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

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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.