Calcium channel agonist, (^ )-Bay K8644, causes an immediate increase in the striatal 1-methyl-4-phenylpyridinium level following systemic administration of the dopaminergic neurotoxin, 1-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine, in Balb/c mice Supriti Samantaray, Kochupurackal P. Mohanakumar * Division of Neurosciences, Indian Institute of Chemical Biology, 4, Raja S. C. Mullick Road, Jadavpur, Calcutta 700 032, India Received 17 February 2003; received in revised form 8 April 2003; accepted 5 May 2003 Abstract In vivo formation of 1-methyl-4-phenylpyridinium ion (MPP þ ) in the striatum, and dopaminergic neurotoxicity following systemic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the presence and absence of calcium channel agonist (^ )-Bay K8644 were analyzed in Balb/c mice. We used HPLC-photodiode array detection, HPLC-electrochemical detection and spectrofluorimetric procedures to measure striatal MPP þ and dopamine (DA) and for the assay of monoamine oxidase-B (MAO-B) activity, respectively. Systemic administration of (^ )-Bay K8644 resulted in a significant increase in striatal MAO-B activity. An MPTP-induced decrease in striatal MAO-B activity was attenuated by pre-treatment with (^ )-Bay K8644 initially, but not on the 3rd day. MPP þ formation in the striatum following systemic administration of MPTP was significantly increased by the pre-treatment of the agonist initially (30 min), but was not different afterwards (at 60 and 90 min). Nevertheless, the total MPP þ formed over a 90 min period was found to be comparable. (^ )- Bay K8644 administration prior to MPTP failed to influence the MPTP-induced striatal DA depletion on the 3rd day. While the transient effect of (^ )-Bay K8644 on striatal MAO-B is reflected as an immediate increase in the levels of MPP þ in the striatum, it failed to affect MPTP-induced DA neurotoxicity in Balb/c mice. q 2003 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Monoamine oxidase-B; Calcium channels; Acute effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; 1-Methyl-4-phenyl-1,2,3,6- tetrahydropyridine metabolism, neurodegeneration and neuroprotection An L-type dihydropyridine sensitive calcium channel agonist, 1,4-dihydro-2,6-dimethyl-5-nitro-4-[2-(trifluoro- methyl) phenyl] pyridine-3-carboxylic acid [(^ )-Bay K8644], is known to possess profound effects on dopamine (DA) release in vitro from striatal slices [7], and synapto- somes prepared from the striatum [17,21]. It has also been shown that intrastriatal infusion of (^ )-Bay K8644 causes increased release of DA in the striatum [14,21], which is transient, lasting for less than an hour. We have recently reported a profound decrease in DA levels following systemic administration of (^ )-Bay K8644 in mice that correlated well with an increase in monoamine oxidase (MAO)-A and -B activity in the brain [18]. Interestingly, both the decreased level and increased release of DA in the striatum as well as the increased MAO activity are shown to result from L-type calcium channel-mediated mechanisms [14,18,21]. We have demonstrated that the increase in MAO-A and -B activity is highly significant, but transient, with a maximum effect occurring at 1 h following (^ )-Bay K8644 administration [18]. We predicted that such an effect of this calcium channel agonist may interfere with the metabolism of drugs and toxins, and may influence the outcome of some of the neuropharmacological investi- gations. A typical example could be the parkinsonian neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which is metabolized in the brain by the action of MAO-B, and is suggested to be acting via calcium channel mechanisms [4,12]. MPTP destroys DA containing neurons in the substantia nigra (SN) resulting in severe depletion of DA in the nerve 0304-3940/03/$ - see front matter q 2003 Elsevier Science Ireland Ltd. All rights reserved. doi:10.1016/S0304-3940(03)00577-9 Neuroscience Letters 346 (2003) 69–72 www.elsevier.com/locate/neulet * Corresponding author. Tel.: þ91-33-2413-3223; fax: þ 91-33-2473- 5197 or þ91-33-2472-3967. E-mail address: mohankumar@iicb.res.in (K.P. Mohanakumar).