Statins Decrease Expression of the Proinflammatory Neuropeptides Calcitonin Gene-Related Peptide and Substance P in Sensory Neurons

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.

Neuronal Phenotype in the Mature Nervous System Is Maintained by Persistent Retrograde Bone Morphogenetic Protein Signaling

“…Intriguingly, BMP ligands are expressed at the target tissues of those neurons (V. May, personal communication). Similarly, systemic statins reduce CGRP expression in adult cutaneous afferents in vivo, likely by inhibition of BMP signaling (Bucelli et al, 2008). These results led the authors of both studies to propose that retrograde BMP signaling is required to maintain normal neuropeptide levels.…”

PKA-Induced Internalization of Slack KNaChannels Produces Dorsal Root Ganglion Neuron Hyperexcitability

“…Neurons are cultured in serum-free medium containing NGF. NGF is critical for embryonic neuronal survival (Chalazo-nitis et al, 1987); however, this condition also produces a highly enriched population of peptidergic DRG neurons (Bucelli et al, 2008). AP properties generally resemble those of mature peptidergic nociceptors (Fig.…”

Migraine-Associated Cerebrovascular Disorders

“…Основываясь на клинических наблюдениях, было проведено несколько клинических исследований влия-ния приема статинов на частоту приступов мигрени, в которых был зарегистрирован профилактический эффект аторвастатина и симвастатина [28]. Механизм терапевти-ческого эффекта этого класса препаратов основан на данных подавления экспрессии CGRP и субстанции P и ослабления активации нейрокининовых рецепторов в каудальном ядре тройничного нерва, что является ключе-вым механизмом формирования боли при мигрени [28].…”

“…Механизм терапевти-ческого эффекта этого класса препаратов основан на данных подавления экспрессии CGRP и субстанции P и ослабления активации нейрокининовых рецепторов в каудальном ядре тройничного нерва, что является ключе-вым механизмом формирования боли при мигрени [28].…”