Enhanced activation of axonally transported stress-activated protein kinases in peripheral nerve in diabetic neuropathy is prevented by neurotrophin-3

Author： Delcroix J.-D.

Publisher： Oxford University Press

ISSN： 1460-2156

Source： Brain, Vol.126, Iss.7, 2003-07, pp. : 1671-1682

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Abstract

The objective was to determine whether stress-activated protein kinases (SAPKs) mediated the transfer of diabetes-induced stress signals from the periphery to somata of sensory neurons. Thus, we characterized axonal transport of SAPKs in peripheral nerve, studied any alteration in streptozotocin (STZ)-diabetic rats and examined effects of neurotrophin-3 (NT-3) on diabetes-induced events. We demonstrate that c-jun N-terminal kinase (JNK) and p38 are bidirectionally axonally transported at fast rates in sciatic nerve. In STZ-diabetic rats the relative levels of retrograde axonal transport of phosphorylated (activated) JNK and p38 were raised compared with age-matched controls (all data are in arbitrary units and expressed as fold increase over control: JNK 54–56 kDa isoforms, control 1.0 ± 0.19, diabetic 2.5 ± 0.26; p38, control 1.0 ± 0.09, diabetic 2.9 ± 0.52; both P < 0.05). transport="" of="" total="" enzyme="" levels="" of="" jnk="" and="" p38="" and="" phosphorylated="" extracellular="" signal-regulated="" kinase="" (erk)="" was="" not="" significantly="" altered="" and="" anterograde="" axonal="" transport="" of="" phosphorylated="" jnk="" and="" p38="" was="" unaffected="" by="" diabetes.="" the="" transcription="" factor="" atf-2,="" which="" is="" phosphorylated="" and="" activated="" by="" jnk="" and="" p38,="" also="" exhibited="" elevated="" retrograde="" axonal="" transport="" in="" stz-diabetic="" animals="" (control="" 1.0 ± 0.07,="" diabetic="" 3.0 ± 0.41;="">P < 0.05). treatment="" of="" stz-diabetic="" animals="" with="" 5 mg/kg="" human="" recombinant="" nt-3="" prevented="" activation="" of="" jnk="" and="" p38="" in="" sciatic="" nerve="" (phosphorylated="" jnk,="" control="" 1.0 ± 0.09,="" diabetic="" 1.95="" ±="" 0.35,="" diabetic="" +="" nt-3="" 1.09 ± 0.12;="">P < 0.05 diabetic="" versus="" others;="" phosphorylated="" p38,="" control="" 1.0 ± 0.16,="" diabetic="" 4.7 ± 0.9,="" diabetic="" +="" nt-3="" 1.19 ± 0.18;="">P < 0.05 diabetic="" versus="" others).="" the="" results="" show="" that="" jnk="" and="" p38="" are="" transported="" axonally="" and="" may="" mediate="" the="" transfer="" of="" diabetes-related="" stress="" signals,="" possibly="" triggered="" by="" loss="" of="" neurotrophic="" support,="" from="" the="" periphery="" to="" the="" neuronal="" soma.="">