Atrial Natriuretic Peptide Reduces Ischemia/Reperfusion-Induced Spinal Cord Injury in Rats by Enhancing Sensory Neuron Activation

Abstract

We recently demonstrated that calcitonin gene-related peptide (CGRP) released from sensory neurons reduces spinal cord injury (SCI) by inhibiting neutrophil activation through an increase in the endothelial production of prostacyclin (PGI 2 ). Carperitide, a synthetic ␣-human atrial natriuretic peptide (ANP), reduces ischemia/reperfusion (I/R)-induced tissue injury. However, its precise therapeutic mechanism(s) remains to be elucidated. In the present study, we examined whether ANP reduces I/R-induced spinal cord injury by enhancing sensory neuron activation using rats. ANP increased CGRP release and cellular cAMP levels in dorsal root ganglion neurons isolated from rats in vitro. The increase in CGRP release induced by ANP was reversed by pretreatment with capsazepine, an inhibitor of vanilloid receptor-1 activation, or with (9S,10S,12R)-2,3,9,10,11,12-hexahydro-10-hydroxy-9-methyl-1-oxo-9,12-epoxy-1H-diindolo[1,2,3-fg:3Ј,2Ј,1Ј-kl]pyrrolo[3,4-i][1,6]-benzodiazocine-10-carboxylic acid hexyl ester (KT5720), an inhibitor of protein kinase A (PKA), suggesting that ANP might increase CGRP release from sensory neurons by activating PKA through an increase in the cellular cAMP level. Spinal cord ischemia was induced in rats using a balloon catheter placed in the aorta. ANP reduced mortality and motor disturbances by inhibiting reduction of the number of motor neurons in animals subjected to SCI. ANP significantly enhanced I/R-induced increases in spinal cord tissue levels of CGRP and 6-keto-prostaglandin F 1␣ . a stable metabolite of PGI 2 . ANP inhibited I/R-induced increases in spinal cord tissue levels of tumor necrosis factor and myeloperoxidase. Pretreatment with 4Ј-chloro-3-methoxycinnamanilide (SB366791), a specific vanilloid receptor-1 antagonist, and indomethacin reversed the effects of ANP. These results strongly suggest that ANP might reduce I/R-induced SCI in rats by inhibiting neutrophil activation through enhancement of sensory neuron activation.

Glycyrrhizin attenuates rat ischemic spinal cord injury by suppressing inflammatory cytokines and HMGB1

“…The motor functions of the rats were assessed at 24 h, 48 h, and 72 h after the procedure using the following modified Tarlov scale [6,17,18] : 0, no voluntary movement (complete paraplegia); 1, perceptible movement at the joint; 2, good joint mobility but unable to stand; 3, ability to stand but unable to walk; 4, weak walking; 5, complete recovery.…”

Stimulation of FcγRI on Primary Sensory Neurons Increases Insulin-Like Growth Factor-I Production, Thereby Reducing Reperfusion-Induced Renal Injury in Mice

“…SB366791 was dissolved in dimethyl sulfoxide (1%) with normal saline solution and was administered i.p. at a dosage of 500 mg/kg 30 min prior to ischemia (22). Anti-IGF-I Ab was dissolved in sterile distilled water and was administered s.c. at a dosage of 50 mg/kg 30 min prior to ischemia (29).…”

“…KT5720, an inhibitor of protein kinase A (PKA) (20), was purchased from Alexis (Basel, Switzerland). The 4-bromophenacyl bromide (4-BPB), an inihibitor of phospholipase A 2 (PLA 2 ) (21), and SB366791, a specific inhibitor of VR-1 (22), were purchased from Sigma-Aldrich (St. Louis, MO). Anti-FcgRI Ab and anti-IGF-I Ab were purchased from Santa Cruz Biochemistry (Santa Cruz, CA).…”

Fasting serum CGRP levels are related to calcium concentrations, but cannot be elevated by short-term calcium/vitamin D supplementation

“…It has been reported that BNP can be expressed in CGRP-containing neurons (Zhang et al, 2010), and BNP may elevate the vasorelaxant responses caused by CGRP (Fiscus et al, 1998). Otherwise, previous studies have shown that the circulating levels of CGRP can be increased obviously by administering ANP, long-acting natriuretic peptide (LANP) or vessel dilator (Vesely et al, 1997), and ANP may enhance the release of CGRP from sensory neurons by activating protein kinase A through increasing the cellular cAMP (Nakayama et al, 2007). All of BNP, NT-proBNP and ANP may be elevated in severe heart failure, and they are considered as essential markers of heart failure (Potter, 2011;von Haehling et al, 2007).…”