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

A. Middlemas; J. D. Delcroix; N. M. Sayers; D. R. Tomlinson; Paul Fernyhough

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

A. Middlemas, J. D. Delcroix, N. M. Sayers, D. R. Tomlinson, Paul Fernyhough

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	1671-1682
Number of pages	11
Journal	Brain
Volume	126
Issue number	7
Publication status	Published - 1 Jul 2003

Keywords

DRG
Neurotrophic factors
NT-3
Peripheral neuropathy
SAPKs

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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@article{0a094c3b54c345e5b0ba0dd3017d6fe0,

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

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.",

keywords = "DRG, Neurotrophic factors, NT-3, Peripheral neuropathy, SAPKs",

author = "A. Middlemas and Delcroix, {J. D.} and Sayers, {N. M.} and Tomlinson, {D. R.} and Paul Fernyhough",

year = "2003",

month = jul,

day = "1",

language = "English",

volume = "126",

pages = "1671--1682",

journal = "Brain",

issn = "0006-8950",

publisher = "Oxford University Press",

number = "7",

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TY - JOUR

T1 - Enhanced activation of axonally transported stress-activated protein kinases in peripheral nerve in diabetic neuropathy is prevented by neurotrophin-3

AU - Middlemas, A.

AU - Delcroix, J. D.

AU - Sayers, N. M.

AU - Tomlinson, D. R.

AU - Fernyhough, Paul

PY - 2003/7/1

Y1 - 2003/7/1

N2 - 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.

AB - 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.

KW - DRG

KW - Neurotrophic factors

KW - NT-3

KW - Peripheral neuropathy

KW - SAPKs

M3 - Article

SN - 0006-8950

VL - 126

SP - 1671

EP - 1682

JO - Brain

JF - Brain

IS - 7

ER -

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

Abstract

Keywords

UN SDGs

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