FK1706, a novel non-immunosuppressive immunophilin ligand, modifies gene expression in the dorsal root ganglia during painful diabetic neuropathy.
OBJECTIVE
FK1706, a non-immunosuppressive immunophilin ligand, potentiated nerve growth factor-induced neurite outgrowth, putatively mediated via FKBP-52 and the Ras/Raf/MAPK signaling pathway. It also improved mechanical allodynia accompanied by the recovery of intraepidermal nerve fiber density in a painful diabetic neuropathy in rats. The aim of this study was to demonstrate the gene expression profiling in dorsal root ganglion in streptozotocin-induced diabetic rats related to pain and anti-allodynia effects of FK1706 administration to elucidate the putative mechanisms of its neurotrophic activity in vivo. Here, we analyzed gene expression of the dorsal root ganglia using microarray together with behavioral measurement of mechanical allodynia in diabetic rats to try to capture the global fingerprint of changes in gene expression associated with FK1706 administration.


METHODS
The withdrawal threshold of streptozotocin-induced diabetic rats was measured by an electronic von Frey system. The gene expression of the ganglia from L4 to L6 obtained from streptozotocin-treated rats with or without chronic administration of FK1706 was analyzed using an Affymetrix GeneChip to extract interesting genes in the development of mechanical allodynia in diabetes and anti-allodynia effect of FK1706.


RESULTS
Daily oral administration of FK1706 improved mechanical allodynia without decreasing plasma glucose levels. From gene expression analysis, the expression of thioredoxin interacting protein gene was sustained to increased change, whereas those of collagen I alpha1, II alpha1 and IX alpha1 genes were decreased from 2 to 4 weeks after streptozotocin injection. While no changes occurred after 1 week of commencing of FK1706 administration (2 weeks after streptozotocin injection), changes in expression more than 1.5-fold were observed for genes such as Ckm, Actn3, Atp2a1, Bglap, Acta1, Myl1, Tnnc2, and Mylpf at 2 weeks of FK1706 administration (3 weeks after streptozotocin injection). The genes RGD1564519, Hbb, LOC689064, Arpc4 and S100a9 were upregulated in comparison with streptozotocin-injected control group at 3 weeks of FK1706 administration; on the other hand, those of Actn3, Atp2a1 were downregulated by FK1706.


CONCLUSIONS
FK1706 ameliorates mechanical allodynia with accompanying increases in gene expressions possibly related to neurite outgrowth, development, differentiation, and nociceptive sensitivity.
Applied Pharmacology Research Labs, Astellas Pharma, Inc, Tsukuba, Ibaraki, Japan. shunji.yamazaki@astellas.com
Shunji
S
Yamazaki
Takayuki
T
Yamaji
Nobuhito
N
Murai
Hiroko
H
Yamamoto
Takashi
T
Matsuda
Raymond Daniel
RD
Price
Nobuya
N
Matsuoka
D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000188:drug therapy / Q000473:pathology*; D004195:Disease Models, Animal; D005727:Ganglia, Spinal / Q000187:drug effects*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D006930:Hyperalgesia / Q000188:drug therapy / Q000209:etiology*; D020104:Immunophilins / Q000378:metabolism*; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D017288:Pain Threshold / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D016559:Tacrolimus / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D013879:Thioredoxins / Q000378:metabolism; D013997:Time Factors
D013879:Thioredoxins; D020104:Immunophilins; C505380:FK1706; D016559:Tacrolimus