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The Journal of Neuroscience, May 15, 2003, 23(10):4127-4133

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Neuroprotection by the Endogenous Cannabinoid Anandamide and Arvanil against In Vivo Excitotoxicity in the Rat: Role of Vanilloid Receptors and Lipoxygenases

W. B. Veldhuis,^1,2 * M. van der Stelt,^3 * M. W. Wadman,³ G. van Zadelhoff,³ M. Maccarrone,⁴ F. Fezza,⁵ G. A. Veldink,³ J. F. G. Vliegenthart,³ P. R. Bär,² K. Nicolay,¹ and V. Di Marzo⁵

¹Department of Experimental In Vivo Nuclear Magnetic Resonance, Image Sciences Institute, ²Department of Experimental Neurology, University Medical Center Utrecht, 3584 CX, Utrecht, The Netherlands, ³Department of Bio-Organic Chemistry, Bijvoet Center for Biomolecular Research, Utrecht University, 3584 CH, Utrecht, The Netherlands, ⁴Department of Biomedical Sciences, University of Teramo, 64100 Teramo, Italy, and ⁵Endocannabinoid Research Group, Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, 80078 Pozzuoli, Naples, Italy

Type 1 vanilloid receptors (VR₁) have been identified recently in the brain, in which they serve as yet primarily undetermined purposes. The endocannabinoid anandamide (AEA) and some of its oxidative metabolites are ligands for VR₁, and AEA has been shown to afford protection against ouabain-induced in vivo excitotoxicity, in a manner that is only in part dependent on the type 1 cannabinoid (CB₁) receptor. In the present study, we assessed whether VR₁ is involved in neuroprotection by AEA and by arvanil, a hydrolysis-stable AEA analog that is a ligand for both VR₁ and CB₁. Furthermore, we assessed the putative involvement of lipoxygenase metabolites of AEA in conveying neuroprotection. Using HPLC and gas chromatography/mass spectroscopy, we demonstrated that rat brain and blood cells converted AEA into 12-hydroxy-N-arachidoylethanolamine (12-HAEA) and 15-hydroxy-N-arachidonoylethanolamine (15-HAEA) and that this conversion was blocked by addition of the lipoxygenase inhibitor nordihydroguaiaretic acid. Using magnetic resonance imaging we show the following: (1) pretreatment with the reduced 12-lipoxygenase metabolite of AEA, 12-HAEA, attenuated cytotoxic edema formation in a CB₁ receptor-independent manner in the acute phase after intracranial injection of the Na⁺/K⁺-ATPase inhibitor ouabain; (2) the reduced 15-lipoxygenase metabolite, 15-HAEA, enhanced the neuroprotective effect of AEA in the acute phase; (3) modulation of VR₁, as tested using arvanil, the VR₁ agonist capsaicin, and the antagonist capsazepine, leads to neuroprotective effects in this model, and arvanil is a potent neuroprotectant, acting at both CB₁ and VR₁; and (4) the in vivo neuroprotective effects of AEA are mediated by CB₁ but not by lipoxygenase metabolites or VR₁.

Key words: arvanil; anandamide; cannabinoid; vanilloid; CNS; excitotoxicity; ouabain; neuroprotection; neurodegeneration

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Received Jan. 21, 2003; revised Mar. 6, 2003; accepted Mar. 6, 2003.

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