Modulating bladder neuro-inflammation: RDP58, a novel anti-inflammatory peptide, decreases inflammation and nerve growth factor production in experimental cystitis.
OBJECTIVE
In interstitial cystitis (IC) inflammation induces and perpetuates neurotrophic changes in the bladder, resulting in the symptoms of frequency, urgency and pain. RDP58 (NH2-arg-norleucine (nle)-nle-arg-nle-nle-nle-gly-tyr-CONH2) (Sangstat Corp., Fremont, California) is a novel synthetic peptide that inhibits early signal transduction pathways for the expression of inflammatory cytokines. In this study we evaluated the effects of intravesical RDP58 on an established model of cystitis.


METHODS
Mice were catheterized and equal volumes of Escherichia coli lipopolysaccharide (LPS) or saline were instilled into the bladder. After 45 minutes the bladders were drained and distilled water or RDP58 (1 mg/ml) was instilled for 30 minutes. At 24 hours later the bladders were excised and cultured for analysis of tumor necrosis factor-alpha (TNF-alpha), substance P (SP) and nerve growth factor (NGF) production, as quantified by enzyme-linked immunosorbent assay.


RESULTS
LPS caused severe inflammation in mouse bladders compared with controls. Exposure to LPS increased the levels of TNF-alpha, SP and NGF production compared with controls (each p <0.05). In LPS exposed mice RDP58 significantly decreased inflammatory parameters by 82% 24 hours after treatment (p <0.05). Within 4 hours RDP58 abolished TNF-alpha production and at 24 hours TNF-alpha remained undetectable. RDP58 also significantly decreased SP and NGF production in LPS exposed bladders by more than 40% and 85%, respectively (each p <0.05).


CONCLUSIONS
Inflammatory models of cystitis result in increased levels of TNF-alpha, SP and NGF production in the bladder, paralleling the hypothesized neuro-inflammatory etiology of IC. RDP58 decreases inflammation and neurotrophic factors in vivo and it may potentially treat bladder disorders with an inflammatory component, such as IC.
Gonzalez
Ricardo R
RR
Weill Medical College of Cornell University, New York, New York 10021, USA.
Fong
Timothy
T
Belmar
Nicole
N
Saban
Marcia
M
Felsen
Diane
D
Te
Alexis
A
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D003556:Cystitis / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism*; D005260:Female; D015395:Histocompatibility Antigens Class I; D051379:Mice; D008810:Mice, Inbred C57BL; D020932:Nerve Growth Factor / Q000096:biosynthesis*; D010455:Peptides / Q000627:therapeutic use*
D000893:Anti-Inflammatory Agents; D015395:Histocompatibility Antigens Class I; D010455:Peptides; C092373:allotrap; D020932:Nerve Growth Factor