Vincenzo Politi

Antioxidant Properties of Indole-3-Pyruvic Acid

Oxidative stress is believed to be involved in the pathogenesis of many important degenerative diseases, especially in the Central Nervous System, where oxygen is utilized in very high amount, and scavengers of toxic substances might be insufficient when neurons are over-stimulated or ageing processes accumulate peroxide lipids (Halliwell, 1992).

Indole-3-Pyruvic Acid as a Direct Precursor of Kynurenic Acid

Kynurenic acid (KYNA) is found in large amounts after tryptophan load, because tryptophan-2, 3-dioxygenase (EC 1.13.11.11), present in the liver, opens its indole ring, while kynurenine transaminase (EC 2.6.1.7) is able to catalyze the transformation of kynurenine to KYNA. In the last few years, it was demonstrated that KYNA is an important endogenous antagonist of excitatory amino acid receptors (Ganong et al., 1983; Stone and Burton, 1988) and that it reduces cerebral ischemic effects when administered at high dosages in vivo (Germano et al., 1987). Unfortunately, tryptophan is not a good precursor of cerebral KYNA, because it simultaneously increases kynurenine and quinolinic acid, two well-known pro-convulsant agents (Lapin, 1983; Foster et al., 1984). On the other hand, indole-3-pyruvic acid (IPA), the keto-analog of tryptophan, increases KYNA content in several rat organs after i.p. injection (Russi et al., 1989). Inside the brain, conversion to KYNA appears more effective for IPA than for tryptophan, suggesting a different metabolic pathway. Experiments were therefore performed in order to find the new pathway leading from IPA to KYNA.

Clinical Experiences with the Use of Indole-3-Pyruvic Acid

In the last few years, Indol-3-pyruvic acid (IPA) has been subjected to 5 pilot clinical trials in volunteers and a phase II study on patients affected by anxiety, with or without sleep problems. Overall, results indicated a very good safety profile, relief from anxiety and a better quality of sleep in patients treated with IPA. Moreover, the drug showed no withdrawal signs, but positive effects on mood, improving feelings of relaxation, calmness and happiness. The mechanism of action of IPA, depending on increased turnover of some indoles in the CNS, appears clearly distinct from that of benzodiazepines, suggesting that the drug might be used in the treatment of symptoms of mild anxiety and stress experienced by busy and anxious people.

A new peptide from Crotalus atrox snake venom

The presence of new hypotensive peptides, possibly not related to ACE inhibition, has been investigated on 66 snake venoms from crotalid, viperid and elapid families. Only the venom of Crotalus atrox showed a substantial amount of a new decapeptide, called POL-236, with the following aminoacid sequence: PYR-LEU-TRP-PRO-ARG-PRO-GLN-ILE-PRO-PRO. Pharmacological assays performed on the synthesized peptide revealed effects on blood pressure, probably derived from vascular and cardiac interferences.

The Regulation of Brain Kynurenic Acid Content: Focus on Indole-3-Pyruvic Acid

The actual interest in the role that kynurenic acid (KYNA), one of the first identified metabolic products of tryptophan, (Ellinger et al., 1904 in Heidelberger et al., 1949; see Fig. 1) may have in physiology or pathology stems from at least three groups of observations. First, KYNA antagonizes in a non-competitive manner excitatory amino acid (EAA) receptors (Perkins and Stone, 1982; Moroni et al., 1986); second, it prevents the excitotoxic actions of the related tryptophan (TRP) metabolite quinolinic acid (QUIN) (Foster et al., 1984) and reduces neuronal damage after anoxic and ischemic brain insults (Germano et al., 1987); and third, it is present in mammalian biological fluids and in the central nervous system (Moroni et al., 1988b).

The Role of Transaminations in the Pharmacological Effects of Indole-3-Pyruvic Acid

Indole-3-pyruvic acid (IPA), the keto-analog of tryptophan, is very much diffused in plants, where it can act as a phytohormone. In the past, it has been used as a substitute for tryptophan, with the aim to stimulate growth in rats (Jackson, 1930) or in chickens (Grigoriev and Truzhnikova, 1971). More recently, it has been shown that IPA decreases kynurenine formation by inhibiting tryptophan-2,3-dioxygenase (TPO; EC 1.13.11.11) (Lavaggi et al., 1987) and increases serotonin turnover in rat brains, inducing remarkable sedation and analgesia (Bacciottini et al., 1987). Because IPA can interfere with aromatic aminoacid metabolism, acting as substrate or inhibitor of transami-inases, the present study was designed to find possible relationships between transaminases present in mammalian bodies and pharmacological effects observed after IPA administration.