Background
(+)-WIN 55,212-2 (mesylate) is a potent aminoalkylindole cannabinoid (CB) receptor agonist with Ki values of 62.3 and 3.3 nM for human recombinant CB1 and CB2 receptors, respectively.1 In primary cultures of rat cerebral cortex neurons, (+)-WIN 55,212-2 (mesylate) (0.01-100 nM) increases extracellular glutamate levels, displaying a bell-shaped concentration-response curve.2 This effect is fully counteracted by rimonabant at a concentration of 10 nM, by decreasing Ca2+ concentrations below 0.2 mM, or by the IP3 receptor antagonist xestospongin C at a concentration of 1 ?M. (+)-WIN 55,212-2 (mesylate) induces release of the proinflammatory neuropeptide CGRP from trigeminal ganglion (TG) neurons in a calcium-dependent manner with an EC50 value of 26 ?M.3
1.Felder, C.C., Joyce, K.E., Briley, E.M., et al.Comparison of the pharmacology and signal transduction of the human cannabinoid CB1 and CB2 receptorsMol. Pharmacol.48(3)443-450(1995)
2.Ferraro, L., Tomasini, M.C., Gessa, G.L., et al.The cannabinoid receptor agonist WIN 55,212-2 regulates glutamate transmission in rat cerebral cortex: An in vivo and in vitro studyCereb. Cortex11(8)728-733(2001)
3.Price, T.J., Patwardhan, A., Akopian, A.N., et al.Cannabinoid receptor-independent actions of the aminoalkylindole WIN 55,212-2 on trigeminal sensory neuronsBr. J. Pharmacol.142(2)257-266(2004)
Protocol
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Animal experiment:
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In experiment 1, different doses of WIN 55,212-2 (0.5, 1, 3, 5, 10 and 15 mg/kg) are injected 60 min prior to the determination of clonic seizure threshold induced by intravenous administration of PTZ solution. Control animals receive the same volume of the vehicle (1% aqueous solution of DMSO). The doses and time point are chosen on the basis of pilot studies. In experiment 2, in order to confirm the anticonvulsant effects of pioglitazone, different doses (10, 20, 40 and 80 mg/kg) are administered 4 h prior to PTZ in distinct groups of mice. The corresponding control groupreceive the appropriate vehicle (CMC 1%) at the same time point. In experiment 3, The additive anti epileptic effects of WIN 55,212-2 and pioglitazone are examined; mice receive acute administration of pioglitazone (10 or 20 mg/kg) 3 h before WIN 55,212-2 (0.5 or 1 mg/kg) and 4 h before PTZ.
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参考文献:
[1]. Felder CC, et al. Comparison of the pharmacology and signal transduction of the human cannabinoid CB1 and CB2 receptors. Mol Pharmacol. 1995 Sep;48(3):443-50.
[2]. Ferraro L, et al. The cannabinoid receptor agonist WIN 55,212-2 regulates glutamate transmission in rat cerebral cortex: an in vivo and in vitro study. Cereb Cortex. 2001 Aug;11(8):728-33.
[3]. Price TJ, et al. Cannabinoid receptor-independent actions of the aminoalkylindole WIN 55,212-2 on trigeminal sensory neurons. Br J Pharmacol. 2004 May;142(2):257-66.
[4]. Payandemehr B, et al. Involvement of PPAR receptors in the anticonvulsant effects of a cannabinoid agonist, WIN 55,212-2. Prog Neuropsychopharmacol Biol Psychiatry. 2015 Mar 3;57:140-5
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