Background and Objectives Activation of cholinergic anti-inflammatory pathway (CAP) has shown to be important for regulation of arthritis, and ongoing trials show promising effects of vagus nerve stimulation (VNS) in RA. While peripheral mechanisms have been thoroughly investigated, central effects remain elusive. We showed recently that central nervous inflammation is a feature of RA (Lampa et al, PNAS 2012), and also coupled to autonomic activity. Moreover, prostaglandin E2 (PGE2) may act as an important neuromediator in this context and we have earlier shown impaired CAP in knockout mice for the PGE2 inducing enzyme mPGES (Le Maître et al, EWRR 2012). Here, we aimed to study the effects of VNS on central prostaglandin system and neuropeptides associated with inflammation.
Materials and Methods After VN isolation, we injected lipopolysaccharide (2 mg/kg) intraperitoneally. The VN was either electrically stimulated for 5 minutes (VNS) or left unstimulated (SHAM). After 6 hours, mice were sacrificed and brains were collected. Expression of the inducible enzymes COX2 and mPGES-1 in frozen brain sections was quantified by immunohistochemistry. mRNA levels of c-FOS and substance P (SP), a key central neuropeptide, were analysed by in situ hybridisation. Investigated areas include Hippocampus (Hi), Hypothalamus (Hy), periaqueductal grey (PAG), Cingulate Cortex (CC) and Dorsal raphe nuclei (DRN).
Results c-FOS mRNA level significantly increased in vagus related areas such as Hi (75.3 ± 5.7 (mean grey value; SHAM) versus 105.0 ± 1.7 (VNS); p < 0.001) and Hy (73.8 ± 9.4 versus 102.2 ± 6.7; p < 0.05). Hi and Hy as well as all other regions displayed a strong trend to VNS-induced increase in mPGES-1 protein, (Hi 0.66 ± 0.29 versus 0.88 ± 0.25 and Hy 0.72 ± 0.44 versus 1.49 ± 0.57). COX2 protein tended to decrease in all areas except CC. Interestingly, VNS exhibited strong inhibitory effects on the SP mRNA expression (Hi 119.9 ± 4.9 versus 98.0 ± 4.2 p < 0.05; Hy 114.0 ± 6.5 versus 83.1 ± 8.2; p < 0.05).
Conclusions These data indicate a role for prostaglandins and mPGES in central mechanisms of the CAP. The decreased brain COX2 expression may be related to the suppression of systemic inflammation caused by peripheral CAP action, while the up regulation of mPGES-1 in vagus-related brain areas seems to be directly related to central CAP action. These effects may be of clinical importance both in the coming VNS RA trials as well as in the current and future pharmacological interventions of the prostaglandin pathway. The strong suppressive effect on SP in vagus projected areas reveals the importance of CAP in complex brain networks.
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