels (r = -0.357, P = 0.07). In conclusion, the response of the endogenous antioxidant system (increase in AA oxidation, decrease in GSH levels) correlates well with the MPTP-induced increase in uric acid levels and provides further evidence for a mechanism of MPTP neurotoxicity involving oxidative stress produced by xanthine oxidase.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1993

Effects of ageing on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxic effects on striatum and brainstem in the rat.

In 3- and 18-month-old male Wistar rats, levels of dopamine (DA), dihydroxyphenylacetic acid (DOPAC), ascorbic acid (AA), dehydroascorbic acid (DHAA), noradrenaline (NA), uric acid, glutathione (GSH) and 1-methyl-4-phenylpyridinium ion (MPP+) were determined by HPLC in the striatum and/or in the brainstem 24 h after single injections of MPTP (12-35 mg/kg i.p.). Aged rats had lower baseline levels of AA and GSH, compared to young rats. In aged rats, MPTP 35 mg/kg induced a 70% death rate and a decrease in striatal DOPAC/DA ratio which was significantly correlated to MPP+ concentrations (r = -0.840, P < 0.005); in addition, MPTP did not increase AA oxidation. In the brainstem, the MPTP-induced decrease in NA levels and increase in uric acid levels were significantly correlated to the MPP+ concentrations (r = -0.709, P < 0.05, and r = +0.888, P < 0.001, respectively). In conclusion, evidence is given of a mechanism of toxicity of MPTP involving oxidative stress produced by xanthine oxidase; in addition, in aged rats the neuronal antioxidant system (levels of AA and GSH) is considerably lower than in young rats and may play an enabling role in the MPTP age-related neurotoxic effects on striatum and brainstem.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1992

Effects of cortical ablation on apomorphine- and scopolamine-induced changes in dopamine turnover and ascorbic acid catabolism in the rat striatum.

Levels of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), ascorbic acid and dehydroascorbic acid (DHAA) were measured by HPLC in the striatum of rats whose fronto-parietal cortex had been unilaterally ablated after a single injection of apomorphine (1 mg/kg s.c.), scopolamine (0.6 mg/kg s.c.) or L-glutamate (500 mg/kg i.p.). Unilateral cortical ablation decreased striatal levels of glutamate in both striata ipsilateral (35%) and contralateral (17-25%) to the lesion. Apomorphine and scopolamine significantly increased (+94 and +122%, respectively) the DHAA/ascorbic acid ratio in the striata ipsilateral to the lesion in unoperated and sham-operated rats (+72 and +34%, respectively), but both drugs failed to increase it in ablated rats. L-Glutamate significantly increased the DHAA/ascorbic acid ratio in unoperated (+53%) and ablated rats (+37%). The increase in sham-operated rats (+34%) did not reach statistical significance. Apomorphine and scopolamine significantly decreased the DOPAC/DA ratio in the striata ipsilateral to the lesion of unoperated, sham-operated and ablated rats. The decrease in the DOPAC/DA ratio induced by apomorphine and scopolamine was greater in ablated rats than in sham-operated rats. L-Glutamate induced only minor changes in striatal DA and DOPAC levels. We conclude that the apomorphine- and scopolamine-induced increase in ascorbic acid oxidation in the striatum requires intact cortico-striatal glutamatergic pathways. Cortical ablation potentiates the apomorphine- and scopolamine-induced inhibition of striatal DA turnover.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1992

The effects of cortical ablation on d-amphetamine-induced changes in striatal dopamine turnover and ascorbic acid catabolism in the rat.

Dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), ascorbic acid (AA) and dehydroascorbic acid (DHAA) levels were determined by HPLC in the striatal synaptosomal fraction and in the whole striatum of rats, whose fronto-parietal cortex had been bilaterally ablated, after a single injection of d-amphetamine (2.0 mg/kg i.p.). d-Amphetamine significantly increased the DHAA/AA ratio in unoperated and sham-operated rats, but failed to increase it in ablated rats, as compared to pertinent saline-treated groups. In the synaptosomal fraction, d-amphetamine significantly decreased the DHAA/AA ratio in unoperated, sham-operated and ablated rats. d-Amphetamine significantly decreased the DOPAC/DA ratio in the whole striatum and significantly increased it in the striatal synaptosomal fraction in all experimental groups. Cortical ablation greatly increased d-amphetamine-induced motor hyperactivity. We conclude that the d-amphetamine-induced increase in AA striatal oxidation requires integrity of the cortico-striatal glutamatergic pathways. Further, AA oxidation occurs in the extracellular space. The cortico-striatal glutamatergic pathways exert an inhibitory modulation on d-amphetamine behavioral effects.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1991

Further investigations into the relationship between the dopaminergic system, ascorbic acid and uric acid in the rat striatum.

Levels of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), ascorbic acid (AA), dehydroascorbic acid (DHAA), and uric acid were determined in the rat striatum following single apomorphine (1 mg/kg), scopolamine (0.6 mg/kg), pilocarpine (4 mg/kg), or pilocarpine + scopolamine (4 and 0.6 mg/kg, respectively) injections. The decrease in DOPAC levels and in the DOPAC/DA ratio, induced by the pharmacological manipulation, was linearly correlated with the increase in DHAA levels (r = -0.9060, P less than 0.05) and with the increase in the DHAA/AA ratio (r = -0.9004, P less than 0.05), respectively. It is concluded that dopaminergic activation or cholinergic inhibition both increase striatal AA oxidation, which is correlated with a decrease in DA turnover.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1991

Investigations into the relationship between the dopaminergic system and ascorbic acid in rat striatum.

Levels of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), ascorbic acid (AA) and dehydroascorbic acid (DHAA) were determined by HPLC in the striatum of male Wistar rats after single or repeated injections of apomorphine (1 mg/kg/day s.c.) and/or haloperidol (1 mg/kg/day i.p.), and 24 h after the last drug administration. Apomorphine significantly reduced the DOPAC/DA ratio and increased the DHAA/AA ratio; these ratio changes were significantly correlated (r = -0.9969, P less than 0.0005). Haloperidol greatly increased the DOPAC/DA ratio; the DHAA/AA ratio was also slightly increased, but there was no significant correlation. When apomorphine was associated with haloperidol, the resulting DOPAC/DA ratio was significantly lower than after haloperidol alone; the DHAA/AA ratio was also significantly reduced in contrast to the effect of apomorphine alone. It is concluded that a non-selective DA receptor activation mediates, in a correlated way, both the inhibition of DA turnover and the increase of AA oxidation in the rat striatum.

Animals↗
PubMed1991

[Cadmium-induced changes in the activity of the dopaminergic and purinergic systems and in ascorbic acid catabolism in the rat striatum].

Levels of dopamine (DA), 3-4-dihydroxyphenylacetic acid (DOPAC), ascorbic acid (AA), dehydroascorbic acid (DHAA), uric acid (UA) and adenosine (ADO), were determined by HPLC in the striatum of male Wistar rats treated with repeated injections of cadmium (as sulfate) 3 mg/kg/day s.c. for 10 consecutive days. Cadmium treatment significantly reduced DOPAC levels with consequent decrease of the DOPAC/DA ratio; AA levels were significantly reduced, while DHAA levels were significantly increased, with consequent increase of DHAA/AA ratio: levels of UA and ADO were both significantly increased. It is concluded that cadmium, given systemically, reduces dopaminergic system activity in the rat striatum; such impairment occurs together with an increase of AA oxidation and of markers of purinergic system activity. The inhibition of striatal dopaminergic activity could be considered the neurochemical basis of behavioral changes induced by cadmium, while the increase of AA oxidation and of purinergic system activity could be considered an antitoxic metabolic response.

