Targeting Molecular Chaperones in Diabetic Peripheral Neuropathy

Li, Chengyuan; Dobrowsky, Rick T.

doi:10.5772/27836

Cited by 2 publications

(2 citation statements)

References 123 publications

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“…Hsp70 is a cytosolic chaperone that has demonstrated prominent neuroprotection in models of cerebral ischaemia and a variety of neurodegenerative disorders associated with aberrant protein aggregates (Li and Dobrowsky, 2012). For example, transgenic overexpression of PMP22 (peripheral myelin protein 22) results in formation of PMP22 aggregates and is a model of CMT1A (Robertson et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Induction of Heat Shock Protein 70 (Hsp70) prevents Neuregulin-Induced Demyelination by Enhancing the Proteasomal Clearance of c-Jun

Zhao

et al. 2012

ASN Neuro

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Modulating molecular chaperones is emerging as an attractive approach to treat neurodegenerative diseases associated with protein aggregation, DPN (diabetic peripheral neuropathy) and possibly, demyelinating neuropathies. KU-32 [N-(7-((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyl-tetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-yl)acetamide] is a small molecule inhibitor of Hsp90 (heat shock protein 90) and reverses sensory deficits associated with myelinated fibre dysfunction in DPN. Additionally, KU-32 prevented the loss of myelinated internodes induced by treating myelinated SC (Schwann cell)-DRG (dorsal root ganglia) sensory neuron co-cultures with NRG1 (neuregulin-1 Type 1). Since KU-32 decreased NRG1-induced demyelination in an Hsp70-dependent manner, the goal of the current study was to clarify how Hsp70 may be mechanistically linked to preventing demyelination. The activation of p42/p44 MAPK (mitogen-activated protein kinase) and induction of the transcription factor c-Jun serve as negative regulators of myelination. NRG1 activated MAPK, induced c-Jun expression and promoted a loss of myelin segments in DRG explants isolated from both WT (wild-type) and Hsp70 KO (knockout) mice. Although KU-32 did not block the activation of MAPK, it blocked c-Jun induction and protected against a loss of myelinated segments in WT mice. In contrast, KU-32 did not prevent the NRG1-dependent induction of c-Jun and loss of myelin segments in explants from Hsp70 KO mice. Overexpression of Hsp70 in myelinated DRG explants prepared from WT or Hsp70 KO mice was sufficient to block the induction of c-Jun and the loss of myelin segments induced by NRG1. Lastly, inhibiting the proteasome prevented KU-32 from decreasing c-Jun levels. Collectively, these data support that Hsp70 induction is sufficient to prevent NRG1-induced demyelination by enhancing the proteasomal degradation of c-Jun.

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Section: Discussionmentioning

confidence: 99%

Induction of Heat Shock Protein 70 (Hsp70) prevents Neuregulin-Induced Demyelination by Enhancing the Proteasomal Clearance of c-Jun

Zhao

et al. 2012

ASN Neuro

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“…The rest of the patients frequently develop diffuse neuropathies characterized by symmetrical distribution, insidious onset and chronic progression. In particular, a distal symmetrical sensorimotor polyneuropathy accounts for 90% of all DPN diagnoses in type 1 and type 2 diabetics and affects all types of peripheral sensory and motor fibers in a temporally non-uniform manner [6,17].…”

Section: A Complex Natural Historymentioning

confidence: 99%

From Animal Models to Clinical Practicality: Lessons Learned from Current Translational Progress of Diabetic Peripheral Neuropathy

Li¹,

Bunner²,

Pippin³

2013

Peripheral Neuropathy - A New Insight Into the Mechanism, Evaluation and Management of a Complex Disorder

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Diabetic peripheral neuropathy (DPN) is a leading risk factor for diabetes‐related mortality and morbidity. Despite promising effects in animal models, none of the pharmacological agents has been successfully translated into effective treatments in humans. Challenges faced by investigators seeking to translate results from animal models into human trials include marked species differences in genotype and behavior, nerve structure and metabolism, duration of diabetes, and tissue vulnerability. While animal experiments have provided much of our understanding of the disease biology, these species differences necessitate a careful reevaluation of the validity of data obtained from experimental approaches. Therefore, we examined these pathogenetic treatments and summarized their clinical outcomes in treating DPN. Moreover, we examined the most commonly used rodent models during preclinical drug screening, including STZ‐diabetic rats and db/db mice. By putting previous observations generated by animal studies into perspective, we investigated the salient features and predictability of these models in relation to the pathophysiological and pharmacological outcomes in diabetic patients. In particular, we identified the molecular, cellular and physiological differences that significantly impair the translation from experimental approached to human clinical setting. We conclude that these findings should be taken into critical consideration by researchers as limitations for efficient pharmacological translation.

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Targeting Molecular Chaperones in Diabetic Peripheral Neuropathy

Cited by 2 publications

References 123 publications

Induction of Heat Shock Protein 70 (Hsp70) prevents Neuregulin-Induced Demyelination by Enhancing the Proteasomal Clearance of c-Jun

Induction of Heat Shock Protein 70 (Hsp70) prevents Neuregulin-Induced Demyelination by Enhancing the Proteasomal Clearance of c-Jun

From Animal Models to Clinical Practicality: Lessons Learned from Current Translational Progress of Diabetic Peripheral Neuropathy

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