Novel protein kinase C-beta isoform selective inhibitor JTT-010 ameliorates both hyper- and hypoalgesia in streptozotocin- induced diabetic rats.

Abstract

AIM:

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.

• Authors: T Sasase, H Yamada, K Sakoda, N Imagawa, T Abe, M Ito, S Sagawa, M Tanaka, M Matsushita
• Journal: Diabetes, obesity & metabolism (Diabetes Obes Metab) Vol. 7 Issue 5 Pg. 586-94 (Sep 2005) ISSN: 1462-8902 [Print] England
• PMID: 16050952 (Publication Type: Journal Article)

Chemical References

• (2R)-3-(2-aminomethyl-2,3-dihydro-1H-3a-azacyclopenta(a)inden-8-yl)-4-phenylaminopyrrole-2,5-dione monomethanesulphonate
• Indans
• Pyrroles
• Protein Kinase C
• Protein Kinase C beta

Topics

• Animals
• Diabetes Mellitus, Experimental (complications, enzymology, physiopathology)
• Diabetic Neuropathies (enzymology, physiopathology, prevention & control)
• Hyperalgesia (enzymology, physiopathology, prevention & control)
• Hypesthesia (enzymology, physiopathology, prevention & control)
• Indans (pharmacology, therapeutic use)
• Male
• Neural Conduction (drug effects)
• Protein Kinase C (antagonists & inhibitors, metabolism, physiology)
• Protein Kinase C beta
• Pyrroles (pharmacology, therapeutic use)
• Rats
• Rats, Sprague-Dawley
• Sciatic Nerve (enzymology, physiopathology)