Abstract
BACKGROUND:
Long term exposure to stress has been demonstrated to cause neuroinflammation through a sustained overproduction of free radicals, including nitric oxide, via an increased inducible nitric oxide synthase (iNOS) activity. We have previously demonstrated that iNOS activity and mRNA are significantly upregulated in the rat hippocampus following just 4 hours of restraint stress. Similar to nitric oxide, endocannabinoids are synthesised on demand, with preclinical observations suggesting that cannabinoid receptor agonists and endocannabinoid enhancers inhibit nitrergic activity. Specifically, previous work has shown that enhancement of endocannabinoids via inhibition of fatty acid amide hydrolase with PF-3845 reduced iNOS-expressing microglia following traumatic brain injury. However, this describes cannabinoid modulation following physical injury and therefore the present study aimed to examine the effects of PF-3845 in the modulation of nitrergic and inflammatory-related genes within the hippocampus after acute stress exposure.
METHODS:
Following vehicle or PF-3845 injections (5 mg/kg; i.p.), male Wistar rats were exposed to 0 (control), 60, 240, or 360 minutes of restraint stress after which plasma and dorsal hippocampus were isolated for further biochemical and gene expression analysis.
RESULTS:
The results demonstrate that pre-treatment with PF-3845 rapidly ameliorates plasma corticosterone release at 60 minutes of stress. An increase in endocannabinoid signalling also induces an overall attenuation in iNOS, tumor necrosis factor-alpha convertase, interleukin-6, cyclooxygenase-2, peroxisome proliferator-activated receptor gamma mRNA, and the transactivation potential of NF-κB in the hippocampus.
CONCLUSIONS:
These results suggest that enhanced endocannabinoid levels in the dorsal hippocampus have an overall anti-nitrosative and anti-inflammatory effect following acute stress exposure.
- PMID: 29579222
- DOI: 10.1093/ijnp/pyy033
