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Targeting apoptosis signalling kinase-1 (ASK-1) does not prevent the development of neuropathy in streptozotocin-induced diabetic mice.

Newton VL, Ali S, Duddy G, Whitmarsh AJ, Gardiner NJ - PLoS ONE (2014)

Bottom Line: Apoptosis signal-regulating kinase-1 (ASK1) is a mitogen-activated protein 3 kinase (MAPKKK/MAP3K) which lies upstream of the stress-activated MAPKs, JNK and p38.As a common upstream activator of both p38 and JNK, we hypothesised that activation of ASK1 contributes to nerve dysfunction in diabetic neuropathy.Levels of ASK1 do not change in the DRG, spinal cord, or sciatic nerve following induction of diabetes.

View Article: PubMed Central - PubMed

Affiliation: Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.

ABSTRACT
Apoptosis signal-regulating kinase-1 (ASK1) is a mitogen-activated protein 3 kinase (MAPKKK/MAP3K) which lies upstream of the stress-activated MAPKs, JNK and p38. ASK1 may be activated by a variety of extracellular and intracellular stimuli. MAP kinase activation in the sensory nervous system as a result of diabetes has been shown in numerous preclinical and clinical studies. As a common upstream activator of both p38 and JNK, we hypothesised that activation of ASK1 contributes to nerve dysfunction in diabetic neuropathy. We therefore wanted to characterize the expression of ASK1 in sensory neurons, and determine whether the absence of functional ASK1 would protect against the development of neuropathy in a mouse model of experimental diabetes. ASK1 mRNA and protein is constitutively expressed by multiple populations of sensory neurons of the adult mouse lumbar DRG. Diabetes was induced in male C57BL/6 and transgenic ASK1 kinase-inactive (ASK1n) mice using streptozotocin. Levels of ASK1 do not change in the DRG, spinal cord, or sciatic nerve following induction of diabetes. However, levels of ASK2 mRNA increase in the spinal cord at 4 weeks of diabetes, which could represent a future target for this field. Neither motor nerve conduction velocity deficits, nor thermal or mechanical hypoalgesia were prevented or ameliorated in diabetic ASK1n mice. These results suggest that activation of ASK1 is not responsible for the nerve deficits observed in this mouse model of diabetic neuropathy.

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Levels of 4-HNE, a marker of oxidative stress, increase in the spinal cord of diabetic mice, this is not prevented or ameliorated by lack of functioning ASK1.4-HNE levels (a secondary product of lipid peroxidation) in spinal cord protein samples, are higher in diabetic mice than in spinal cords obtained from control mice (C57 and ASK1n mice after 8 and 12 weeks of diabetes; *p<0.05, overall in a 2-way ANOVA, although not significantly different in post hoc tests n = 5). Data are expressed as mean values + SD.
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pone-0107437-g006: Levels of 4-HNE, a marker of oxidative stress, increase in the spinal cord of diabetic mice, this is not prevented or ameliorated by lack of functioning ASK1.4-HNE levels (a secondary product of lipid peroxidation) in spinal cord protein samples, are higher in diabetic mice than in spinal cords obtained from control mice (C57 and ASK1n mice after 8 and 12 weeks of diabetes; *p<0.05, overall in a 2-way ANOVA, although not significantly different in post hoc tests n = 5). Data are expressed as mean values + SD.

Mentions: Since increased oxidative stress is associated with diabetes [25], and also with activation of ASK1, we investigated the levels of 4-hydroxynonenal (4-HNE, a secondary product of lipid peroxidation) in the spinal cord. Levels of 4-HNE in spinal proteins from 8-week diabetic mice (Fig. 6; C57: 0.16 µg/µg±0.07 v.s. ASK1n: 0.15 µg/µg±0.04) were significantly greater than control levels (C57: 0.12 µg/µg±0.04 v.s. ASK1n: 0.09 µg/µg±0.01; p<0.05, overall in a 2-way ANOVA). Spinal 4-HNE levels of the 12-week cohort of mice showed a similar trend, although the difference between control and diabetic mice did not reach significance (Fig. 6). Whilst data shows a trend towards a lower baseline level of lipid peroxidation in ASK1n mice compared with C57s, this was not significant.