Adenosine↗
PubMed1991

Analysis of the mechanism of d-amphetamine-and apomorphine-induced changes of ascorbic acid catabolism in discrete brain areas of the rat.

Ascorbic acid (AA) levels and dehydroascorbic acid/ascorbic acid (DHAA/AA) ratios were determined in hypothalamus, striatum, and remaining brain of male Wistar rats, after single or repeated injections of d-amphetamine (1.8 mg/kg/day s.c.), apomorphine (1.0 mg/kg/day s.c.), and/or haloperidol (0.1 mg/kg/day i.p.). Major changes were observed in hypothalamus, in which all drugs significantly increased DHAA/AA ratio. Apomorphine and haloperidol consistently decreased AA level as well. The DHAA/AA ratio increase was observed also when apomorphine and d-amphetamine were associated with haloperidol. In striatum, apomorphine (single) and d-amphetamine (repeated) injections increased DHAA/AA ratios; such AA oxidation increase was inhibited by haloperidol; the increases (d-amphetamine) or decrease (apomorphine) of AA levels were also inhibited by haloperidol; haloperidol alone did not modify DHAA/AA ratio and induced minor changes of striatal AA level. In remaining brain, apomorphine (single) and d-amphetamine (repeated) treatment increased DHAA/AA ratio; such increase was observed also when haloperidol was associated with apomorphine or d-amphetamine; moreover, haloperidol by itself increased AA oxidation, although to a lesser extent than it did in hypothalamus. It is concluded that AA catabolism can be activated in the rat striatum by a dopaminergic mechanism; in hypothalamus and in remaining brain, the AA catabolism activation appears rather to be a non-specific effect of the pharmacological manipulation.

Animals↗
PubMed1991

Stereotypes of young and old: does age outweigh gender?

Stereotypes of age and gender are examined with 35-year-old and 65-year-old men and women as target persons. Age stereotypes were more pronounced than gender stereotypes; respondents offered more elaborate free-response descriptions of older targets than of younger targets and described same-age targets more similarly than same-sex targets. On the rating scales, older people were judged less likely to possess masculine characteristics, but ratings of feminine characteristics were largely unaffected by age. Older people were not uniformly devalued on the age-stereotypic characteristics, but when negative evaluations occurred they were of the older targets. These results attest to the importance of a multidimensional conception of age and gender stereotypes.

Adult↗
PubMed1990

[Selective pharmacological changes of regional ascorbic acid metabolism in the brain].

A growing body of evidence indicates for ascorbate a very important role in CNS functioning, rather than just fulfilling the relatively passive roles of general reducing agent and enzymatic cofactor. On-going modulation of synaptic events, locomotor activity, intermodulation with the consciousness state, are new fields of ascorbate activity. Several CNS drugs, according to their kind of activity, induce increase or decrease of extracellular brain ascorbate levels; moreover, they can, like d-amphetamine, activate the ascorbate transport system to CNS. Also regional brain ascorbate metabolism can be selectively activated by drugs. Activation of postsynaptic dopaminergic receptors increases ascorbate oxidation in striatum, but not in hypothalamus. Finally, the active transport of ascorbate to neural tissue and its efficient homeostatic system limit the ascorbate therapeutic potential on CNS.

Analysis of Variance↗
PubMed1989

The presence of amplified regions affects the stability of chromosomes in drug-resistant Chinese hamster cells.

The stability of chromosomes carrying amplified CAD (carbamyl phosphate synthetase-aspartate transcarbamylase-dihydroorotase) or DHFR (dihydrofolate reductase) genes was studied in V79 Chinese hamster cell derivatives resistant to PALA (N-phosphonacetyl-L-aspartate) and MTX (methotrexate), respectively. Cells were maintained in the presence of the selective drugs during the study. In both metaphase chromosomes and interphase nuclei, amplified regions were localized by in situ hybridization. In MTX-resistant cells, the amplification-bearing chromosome moved sluggishly at anaphase and gave rise to bud-shaped formations in interphase nuclei. It is suggested that these buds could eventually separate as micronuclei. In both MTX- and PALA-resistant cells, amplified DNA was observed in micronuclei in interphase and in displaced chromosomes in metaphase. Finally, amplification-bearing dicentric chromosomes were found in both drug-resistant cell lines. Cumulatively, these observations indicate that the presence of the amplified region in a chromosome renders it unstable: chromosomes bearing an amplified region tended to be excluded from cells, and rearrangements were more frequent than in normal chromosomes.

