Monoamine oxidase inhibitors: effects on tryptophan concentrations in rat brain.

It has been suggested that inhibition of tryptophan (Trp) pyrrolase and a subsequent elevation of brain Trp may contribute to the actions of antidepressant drugs. In our laboratories, we have conducted a series of experiments measuring brain Trp levels in the rat after both acute and chronic administration of several monoamine oxidase (MAO) inhibitors. The drugs studied during the course of the long-term (28 day) experiments were phenelzine, N2-acetylphenelzine, tranylcypromine, 4-fluorotranylcypromine, 4-methoxytranylcypromine and (-)-deprenyl. High-pressure liquid chromatography with electrochemical detection was employed to measure Trp levels in brains of both MAO inhibitor- and vehicle-treated animals. No significant increases in brain Trp levels were observed as a consequence of MAO inhibitor treatment. Acute time-response (up to 24 h) and dose-response studies were conducted following the administration of phenelzine and tranylcypromine. Only after administration of high doses of these drugs was an elevation in brain Trp observed and the increase was relatively short-lived. These results suggest that elevation of brain Trp may be an important factor in the actions of MAO inhibitors only at high doses of these drugs.

Insights into the mechanisms of action of the MAO inhibitors phenelzine and tranylcypromine: a review.

Although the non-selective monoamine oxidase inhibitors phenelzine and tranylcypromine have been used for many years, much still remains to be understood about their mechanisms of action. Other factors, in addition to the inhibition of monoamine oxidase and the subsequent elevation of brain levels of the catecholamines and 5-hydroxytryptamine, may contribute to the overall pharmacological profiles of these drugs. This review also considers the effects on brain levels of amino acids and trace amines, uptake and release of neurotransmitter amines at nerve terminals, receptors for amino acids and amines, and enzymes other than monoamine oxidase, including enzymes involved in metabolism of other drugs. The possible contributions of metabolism and stereochemistry to the actions of these monoamine oxidase inhibitors are discussed.

Interaction of antioxidants with depth-dependent fluorescence quenchers and energy transfer probes in lipid bilayers.

Three fluorescent, lipophilic, heterocyclic antioxidants were incorporated into lipid bilayers and exposed to depth-dependent nitroxyl fatty acid quenchers. The Stern-Volmer plots curved upward at low quencher concentrations. Quantitative analysis of the results showed that this behavior is consistent with complex formation between quencher and fluorescent antioxidant, where the complex is 2-3 times more fluorescent than the parent fluorophore. At higher quencher concentrations, both free antioxidant and 'bright complex' are quenched dynamically, albeit quenching of the latter is less efficient. The complex probably results from ionic, hydrogen bond and pi-pi interactions. Formation of such a 'bright complex' is also observable in a homogeneous solution of the reactants in cyclohexane. Additional evidence for the complexation of these antioxidants with fatty acids in lipid bilayers is provided by the fact that energy transfer from the antioxidants to anthroyloxy fatty acids occurs at surface concentrations where radiative energy transfer between free molecules should be not be efficient. For directly probing the relative depths of these fluorophores in lipid bilayers we used the aqueous quenchers acrylamide and iodide. They showed that in terms of increasing depth in the bilayer, the order was U-78, 517f < U-78,518e < U-75,412e. Our results, in toto, demonstrate that the Lazaroid antioxidants are incorporated into the lipid bilayer where they occupy strictly defined positions and orientations. Complexation with fatty acyl chains should be mechanistically relevant, since it may enhance antioxidant activity by hindering free radical chain propagation.

4-Methoxytranylcypromine, a monoamine oxidase inhibitor: effects on biogenic amines in rat brain following chronic administration.

4-Methoxytranylcypromine (MeOTCP), a ring-substituted analogue of the monoamine oxidase (MAO)-inhibiting antidepressant tranylcypromine (TCP), was investigated in the rat after chronic (28-day) administration and the results compared with those observed with TCP using equimolar doses of both drugs. At the dose tested, MeOTCP produced a greater inhibition of type A MAO in brain, liver, and heart than did TCP. Both drugs caused a reduction in the specific binding to beta-adrenergic and tryptamine receptors in cortex from brain. MeOTCP produced a marked increase in 5-hydroxytryptamine levels in pons-medulla, hypothalamus, and hippocampus relative to values in vehicle-treated rats and also produced a significant increase in these levels over those observed in the TCP-treated rats.