Effects of liposome-based local suppression of nerve growth factor in the bladder on autonomic dysreflexia during urinary bladder distention in rats with spinal cord injury.
To examine (1) whether spinal cord injury (SCI) time-dependently increases the severity of autonomic dysreflexia (AD) and expression levels of bladder nerve growth factor (NGF) protein, and (2) whether local suppression of NGF in the bladder improves SCI-induced AD in rats.



SCI was produced by the transection of the T2/3 spinal cord in female Sprague-Dawley rats. At 4 or 8weeks after SCI, differences in the mean arterial blood pressure (ΔMAP) and heart rate (ΔMHR) during graded increases in intravesical pressure to 20, 40 and 60cm H2O from those before bladder distention and NGF protein levels in the bladder wall were evaluated in spinal intact and SCI rats under urethane anesthesia. Seven weeks after SCI liposome-NGF antisense conjugates were administered intravesically to the animals. At 1week after intravesical treatment (8weeks after SCI), ΔMAP and ΔMHR during bladder distention and bladder NGF protein expression were evaluated.



The ΔMAP and ΔMHR were increased in a graded manner in response to bladder distention at intravesical pressures of 20, 40 and 60cm H2O in SCI rats. These AD-like cardiovascular responses and NGF protein expression in the bladder mucosal and muscle layers were increased after SCI in a time-dependent manner. The liposome-NGF antisense treatment significantly reduced the NGF protein overexpression in the mucosal layer of SCI rat bladder and reduced ΔMAP and ΔMHR elicited by bladder distention.



These results indicate that the duration of the post-SCI recovery period affects the severity of AD induced by bladder distention as well as the level of bladder NGF protein, and that local suppression of NGF expression in the bladder reduces SCI-induced AD. Thus, Intravesical application of liposome-NGF antisense conjugates can be a new effective therapy for bladder distention-induced AD after SCI.
Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Southern Knights' Laboratory, Okinawa, Japan; Okinawa Kyodo Hospital, Okinawa, Japan.
Katsumi
K
Kadekawa
Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Tsuyoshi
T
Yoshizawa
Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Naoki
N
Wada
Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Takahiro
T
Shimizu
Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Tsuyoshi
T
Majima
Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Pradeep
P
Tyagi
Department of Pharmacology & Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
William C
WC
de Groat
Southern Knights' Laboratory, Okinawa, Japan.
Kimio
K
Sugaya
Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Pharmacology & Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Electronic address: nyos@pitt.edu.
Naoki
N
Yoshimura
D000704:Analysis of Variance; D000818:Animals; D020211:Autonomic Dysreflexia / Q000188:drug therapy* / Q000209:etiology; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D008081:Liposomes / Q000627:therapeutic use*; D020932:Nerve Growth Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013119:Spinal Cord Injuries / Q000150:complications; D013997:Time Factors; D001743:Urinary Bladder / Q000187:drug effects / Q000294:innervation / Q000378:metabolism*; D014563:Urodynamics / Q000187:drug effects
D008081:Liposomes; D020319:Oligodeoxyribonucleotides, Antisense; D020932:Nerve Growth Factor
Autonomic dysreflexia; Liposome NGF antisense; Rat; Spinal cord injury