title: AS1069562, the (+)-isomer of indeloxazine, but not duloxetine has a curative-like analgesic effect in a rat model of streptozotocin-induced diabetic neuropathy.
abstract: 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.
authors.affiliation: Pharmacology Research Laboratories, Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan. Electronic address: nobuhito.murai@astellas.com.
authors.forename: Nobuhito
authors.initials: N
authors.lastname: Murai
authors.affiliation: Pharmacology Research Laboratories, Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Aoki
authors.affiliation: Pharmacology Research Laboratories, Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Tamura
authors.affiliation: Pharmacology Research Laboratories, Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Yamamoto
authors.affiliation: Analysis & Pharmacokinetics Research Laboratories, Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan.
authors.forename: Nozomu
authors.initials: N
authors.lastname: Hamakawa
authors.affiliation: Pharmacology Research Laboratories, Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan.
authors.forename: Nobuya
authors.initials: N
authors.lastname: Matsuoka
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology; D003929:Diabetic Neuropathies / Q000188:drug therapy* / Q000503:physiopathology; D000068736:Duloxetine Hydrochloride; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000378:metabolism; D005727:Ganglia, Spinal / Q000187:drug effects / Q000503:physiopathology; D006930:Hyperalgesia / Q000188:drug therapy / Q000503:physiopathology; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008297:Male; D009025:Morpholines / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D009431:Neural Conduction / Q000187:drug effects; D014179:Neurotransmitter Uptake Inhibitors / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000187:drug effects / Q000503:physiopathology; D013311:Streptozocin; D013876:Thiophenes / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D000700:Analgesics; D009025:Morpholines; D014179:Neurotransmitter Uptake Inhibitors; D012333:RNA, Messenger; D013876:Thiophenes; C548904:insulin-like growth factor-1, rat; D016222:Fibroblast Growth Factor 2; D013311:Streptozocin; D007334:Insulin-Like Growth Factor I; C020852:indeloxazine; D000068736:Duloxetine Hydrochloride
keywords: AS1069562; Allodynia; Antidepressant; Diabetic neuropathy; Duloxetine; Pain