Statins decrease expression of the proinflammatory neuropeptides calcitonin gene-related peptide and substance P in sensory neurons

Robert C. Bucelli, Eugene A. Gonsiorek, Woo Yang Kim, Donald Bruun, Richard A. Rabin, Dennis Higgins, Pamela J Lein

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Clinical and experimental observations suggest that statins may be useful for treating diseases presenting with predominant neurogenic inflammation, but the mechanism(s) mediating this potential therapeutic effect are poorly understood. In this study, we tested the hypothesis that statins act directly on sensory neurons to decrease expression of proinflammatory neuropeptides that trigger neurogenic inflammation, specifically calcitonin gene-related peptide (CGRP) and substance P. Reverse transcriptase-polymerase chain reaction, radioimmunoassay, and immunocytochemistry were used to quantify CGRP and substance P expression in dorsal root ganglia (DRG) harvested from adult male rats and in primary cultures of sensory neurons derived from embryonic rat DRG. Systemic administration of statins at pharmacologically relevant doses significantly reduced CGRP and substance P levels in DRG in vivo. In cultured sensory neurons, statins blocked bone morphogenetic protein (BMP)-induced CGRP and substance P expression and decreased expression of these neuropeptides in sensory neurons pretreated with BMPs. These effects were concentration-dependent and occurred independent of effects on cell survival or axon growth. Statin inhibition of neuropeptide expression was reversed by supplementation with mevalonate and cholesterol, but not isoprenoid precursors. BMPs signal via Smad activation, and cholesterol depletion by statins inhibited Smad1 phosphorylation and nuclear translocation. These findings identify a novel action of statins involving down-regulation of proinflammatory neuropeptide expression in sensory ganglia via cholesterol depletion and decreased Smad1 activation and suggest that statins may be effective in attenuating neurogenic inflammation.

Original languageEnglish (US)
Pages (from-to)1172-1180
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume324
Issue number3
DOIs
StatePublished - Mar 2008
Externally publishedYes

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Hydroxymethylglutaryl-CoA Reductase Inhibitors
Calcitonin Gene-Related Peptide
Sensory Receptor Cells
Substance P
Neuropeptides
Neurogenic Inflammation
Spinal Ganglia
Cholesterol
Sensory Ganglia
Mevalonic Acid
Bone Morphogenetic Proteins
peptide P
Terpenes
Therapeutic Uses
Reverse Transcriptase Polymerase Chain Reaction
Radioimmunoassay
Axons
Cell Survival
Down-Regulation
Immunohistochemistry

ASJC Scopus subject areas

  • Pharmacology

Cite this

Statins decrease expression of the proinflammatory neuropeptides calcitonin gene-related peptide and substance P in sensory neurons. / Bucelli, Robert C.; Gonsiorek, Eugene A.; Kim, Woo Yang; Bruun, Donald; Rabin, Richard A.; Higgins, Dennis; Lein, Pamela J.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 324, No. 3, 03.2008, p. 1172-1180.

Research output: Contribution to journalArticle

Bucelli, Robert C. ; Gonsiorek, Eugene A. ; Kim, Woo Yang ; Bruun, Donald ; Rabin, Richard A. ; Higgins, Dennis ; Lein, Pamela J. / Statins decrease expression of the proinflammatory neuropeptides calcitonin gene-related peptide and substance P in sensory neurons. In: Journal of Pharmacology and Experimental Therapeutics. 2008 ; Vol. 324, No. 3. pp. 1172-1180.
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