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Previous Article | Next Article
The Journal of Neuroscience, November 15, 2001, 21(22):8765-8771
Exogenous Anandamide Protects Rat Brain against Acute Neuronal Injury In Vivo
M. van der Stelt1, W. B. Veldhuis2, 3, G. W. van Haaften1, F. Fezza4, T. Bisogno4, P. R. Bär3, G. A. Veldink1, J. F. G. Vliegenthart1, V. Di Marzo4, and K. Nicolay2 1 Department of Bio-organic Chemistry, Bijvoet Center for Biomolecular Research, Utrecht University, 3584 CH Utrecht, The Netherlands, 2 Department of Experimental In Vivo Nuclear Magnetic Resonance, Image Sciences Institute, Utrecht University Medical Center, 3584 CJ Utrecht, The Netherlands, 3 Department of Experimental Neurology, Utrecht University Medical Center, 3584 CX Utrecht, The Netherlands, and 4 Endocannabinoid Research Group, Istituto per la Chimica di Molecole di Interesse Biologico, Consiglio Nazionale delle Ricerche, 80078 Pozzuoli, Naples, Italy
The endocannabinoid anandamide [N-arachidonoylethanolamine (AEA)] is thought to function as an endogenous protective factor of the brain against acute neuronal damage. However, this has never been tested in an in vivo model of acute brain injury. Here, we show in a longitudinal pharmacological magnetic resonance imaging study that exogenously administered AEA dose-dependently reduced neuronal damage in neonatal rats injected intracerebrally with the Na+/K+-ATPase inhibitor ouabain. At 15 min after injury, AEA (10 mg/kg) administered 30 min before ouabain injection reduced the volume of cytotoxic edema by 43 ± 15% in a manner insensitive to the cannabinoid CB1 receptor antagonist SR141716A. At 7 d after ouabain treatment, 64 ± 24% less neuronal damage was observed in AEA-treated (10 mg/kg) rats compared with control animals. Coadministration of SR141716A prevented the neuroprotective actions of AEA at this end point. In addition, (1) no increase in AEA and 2-arachidonoylglycerol levels was detected at 2, 8, or 24 hr after ouabain injection; (2) application of SR141716A alone did not increase the lesion volume at days 0 and 7; and (3) the AEA-uptake inhibitor, VDM11, did not affect the lesion volume. These data indicate that there was no endogenous endocannabinoid tone controlling the acute neuronal damage induced by ouabain. Although our data seem to question a possible role of the endogenous cannabinoid system in establishing a brain defense system in our model, AEA may be used as a structural template to develop neuroprotective agents.
Key words: anandamide; 2-AG; astrogliosis; cannabinoid; excitotoxicity; ischemia; magnetic resonance imaging; neonatal rat; neuronal injury; neuroprotection; ouabain
Copyright © 2001 Society for Neuroscience 0270-6474/01/21228765-07$05.00/0
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