Targeting apoptosis signalling kinase-1 (ASK-1) does not prevent the development of neuropathy in streptozotocin-induced diabetic mice.

Newton VL, Ali S, Duddy G, Whitmarsh AJ, Gardiner NJ - PLoS ONE (2014)

Levels of 4-HNE, a marker of oxidative stress, increase in the spinal cord of diabetic mice, this is not prevented or ameliorated by lack of functioning ASK1.4-HNE levels (a secondary product of lipid peroxidation) in spinal cord protein samples, are higher in diabetic mice than in spinal cords obtained from control mice (C57 and ASK1n mice after 8 and 12 weeks of diabetes; *p<0.05, overall in a 2-way ANOVA, although not significantly different in post hoc tests n = 5). Data are expressed as mean values + SD.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4199525&req=5

pone-0107437-g006: Levels of 4-HNE, a marker of oxidative stress, increase in the spinal cord of diabetic mice, this is not prevented or ameliorated by lack of functioning ASK1.4-HNE levels (a secondary product of lipid peroxidation) in spinal cord protein samples, are higher in diabetic mice than in spinal cords obtained from control mice (C57 and ASK1n mice after 8 and 12 weeks of diabetes; *p<0.05, overall in a 2-way ANOVA, although not significantly different in post hoc tests n = 5). Data are expressed as mean values + SD.
Mentions: Since increased oxidative stress is associated with diabetes [25], and also with activation of ASK1, we investigated the levels of 4-hydroxynonenal (4-HNE, a secondary product of lipid peroxidation) in the spinal cord. Levels of 4-HNE in spinal proteins from 8-week diabetic mice (Fig. 6; C57: 0.16 µg/µg±0.07 v.s. ASK1n: 0.15 µg/µg±0.04) were significantly greater than control levels (C57: 0.12 µg/µg±0.04 v.s. ASK1n: 0.09 µg/µg±0.01; p<0.05, overall in a 2-way ANOVA). Spinal 4-HNE levels of the 12-week cohort of mice showed a similar trend, although the difference between control and diabetic mice did not reach significance (Fig. 6). Whilst data shows a trend towards a lower baseline level of lipid peroxidation in ASK1n mice compared with C57s, this was not significant.

Bottom Line: Apoptosis signal-regulating kinase-1 (ASK1) is a mitogen-activated protein 3 kinase (MAPKKK/MAP3K) which lies upstream of the stress-activated MAPKs, JNK and p38.As a common upstream activator of both p38 and JNK, we hypothesised that activation of ASK1 contributes to nerve dysfunction in diabetic neuropathy.Levels of ASK1 do not change in the DRG, spinal cord, or sciatic nerve following induction of diabetes.

View Article: PubMed Central - PubMed

Affiliation: Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.

ABSTRACT
Apoptosis signal-regulating kinase-1 (ASK1) is a mitogen-activated protein 3 kinase (MAPKKK/MAP3K) which lies upstream of the stress-activated MAPKs, JNK and p38. ASK1 may be activated by a variety of extracellular and intracellular stimuli. MAP kinase activation in the sensory nervous system as a result of diabetes has been shown in numerous preclinical and clinical studies. As a common upstream activator of both p38 and JNK, we hypothesised that activation of ASK1 contributes to nerve dysfunction in diabetic neuropathy. We therefore wanted to characterize the expression of ASK1 in sensory neurons, and determine whether the absence of functional ASK1 would protect against the development of neuropathy in a mouse model of experimental diabetes. ASK1 mRNA and protein is constitutively expressed by multiple populations of sensory neurons of the adult mouse lumbar DRG. Diabetes was induced in male C57BL/6 and transgenic ASK1 kinase-inactive (ASK1n) mice using streptozotocin. Levels of ASK1 do not change in the DRG, spinal cord, or sciatic nerve following induction of diabetes. However, levels of ASK2 mRNA increase in the spinal cord at 4 weeks of diabetes, which could represent a future target for this field. Neither motor nerve conduction velocity deficits, nor thermal or mechanical hypoalgesia were prevented or ameliorated in diabetic ASK1n mice. These results suggest that activation of ASK1 is not responsible for the nerve deficits observed in this mouse model of diabetic neuropathy.

Show MeSH
Related in: MedlinePlus