Poly(ADP-Ribose) polymerase inhibition improves erectile function in diabetic rats.
BACKGROUND
Erectile dysfunction (ED) is a common and hard-to-treat complication of diabetes mellitus (DM). Multiple lines of evidence have shown that poly(ADP-ribose) polymerase (PARP) activation plays an important role in neurovascular dysfunction in diabetes, which is the crucial mechanism for diabetic ED.


OBJECTIVE
To investigate the preventive benefit of a PARP inhibitor in a rat model of ED induced by diabetes.


METHODS
Established streptozotocin-diabetic male Sprague-Dawley rats were given PJ-34, a selective PARP inhibitor, by oral gavage at a dose of 10 mg/kg twice daily for 8 weeks. Erectile responses under electrical stimulation of the cavernous nerve, PARP activity and reactive oxygen species (ROS) production were measured. Nitric oxide synthase (NOS) isoforms were evaluated by Western blot and real-time quantitative PCR. Nuclear factor-kappa B activition and apoptosis in corpus cavernosa (CC) were also investigated.


METHODS
The effects of PARP inhibition on the development of diabetic ED were determined.


RESULTS
Diabetes markedly attenuated the erectile responses (intracavernosal pressure/mean systemic arterial blood pressure) and these were partially prevented by PJ-34 treatment. Promoted oxidative stress associated PARP activation was found in CC from vehicle-treated diabetic rats. PJ-34 blocked PARP activity and the diabetes-associated ROS generation. Decreased expression and activity of constitutive NOS (cNOS), including endothelial NOS (eNOS) and neuronal NOS (nNOS), associated with enhanced inducible NOS (iNOS) expression and activity were observed in vehicle-treated diabetic rats. Although PJ-34 had no effect on eNOS expression, it significantly prevented the decrease in nNOS expression and cNOS activity, and inhibited iNOS expression and activity in diabetic rats. PARP blockade by PJ-34 to some extent prevented diabetes-associated apoptosis and NF-κB activation.


CONCLUSIONS
Our results indicate that PARP activation plays an important role in the pathogenesis of diabetic ED and PARP inhibition may be a promising strategy to prevent development of diabetic ED.
Wan
Zhihua H
ZH
Department of Urology, the Central Hospital of Wuhan, Wuhan, Hubei, China.
Li
Wenzhou Z
WZ
Li
Yunzhu Z
YZ
Chen
Lin
L
Li
Guohao H
GH
Hu
Weifeng F
WF
Peng
Song
S
Yu
Jiajun J
JJ
Guo
Feng
F
D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D003920:Diabetes Mellitus; D003928:Diabetic Nephropathies; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects*; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects; D010410:Penile Erection / Q000187:drug effects*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species; D012307:Risk Factors
D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D017382:Reactive Oxygen Species