Limaprost reduces motor disturbances by increasing the production of insulin-like growth factor I in rats subjected to spinal cord injury.
Calcitonin gene-related peptide (CGRP) released from sensory neurons increases the production of a neuroprotective substance insulin-like growth factor I (IGF-I), and sensory neuron stimulation contributes to a reduction of spinal cord injury (SCI) by inhibiting inflammatory responses in rats. Because receptors for prostaglandin E₂ (EP receptors) are present on sensory neurons, it is possible that prostaglandin E₁ analog limaprost reduces SCI by increasing IGF-I production through sensory neuron stimulation. We examined this possibility in rats subjected to compression-trauma-induced SCI. Limaprost increased the CGRP release from dorsal root ganglion (DRG) neurons isolated from rats, and this increase was reversed by pretreatment with the EP4 receptor antagonist ONO-AE3-208. Spinal cord tissue levels of CGRP and IGF-I were increased after the induction of SCI, peaking at 2 h postinduction. The intravenous administration of limaprost enhanced increases of spinal cord tissue levels of CGRP, IGF-I, and IGF-I mRNA at 2 h after the induction of SCI. Increases of spinal cord tissue levels of tumor necrosis factor, caspase-3, myeloperoxidase, and the number of apoptotic nerve cells were inhibited by the administration of limaprost. Motor disturbances of hind legs in animals subjected to the compression-trauma-induced SCI were reduced by the administration of limaprost. These effects of limaprost were reversed completely by pretreatment with a specific transient receptor potential vanilloid 1 inhibitor SB366791 and by sensory denervation. These observations strongly suggest that limaprost may increase the IGF-I production by stimulating sensory neurons in the spinal cord, thereby ameliorating compression-trauma-induced SCI through attenuation of inflammatory responses.
Umemura
Takehiro
T
Department of Emergency and Critical Care Medicine, School of Medicine, Fukuoka University, Fukuoka, Japan.
Harada
Naoaki
N
Kitamura
Taisuke
T
Ishikura
Hiroyasu
H
Okajima
Kenji
K
D000527:Alprostadil / Q000031:analogs & derivatives* / Q000494:pharmacology; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D002211:Capsaicin / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D002934:Cinnamates / Q000494:pharmacology; D003714:Denervation; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression / Q000187:drug effects; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism*; D008297:Male; D009068:Movement / Q000187:drug effects* / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018689:Sensory System Agents / Q000494:pharmacology; D013047:Specific Pathogen-Free Organisms; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D014665:Vasodilator Agents / Q000494:pharmacology*
D000813:Anilides; D002934:Cinnamates; C477659:N-(3-methoxyphenyl)-4-chlorocinnamanilide; D012333:RNA, Messenger; D018689:Sensory System Agents; D014665:Vasodilator Agents; C548904:insulin-like growth factor-1, rat; D007334:Insulin-Like Growth Factor I; D053148:Caspase 3; D000527:Alprostadil; D015740:Calcitonin Gene-Related Peptide; C059238:limaprost; D002211:Capsaicin