Monoamine oxidase (MAO) catalyzes the oxidative deamination of monoamine neurotransmitters such as serotonin, dopamine, and norepinephrine, and appears to play important roles in several psychiatric and neurological disorders. 1,2) MAO has been divided into two subtypes, MAO-A and MAO-B, on the basis of their amino acid sequence, substrate and inhibitor selectivity, and tissue distribution.2-4) MAO-A inhibitors are useful in the therapy of mental disorders, mainly as antidepressants, whereas MAO-B inhibitors are expected to be useful in the therapy of Parkinson's and Alzheimer's disease. 1,5) To date, a number of MAO inhibitors such as coumarins, xanthones, and isoquinoline alkaloids have been isolated from natural products or synthesized.
6-9)Piper longum L. (Piperaceae), a slender aromatic climber, is a native of the Indo-Malayan region and grows wild in the tropical rain forests of India. The extract of the crude drug "Piperis Longi Fructus," the fruits of P. longum, is frequently used in folk medicine to treat bronchial trouble and is used as a carminative and analgesic. 10,11) Piperine was the first amide isolated from Piper species and was reported to display central nervous system depression, antipyretic, and anti-inflammatory activity. 12,13) Moreover, previous studies have demonstrated that piperine and its derivatives present sedative-hypnotic, tranquilizing, and muscle-relaxing actions and can intensify the depressive action of other depressants.14) Based on the aforementioned evidence, it might be suggested that piperine could be useful for the control of CNS-related conditions, including mood disorders and moderate or mild depression states.In the present work, we have investigated the activityguided isolation and inhibitory effect of piperine on MAO activity in mouse brain. We also investigate the antidepressant-like activity of piperine in the in vivo tail suspension test.
Results and DiscussionIn our ongoing search for naturally occurring MAO inhibitors, an ethanol extract of the fruits of P. longum exhibited strong inhibitory activity on mouse brain MAO. A bioassay-guided isolation of the extract yielded a known piperidine alkaloid, piperine, as an active component. The structure was identified by physicochemical and spectroscopic methods (mp, UV, IR, MS, 1 H-and 13 C-NMR) and by comparing the data obtained with those of published values (Fig. 1). 15,16) Piperine exhibited 38.0% inhibition of MAO activity at 8 mM, with an IC 50 value of 11.1 mM, which is comparable to iproniazid as a positive control (Table 1). According to the kinetic properties of MAO from the mouse brain, the values of K m and V max by using kynuramine were 72.2Ϯ5.60 mM and 3.97Ϯ0.18 nmol/min/mg protein, respectively (nϭ3) (data not shown).In order to verify the selectivity of the MAO activity, l-deprenyl-pretreated MAO preparation was used for the measurement of MAO-A activity, whereas a clorgyline-pretreated preparation was used for MAO-B. This result indicated that
