Overexpression of CB2 cannabinoid receptors results in neuroprotection against behavioral and neurochemical alterations induced by intracaudate administration of 6-hydroxydopamine

The role of CB2 cannabinoid receptors in the behavioral and neurochemical changes induced by intracaudate administration of 6-hydroxydopamine (6-OHDA) was evaluated. 6-OHDA (12 μg/4 μL) or its vehicle was injected in the caudate-putamen (CPu) of mice overexpressing the CB2 cannabinoid receptor (CB2xP) and wild type (WT) mice. Motor impairment, emotional behavior, and cognitive alterations were evaluated. Tyrosine hydroxylase (TH), glial fibrillary acidic protein (GFAP), and ionized calcium-binding adapter molecule 1 (Iba-1) were measured by immunocytochemistry in the CPu and/or substantia nigra (SN) of CB2xP mice and WT mice. Oxidative/nitrosative and neuroinflammatory parameters were also measured in the CPu and cortex of 6-OHDA-treated and sham-treated mice. 6-OHDA-treated CB2xP mice presented significantly less motor deterioration than 6-OHDA-treated WT mice. Immunocytochemical analysis of tyrosine hydroxylase in the SN and CPu revealed significantly fewer lesions in CB2xP mice than in WT mice. GFAP and Iba-1 immunostaining revealed less astrocyte and microglia recruitment to the treated area of the CPu in CB2xP mice. Malonyldialdehyde (MDA) concentrations were lower in the striatum and cerebral cortex of sham-treated CB2xP mice than in sham-treated WT mice. The administration of 6-OHDA increased MDA levels in both WT mice and CB2xP mice; it increased the oxidized (GSSG)/reduced (GSH) glutathione ratio in the striatum in WT mice alone compared with matched sham-treated controls. The results revealed that overexpression of CB2 cannabinoid receptors decreased the extent of motor impairment and dopaminergic neuronal loss, reduced the recruitment of astrocytes and microglia to the lesion, and decreased the level of various oxidative parameters. These results suggest that CB2 receptors offer neuroprotection against dopaminergic injury. © 2012 Elsevier Inc.This work was also supported by the >Fundacion para la Investigacion Sanitaria en Castilla-La Mancha (FISCAM)> project PI-2008/21 to MFG, >Incorporacion de Grupos Emergentes> FIS-Carlos III and project PI-080693 from ISCII-Carlos III to MFG and MES. AT, JMPO, and AOA are postdoctoral fellows from FISCAM. MSGG and FN are predoctoral fellows from the Spanish Ministry of Health and the Spanish Ministry of Science and Innovation, respectively.Peer Reviewe