Giorgio Stramentinoli

Age-related modification of dopaminergic and β-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.

Protective role of S-adenosyl-l-methionine against acetaminophen induced mortality and hepatotoxicity in mice

Abstract Acetaminophen toxicity is demonstrated to he related to the protein binding of a reactive metabolite formed by the action of a P 450 mixed function oxidase. Results of the present study indicate that S -adenosyl- l -methionine (SAMe) protects against mortality induced by high doses (710 mg/kg) of acetaminophen. The liver toxicity induced by acetaminophen also appears to be reduced by SAMe, as shown both by GOT and GPT plasma activities and by histologic observation of the liver. The results of experiments on in vivo and in vitro binding of the radioactivity from acetaminophen to liver microsomal proteins suggest that SAMe protection is related to its metabolism to thiol derivatives in the transmethylation-trans-sulfuration pathway.

Influence of S-adenosyl-L-methionine on irreversible binding of ethynylestradiol to rat liver microsomes, and its implication in bile secretion.

Abstract A three-day administration of ethynylestradiol (EE) (5 mg/kg per day) is shown to decrease the bile flow in the rat by reducing both the bile salt dependent and independent fractions of the bile. Protection against this effect is observed in rats given S -adenosyl- l -methionine (SAMe) in addition to EE. The protection is accompanied by a significant decrease of the binding of EE to liver microsomal proteins suggesting that SAMe administration may favour the estrogen elimination as a methylated derivative.

A radioenzymatic method for S-adenosyl-L-methionine determination in biological fluids

Current methods for the radioenzymatic assay of S-adenosyl-L-methionine (AdoMet) in biological fluids have been modified in order to increase sensitivity. The modified procedure has allowed to measure AdoMet content also in plasma and cerebrospinal fluid where the concentrations have been found to range between 17 and 72 ng/ml in the different animal species.

S-adenosyl-l-methionine protection against α-naphthyl- isothiocyanate-induced cholestasis in the rat

Abstract The effect of S -adenosyl- l -methionine (SAMe) on cholestasis induced by α-naphthylisothiocyanate (ANIT) was studied in rats. SAMe significantly attenuated both bile flow impairment and elevated values of serum bilirubin, glutamic pyruvic transaminase and alkaline phosphatase in ANIT-treated animals. These results suggest that SAMe protects the rat liver against the toxic effects of ANIT.

Effects of the novel antidepressant S-adenosyl-methionine on α1- and β-adrenoceptors in rat brain

Abstract α 1 - and β-adrenoceptors were studied ex vivo in the brains of rats receiving repeated daily treatment with the standard antidepressant imipramine or the atypical antidepressant S-adenosyl-L-methionine (SAM), which has minimal effects on monoamine reuptake or turnover. Consistent with past studies, a decrease in the density of β receptors at three weeks and an increase in the affinity of α 1 receptors for the agonist phenylephrine at one week of treatment was observed with imipramine. By comparison, an increase in the density of β receptors and a decrease in the affinity of α 1 receptors for phenylephrine was observed at one week of treatment with SAM. These changes were no longer apparent at three weeks of treatment. The results suggest that treatment with SAM does lead to changes in adrenergic neurotransmission, but that down regulation of β receptors or increased agonist affinity of α 1 receptors may not be necessary for the production of antidepressant effects.

S-adenosylmethionine protects against erythrocyte membrane alterations induced in rabbits by cholesterol-rich diet

In the erythrocyte membranes of rabbits fed a cholesterol rich diet for two months the cholesterol/phospholipid ratio was twice higher than in controls. The same diet induced a significant decrease in membrane fluidity and acetylcholinesterase activity. Two daily administrations of 25 mg X kg-1 b.w.-1 of S-adenosylmethionine (SAMe) have shown to protect against membrane alterations induced by hypercholesterolemic regimen. This observation would suggest the use of SAMe in those pathological conditions like hyperlipoproteinemias and liver diseases where membrane alterations are reported.

Metabolism of exogenously administered SAM

In view of the efficacy of SAM reported in its clinical use in various pathologies (Agnoli et al. , 1976; Salvadorini et al. , 1980; Fiaccadori, 1981) we became interested to approach the problem of the in vivo metabolism of the compound. To this purpose S-adenosyl-L-[1-14C]methionine (1-14C-SAM), S-adenosyl-L- [3,4-14c] methionine (3,4-14C-SAM), or S-adenosyl-L-[methyl-14C]methionine (14CH3-SAM) was administered to rats by i.v. injection either at the specific radioactivity of the commercial material (trace dose) or mixed with unlabelled SAM.

Implications of SAM in estrogen metabolism

Both natural and synthetic estrogens can interfere with bile formation mechanisms by inducing intrahepatic cholestasis or cholesterol supersaturation of bile (Kern et al., 1978).

Biochemical and behavioural indices of striatal dopaminergic activity after 6-methyltetrahydropterin

The biochemical effects of 6-methyltetrahydropterin (6-MPH4), a synthetic analogue of tetrahydrobiopterin (BH4), the hydroxylase cofactor, were investigated on striatal dopaminergic neurons in the rat. Although a single parenteral dose of 6-MPH4 (18 or 54 mg/kg) did not significantly increase the content of dopamine (DA) or its acidic metabolites, L-didrohyphenylanine (L-DOPA) accumulation after decarboxylase inhibition was evident in rats receiving 54 mg/kg of 6-MPH4. On the other hand, 6-MPH4 (18 mg/kg) potentiated the reserpine-induced DA metabolism as demonstrated by increased HVA levels. In a behavioural test, 6-MPH4 partially prevented haloperidol-induced catalepsy. BH4 concentrations could thus be subsaturating with respect to tyrosine hydroxylase (TH), particularly when the enzyme activity is stimulated and the results suggest that cofactor supply may have pharmacological significance.