Inhibition of lipopolysaccharide-induced microglia activation by calcitonin gene related peptide and adrenomedullin

Abstract

Calcitonin gene related peptide (CGRP) and adrenomedullin are potent biologically active peptides that have been proposed to play an important role in vascular and inflammatory diseases. Their function in the central nervous system is still unclear since they have been proposed as either pro-inflammatory or neuroprotective factors. We investigated the effects of the two peptides on astrocytes and microglia, cells of the central nervous system that exert a strong modulatory activity in the neuroinflammatory processes. In particular, we studied the ability of CGRP and adrenomedullin to modulate microglia activation, i.e. its competence of producing and releasing pro-inflammatory cytokines/chemokines that are known to play a crucial role in neuroinflammation. In this work we show that the two neuropeptides exert a potent inhibitory effect on lipopolysaccharide-induced microglia activation in vitro, with strong inhibition of the release of pro-inflammatory mediators (such as NO, cytokines and chemokines). Both CGRP and adrenomedullin are known to promote cAMP elevation, this second messenger cannot fully account for the observed inhibitory effects, thereby suggesting that other signaling pathways are involved. Interestingly, the inhibitory effect of CGRP and adrenomedullin appears to be stimulus specific, since direct activation with pro-inflammatory cytokines was not affected.Our findings clarify aspects of microglia activation, and contribute to the comprehension of the switch from reparative to detrimental function that occurs when glia is exposed to different conditions. Moreover, they draw the attention to potential targets for novel pharmacological intervention in pathologies characterized by glia activation and neuroinflammation.

Calcitonin Gene-Related Peptide Ameliorates Hyperoxia-Induced Lung Injury in Neonatal Rats

“…In fact, the sensory neurons and their peptides may contribute to the maintenance of tissue integrity by regulating the inflammatory response, as suggested by the results of the current study. Consistent with these findings, researchers have noted that CGRP treatment can inhibit the production of TNF-α and other pro-inflammatory cytokines (Millet et al 2000;Consonni et al 2011). In addition, as one of the prostaglandins, PGI2 can exert anti-inflammatory effects by inhibiting the production of TNF through inhibition of its transcription (Jorres et al 1997).…”

Involvement of calcitonin gene-related peptide and receptor component protein in experimental autoimmune encephalomyelitis

“…Primary microglia was prepared according to Consonni et al (2011) and a pCDNA3 expression plasmid encoding Venus-RCP was transfected by Lipofectamine 2000 (Life Technologies) following manufacturer's instructions. Quantification of Venus-RCP in the nucleus was performed by IN Cell Analyzer 1000 (GE Lifesciences).…”

“…CGRP and adrenomedullin brain-restricted actions have been analyzed in headaches studies, but whether the action is restricted to sensory endings of brain vasculature or brain parenchyma has not yet been defined. We recently showed that both CGRP and adrenomedullin inhibit the secretion of pro-inflammatory mediators from activated microglia (Consonni et al, 2011), and in the current studies we have addressed the role of these peptides in neuroinflammation.…”

Ceruloplasmin potentiates nitric oxide synthase activity and cytokine secretion in activated microglia

“…Cytokine concentrations were used according to the literature as to obtain maximal effect on glial cells (see [43] and references therein) [41,44]. In some cases N ω -Nitro-L-arginine methyl ester hydrochloride (L-NAME), an arginine-analog that selectively inhibits iNOS function was administered at different concentrations (0.1, 0.25 and 1 mM) 1 hour before pro-inflammatory stimuli administration and left for the entire duration of the treatment.…”