The presence of functional cannabinoid CB 2 receptors in the CNS has provoked considerable controversy over the past few years. Formerly considered as an exclusively peripheral receptor, it is now accepted that it is also present in limited amounts and distinct locations in the brain of several animal species, including humans. Furthermore, the inducible nature of these receptors under neuroinflammatory conditions, in contrast to CB 1 , makes them attractive targets for the development of novel therapeutic approaches. In fact, the undesired psychoactive effects caused by CB 1 activation have largely limited the clinical use of cannabinoid-related compounds that act on these receptors. In this review some recent findings on the antiinflammatory properties of CB 2 receptors are presented, as well as new perspectives that have been obtained based on studies of human postmortem brain samples. In addition, various working hypotheses are also proposed and discussed.

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ABSTRACT:To test the neuroprotective effects of the nonpsychoactive cannabinoid cannabidiol (CBD), piglets received i.v. CBD or vehicle after hypoxia-ischemia (HI: temporary occlusion of both carotid arteries plus hypoxia). Nonhypoxic-ischemic sham-operated piglets remained as controls. Brain damage was studied by near-infrared spectroscopy (NIRS) and amplitudeintegrated electroencephalography (aEEG) and by histologic assessment (Nissl and FluoroJadeB staining). In HIϩvehicle, HI led to severe cerebral hemodynamic and metabolic impairment, as reflected in NIRS by an increase in total Hb index (THI) and a decrease in the fractional tissue oxygenation extraction (FTOE); in HIϩCBD the increase of THI was blunted and FTOE remained similar to SHAM. HI profoundly decreased EEG amplitude, which was not recovered in HIϩvehicle, indicating cerebral hypofunction; seizures were observed in all HIϩvehicle. In HIϩCBD, however, EEG amplitude recovered to 46.4 Ϯ 7.8% baseline and seizures appeared only in 4/8 piglets (both p Ͻ 0.05). The number of viable neurons decreased and that of degenerating neurons increased in HIϩvehicle; CBD reduced both effects by more than 50%. CBD administration was free from side effects; moreover, CBD administration was associated with cardiac, hemodynamic, and ventilatory beneficial effects. In conclusion, administration of CBD after HI reduced short-term brain damage and was associated with extracerebral benefits. (Pediatr Res 64: 653-658, 2008)

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