Novel protein kinase C-beta isoform selective inhibitor JTT-010 ameliorates both hyper- and hypoalgesia in streptozotocin- induced diabetic rats.
OBJECTIVE
Activation of protein kinase C (PKC) is thought to play an important role in the pathogenesis of diabetic microvascular complications. PKC-beta is elevated in hyperglycaemic conditions, both in vivo and in vitro. In this study, pharmacological effects of a novel PKC-beta isoform selective inhibitor, JTT-010 ((2R)-3-(2-aminomethyl-2,3-dihydro-1H-3a-azacyclopenta(a)inden-8-yl)-4-phenylaminopyrrole-2,5-dione monomethanesulphonate), on diabetic neuropathy were examined.


METHODS
PKC inhibitory activity of JTT-010 was evaluated with an enzyme assay. For the in vivo study, streptozotocin (STZ)-induced diabetic rats were treated with JTT-010 for 12 weeks and tail/sciatic nerve conduction velocity (NCV) evaluated. Hyper/hypoalgesia was evaluated using tail-flick and formalin tests.


RESULTS
JTT-010 inhibited PKC-betaI and -betaII with IC50 values of 4.0 and 2.3 nm respectively. For other PKC isoforms, IC50 values were 54 nm or greater. In STZ-induced diabetic rats showing a reduction in tail/sciatic nerve conduction velocities, JTT-010 (0.3-3 mg/kg) ameliorated the reduction of these velocities. In a formalin test, STZ-induced diabetic rats had hyperalgesia in the first phase. JTT-010 reduced nociceptive response at doses of 0.1 mg/kg or higher. Furthermore, STZ-induced diabetic rats showed hypoalgesia in the second phase of the formalin test and tail-flick test. JTT-010 also ameliorates these symptoms at doses of 0.1 mg/kg or higher.


CONCLUSIONS
These observations suggest that PKC-beta contributes not only to diabetic hyperalgesia, but also to hypoalgesia and also contributes to defects in NCV. PKC-beta inhibitor, JTT-010, may be beneficial in suppressing the development of diabetic nerve dysfunction, including hyperalgesia and hypoalgesia.
Sasase
T
T
Japan Tobacco, Central Pharmaceutical Research Institute, Murasaki-cho, Takatsuki, Osaka, Japan. tomohiko.sasase@ims.jti.co.jp
Yamada
H
H
Sakoda
K
K
Imagawa
N
N
Abe
T
T
Ito
M
M
Sagawa
S
S
Tanaka
M
M
Matsushita
M
M
D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000201:enzymology / Q000503:physiopathology; D003929:Diabetic Neuropathies / Q000201:enzymology / Q000503:physiopathology / Q000517:prevention & control*; D006930:Hyperalgesia / Q000201:enzymology / Q000503:physiopathology / Q000517:prevention & control*; D006987:Hypesthesia / Q000201:enzymology / Q000503:physiopathology / Q000517:prevention & control; D007189:Indans / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D009431:Neural Conduction / Q000187:drug effects; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D064546:Protein Kinase C beta; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000201:enzymology / Q000503:physiopathology
C508122:(2R)-3-(2-aminomethyl-2,3-dihydro-1H-3a-azacyclopenta(a)inden-8-yl)-4-phenylaminopyrrole-2,5-dione monomethanesulphonate; D007189:Indans; D011758:Pyrroles; D011493:Protein Kinase C; D064546:Protein Kinase C beta