AS1069562 is the (+)-isomer of
indeloxazine, which had been clinically used as a cerebral activator for the treatment of
cerebrovascular diseases with
serotonin and
norepinephrine reuptake inhibition (
SNRI) and neuroprotection. Here, we compared the
analgesic effects of repeated treatment with
AS1069562 and
duloxetine, a selective
SNRI, on
pain-related behavior in a rat model of
streptozotocin (STZ)-induced
diabetic neuropathy. Further, we also evaluated the effects on the expression of
neurotrophic factors and nerve conduction velocity.
AS1069562 and
duloxetine by single daily administration for 4 weeks significantly improved
mechanical allodynia in STZ-induced diabetic rats and did not affect plasma
glucose level or
body weight. Interestingly, the
analgesic effect of
AS1069562 continued after a consecutive 1-week treatment discontinuation, although the plasma concentration of
AS1069562 was reduced to undetectable levels. In contrast, the efficacy of
duloxetine disappeared
after treatment discontinuation. Expression analysis demonstrated that
AS1069562 significantly restored decreased
insulin-like growth factor 1 and
fibroblast growth factor 2 mRNA levels in dorsal root ganglion and spinal cord, respectively, whereas
duloxetine did not affect the expression levels of
neurotrophic factors. In addition,
AS1069562 reversed the slowing of nerve conduction velocity. The results of this study indicate that the
analgesic effect of repeated dosing of
AS1069562 but not
duloxetine is persistent even after a 1-week
drug discontinuation in STZ-induced diabetic rats. Restoration of
neurotrophic factors may be involved in the curative-like pharmacological effect of this agent. Thus,
AS1069562 may potentially offer a better treatment option for patients with
painful diabetic neuropathy than
duloxetine via different mechanisms.