Animals↗
PubMed1989

Diuretic agents related to indapamide. III--Synthesis and pharmacological activity of N-(4-chloro-3-sulfamoylbenzamido)-1,2,3,4-tetrahydroquinolines and 1,2,3,4-tetrahydroisoquinolines.

A series of N-(4-chloro-3-sulfamoylbenzamido)-1,2,3,4-tetrahydroquinoline++ + (IV-1) and isoquinoline (IV-2) have been synthesized and their diuretic and antihypertensive activities evaluated. While none of the test compounds was found to be provided with antihypertensive properties, most of them displayed a diuretic activity comparable to (IV-2 a) or higher (IV-1 a,b) (IV-2 c) than those of indapamide and clopamide, taken as reference drugs.

Animals↗
PubMed1988

Chromosome aberrations associated with CAD gene amplification in Chinese hamster cultured cells.

Eleven sublines with increasing resistance to N-phosphonacetyl-L-aspartate (PALA) were isolated from the V79,B7 Chinese hamster cell line. Aspartate transcarbamylase activity and CAD gene copy number increased with increasing resistance of sublines. In situ hybridization with a DNA probe for the CAD gene showed that the amplified sequences resided in the terminal region of a marker chromosome with elongated q arms. This region stained homogeneously after G-banding. A high incidence of both numerical and structural chromosome aberrations was found in PALA-resistant cells. In hyperdiploid and polyploid cells, containing 2 copies of the marker chromosome, dicentrics were found at a very high frequency. As indicated by in situ hybridization and G-banding, they originated from a rearrangement involving 2 homologous marker chromosomes.

Animals↗
PubMed1988

d-amphetamine and active behavior--induced changes of regional brain ascorbic acid levels in the rat.

In male Wistar rats, shuttle-box avoidance test (5 daily sessions of 50 min) significantly decreased (P less than 0.001) by 30% ascorbic acid (AsAc) level in hypothalamus (HYP), while it left it unmodified in striatum (ST) and in the remaining brain (RB), as opposed to untested rats; AsAc level in HYP showed a significant (P less than 0.001) trend to recovery 24 hours after the end of the test. No correlation was found between the rate of conditioned avoidance responses (CAR) and AsAc levels in the above brain regions. d-Amphetamine (d-A), given s.c. at the dose of 1.0 mg/kg/day for 5 consecutive days, significantly increased AsAc levels by 26% in HYP (P less than 0.005), by 14% in ST (P less than 0.05), and by 33% in RB (P less than 0.001), as opposed to untreated rats; return of AsAc toward baseline levels was negligible 24 hours after d-A withdrawal. The above d-A treatment schedule significantly increased (P 0.05) the rate of CAR in the shuttle-box test. AsAc levels resulted also significantly higher (P less than 0.001) in HYP (+81%) and in RB (+46%) at the end of the test; the AsAc level increase was negligible in ST. Twenty-four hours later, AsAc levels were still significantly higher in RB, but returned toward baseline level in HYP. Again, no correlation was found between CAR rate and regional brain AsAc levels. These results demonstrate that d-A is able to increase regional brain AsAc levels both in control and in tested rats. Since it is well known that systemic administration of AsAc antagonizes some d-A behavioral effects, it is suggested, as a working hypothesis, that the d-A CNS stimulating effect may cause a recruitment of endogenous AsAc, whose task could be a negative neuromodulatory action on the overall effect of d-A on neuronal activity.

Animals↗