Characteristics of the Inhibition of Rat Brain Monoamine Oxidase In Vitro by MD780515

Abstract

The inhibiton of type A and B MAO in rat forebrain crude membrane preparation by MD780515, (3-(4-[(3-cyanophenyl)methoxy]phenyl)-5-(methoxymethyl)-2-oxazolidinone-Centre de Recherche Delalande, France) has been investigated in vitro with 5-hydroxytryptamine and beta-phenylethylamine as substrates. The inhibition of the high-affinity binding of [3H]harmaline, a specific marker of type A MAO, was also studied. In the experimental conditions used, MD780515 appeared to be a pure mixed MAO inhibitor (MAOI) of 5-HT deamination, both Km and Vmax being altered [Ki (Dixon) = Ki, (slope) = 2 nM; Ki (intercept) = 12 nM]. Phenylethylamine oxidation could be considered to be noncompetitively inhibited by MD780515 (Ki (slope) = 78 nM; Ki (intercept) = 103 nM). Dixon and intercept replots were hyperbolic, suggesting that, at high concentrations, PEA could be deaminated by both forms of MAO. This hypothesis was confirmed by biphasic inhibition curves of 80 microM-PEA obtained when MD780515, clorgyline, harmaline and deprenyl were used at MAOIs. MD780515 was a potent inhibitor (IC50 = 1-2 nM) of [3H]harmaline binding. Comparatively, clorgyline, 'cold' harmaline and Lilly 51641 inhibited 3H ligand binding, with IC50 of 5, 7 and 40 nM respectively. In conclusion, MD780515 is a reversible, specific and potent type A MAOI.

The Metabolism of Dopamine by Both Forms of Monoamine Oxidase in the Rat Brain and Its Inhibition by Cimoxatone

“…6-Phenethylamine was metabolised by MAO-B, although a small (12-26%, depending on the tissue) component of MAO-A was also found (Table 1). Such a result is consistent with other studies (see, e.g., Kinemuchi et al, 1980;Kan and Strolin Benedetti, 1981;Suzuki et al, 19816) that have demonstrated a considerable MAO-A component of P-phenethylamine oxidation at high substrate concentrations, although the extent of the MAO-A contribution has been overestimated in some cases since P-phenethylamine, at high concentrations, can act as a time-dependent inhibitor of MAO-B activity (Kinemuchi et al, 1981). At a concentration of 50 p M , 80-90% of the dopamine was metabolised by MAO-A, whereas at a concentration of 1000 p M , the contribution of MAO-A was slightly lower (Table 1).…”

Antiaging effect of Cordyceps sinensis extract

“…Catalase activity was determined by monitoring the absorbance of H 2 O 2 at 230 nm (Aebi, 1987). Monoamine oxidase B (MAO-B) activity was determined by detecting the amount of benzylaldehyde at 242 nm (Kan and Benedetti, 1981). Lipid peroxidation was assayed by the measurement of malondialdehyde level on the basis of malondialdehyde reacting with thiobarbituric acid (detected at 532 nm) (Ohkawa et al, 1979).…”

Deamination of 5‐Hydroxytryptamine by Both Forms of Monoamine Oxidase in the Rat Brain

“…Early investigations indicated that in the rat brain, 5-hydroxytryptamine (5-HT) is a substrate for MAO-A alone, P-phenethylamine and benzylamine for MAO-B alone, and tyramine for both forms of the enzyme (Johnston, 1968; Yang and Neff, 1973). Recent investigations in the rat brain and liver, however, have indicated that 0-phenethylamine is also a substrate for MAO-A, although the metabolism takes place at a slower rate and with a higher K , value than with MAO-B (Kinemuchi et al, 1979;Suzuki et al, 1979;Tipton and Mantle, 1981;Kan and Strolin Benedetti, 1981;Tipton et al, 1981).In a recent study, it was suggested that 5-HT is a substrate exclusively for MAO-A in the rat striatum (Schoepp and Azzaro, 1981). However, studies in the pig liver and rat liver have suggested that 5-HT is, in fact, metabolised by MAO-B, albeit with a much lower V,,, and a higher K , value than for the A form of the enzyme (Ekstedt, 1979;Tipton and Mantle, 1981;Tipton et al, 1982).…”

“…Early investigations indicated that in the rat brain, 5-hydroxytryptamine (5-HT) is a substrate for MAO-A alone, P-phenethylamine and benzylamine for MAO-B alone, and tyramine for both forms of the enzyme (Johnston, 1968; Yang and Neff, 1973). Recent investigations in the rat brain and liver, however, have indicated that 0-phenethylamine is also a substrate for MAO-A, although the metabolism takes place at a slower rate and with a higher K , value than with MAO-B (Kinemuchi et al, 1979;Suzuki et al, 1979;Tipton and Mantle, 1981;Kan and Strolin Benedetti, 1981;Tipton et al, 1981).…”