Regulatory role of the cannabinoid CB2 receptor in stress-induced neuroinflammation in mice.
OBJECTIVE
Stress exposure produces excitotoxicity and neuroinflammation, contributing to the cellular damage observed in stress-related neuropathologies. The endocannabinoids provide a homeostatic system, present in stress-responsive neural circuits. Here, we have assessed the possible regulatory role of cannabinoid CB2 receptors in stress-induced excitotoxicity and neuroinflammation.


METHODS
We used wild type (WT), transgenic overexpressing CB2 receptors (CB2xP) and CB2 receptor knockout (CB2-KO) mice exposed to immobilization and acoustic stress (2 h·day(-1) for 4 days). The CB2 receptor agonist JWH-133 was administered daily (2 mg·kg(-1), i.p.) to WT and CB2-KO animals. Glutamate uptake was measured in synaptosomes from frontal cortex; Western blots and RT-PCR were used to measure proinflammatory cytokines, enzymes and mediators in homogenates of frontal cortex.


RESULTS
Increased plasma corticosterone induced by stress was not modified by manipulating CB2 receptors. JWH-133 treatment or overexpression of CB2 receptors increased control levels of glutamate uptake, which were reduced by stress back to control levels. JWH-133 prevented the stress-induced increase in proinflammatory cytokines (TNF-α and CCL2), in NF-κB, and in NOS-2 and COX-2 and in the consequent cellular oxidative and nitrosative damage (lipid peroxidation). CB2xP mice exhibited anti-inflammatory or neuroprotective actions similar to those in JWH-133 pretreated animals. Conversely, lack of CB2 receptors (CB2-KO mice) exacerbated stress-induced neuroinflammatory responses and confirmed that effects of JWH-133 were mediated through CB2 receptors.


CONCLUSIONS
Pharmacological manipulation of CB2 receptors is a potential therapeutic strategy for the treatment of stress-related pathologies with a neuroinflammatory component, such as depression.
Departamento de Farmacología, Facultad de Medicina, Universidad Complutense de Madrid (UCM), Madrid, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain; Instituto de Investigación Sanitaria Hospital 12 de Octubre, Madrid, Spain; Instituto UCM de Investigación en Neuroquímica, Madrid, Spain.
S
S
Zoppi
J L
JL
Madrigal
J R
JR
Caso
M S
MS
García-Gutiérrez
J
J
Manzanares
J C
JC
Leza
B
B
García-Bueno
D000818:Animals; D002186:Cannabinoids / Q000494:pharmacology; D018932:Chemokine CCL2 / Q000235:genetics; D003345:Corticosterone / Q000097:blood; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D005625:Frontal Lobe / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism*; D008297:Male; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000378:metabolism*; D013315:Stress, Psychological / Q000378:metabolism*; D013574:Synaptosomes / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D002186:Cannabinoids; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D016328:NF-kappa B; D009573:Nitrites; D043885:Receptor, Cannabinoid, CB2; D014409:Tumor Necrosis Factor-alpha; D018698:Glutamic Acid; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D015232:Dinoprostone; C432747:1,1-dimethylbutyl-1-deoxy-Delta(9)-THC; D003345:Corticosterone
CB2 receptor; CB2xP mice; JWH-133; brain frontal cortex; excitotoxicity; neuroinflammation; stress