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1. Biotransformations by gut microflora play a pivotal role in determining the biological activity of isoflavones that occur in soya-based foods predominantly as betaglycosyl conjugates. Microflora prepared from rat caecae and human faeces were used to investigate the metabolic fate of genistein beta-glycosides extracted from soya flour. The end-products of such metabolism were determined by parallel incubations of microflora with [2',3,5',6'-3H] and [4-14C]-labelled genistein. 2. Quantitative analysis by LC-MS/IS indicated very rapid and complete degradation of genistin, which was associated with a transient increase in genistein. Qualitative studies indicated that the malonyl and acetyl glycosides of genistein were also degraded by the microflora. 3. Incubation of caecal and faecal microflora with [3H] and [14C]genistein yielded similar radiolabelled metabolites, which were identified by radio-LC-MS(n) as the intermediates dihydrogenistein and 6'-hydroxy-O-desmethylangolensin and end-product 4-hydroxyphenyl-2-propionic acid. This profile of genistein metabolites indicated selective hydrolysis of 6'-hydroxy-O-desmethylangolensin between carbon atoms 1' and 1 to yield the end-products 4-hydroxyphenyl-2-propionic acid and 1,3,5-trihydroxybenzene. 4. The biological significance of the products of genistein metabolism warrant further investigation since they may play an important role in mediating the beneficial antioxidant health effects associated with the consumption of isoflavones in food.

Recent neuroanatomical and functional investigations focusing on dopamine (DA) D 3 receptors have suggested a potential role of this receptor in psychiatric diseases such as schizophrenia and drug dependence. In line with the key role of the prefrontal cortex in psychiatric disorders, the present study aimed at assessing the effects of the acute systemic administration of the selective DA D 3 receptor antagonist SB-277011-A on the in vivo extracellular levels of monoamines (DA, norepinephrine (NE), and serotonin (5-HT)) and acetylcholine (ACh) in the anterior cingulate subregion of the medial prefrontal cortex. The in vivo neurochemical profile of SB-277011-A (10 mg/kg, i.p.) in the anterior cingulate cortex was compared with both typical and atypical antipsychotics including clozapine (10 mg/kg, s.c.), olanzapine (10 mg/kg, s.c.), sulpiride (10 mg/kg, s.c.), and haloperidol (0.5 mg/kg, s.c.). The acute administration of SB-277011-A, clozapine, and olanzapine produced a significant increase in extracellular levels of DA, NE, and ACh without affecting levels of 5-HT. Sulpiride also significantly increased extracellular DA, but with a delayed onset over SB-277011-A, clozapine, and olanzapine. In contrast, haloperidol failed to alter any of the three monoamines and ACh in the anterior cingulate cortex. These findings add to a growing body of evidence suggesting a differentiation between typical and atypical antipsychotic drugs (APDs) in the anterior cingulate cortex and a role of DA D 3 receptors in desired antipsychotic drug profile. Similar to their effects on DA and NE, SB-277011-A, clozapine, and olanzapine increased extracellular levels of ACh, whereas haloperidol and sulpiride did not alter ACh. The results obtained in the present study provide evidence of the important role of DA D 3 receptors in the effect of pharmacotherapeutic agents that are used for the treatment of psychiatric disorders such as schizophrenia and drug dependence.

Background and purpose: The peroxisome proliferator-activated receptor-g (PPARg) agonist pioglitazone has previously been shown to attenuate dopaminergic cell loss in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease, an effect attributed to its anti-inflammatory properties. In the present investigation, we provide evidence that pioglitazone is effective in the MPTP mouse model, not via an anti-inflammatory action, but through inhibition of MAO-B, the enzyme required to biotransform MPTP to its active neurotoxic metabolite 1-methyl-4-phenylpyridinium (MPP þ ). Experimental approach: Mice were treated with pioglitazone (20 mg kg À1 b.i.d. (twice a day), p.o., for 7 days), prior and post or post-MPTP (30 mg kg À1 s.c.) treatment. Mice were then assessed for motor impairments on a beam-walking apparatus and for reductions in TH immunoreactivity in the substantia nigra and depletions in striatal dopamine. The effects of pioglitazone on striatal MPP þ levels and MAO-B activity were also assessed. Key results: Mice treated with MPTP showed deficits in motor performance, marked depletions in striatal dopamine levels and a concomitant reduction in TH immunoreactivity in the substantia nigra. Pretreatment with pioglitazone completely prevented these effects of MPTP. However, pretreatment with pioglitazone also significantly inhibited the MPTP-induced production of striatal MPP þ and the activity of MAO-B in the striatum. Conclusions and implications:The neuroprotection observed with pioglitazone pretreatment in the MPTP mouse model was due to the blockade of the conversion of MPTP to its active toxic metabolite MPP þ , via inhibition of MAO-B.