Suppression of Detrusor-Sphincter Dyssynergia by Herpes Simplex Virus Vector Mediated Gene Delivery of Glutamic Acid Decarboxylase in Spinal Cord Injured Rats

Abstract

We investigated whether replication defective herpes simplex virus vectors encoding genes of glutamic acid decarboxylase, the gamma-aminobutyric acid synthesis enzyme, could suppress detrusor-sphincter dyssynergia in rats with spinal cord injury. One week after spinalization herpes simplex virus vectors expressing glutamic acid decarboxylase and green fluorescent protein were injected into the bladder wall. Spinal cord injured rats without herpes simplex virus injection (sham treated) and those injected with LacZ encoding herpes simplex virus vectors served as controls. Three weeks after viral injection we simultaneously recorded urethral and intravesical pressure in awake rats. In the glutamic acid decarboxylase group the urethral pressure increase during bladder contraction was significantly decreased by 77% to 79% compared with that in the sham treated and LacZ groups. Bladder activity and urethral baseline pressure did not differ among the 3 groups. Intrathecal application of the gamma-aminobutyric acid-A receptor antagonist bicuculline almost completely reversed the decrease in the urethral pressure increase during bladder contractions while intrathecal saclofen (Tocris Cookson, Ellisville, Missouri), a gamma-aminobutyric acid-B receptor antagonist, partially reversed it. In the glutamic acid decarboxylase group the mRNA of glutamic acid decarboxylase 67 was significantly increased in L6-S1 dorsal root ganglia, which is where bladder afferents originate, compared with that in the LacZ group. Herpes simplex virus based glutamic acid decarboxylase gene transfer to bladder afferent pathway may represent a novel approach to detrusor-sphincter dyssynergia in cases of spinal cord injury.