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Role of Oxidative Stress and Ca2+ Signaling on Molecular Pathways of Neuropathic Pain in Diabetes: Focus on TRP Channels

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Abstract

Diabetes mellitus, a debilitating chronic disease, affects ~100 million people. Peripheral neuropathy is one of the most common early complications of diabetes in ~66 % of these patients. Altered Ca2+ handling and Ca2+ signaling were detected in a huge variety of preparations isolated from animals with experimentally induced type 1 and 2 diabetes as well as patients suffering from the disease. We reviewed the role of Ca2+ signaling through cation channels and oxidative stress on diabetic neuropathic pain in sensory neurons. The pathogenesis of diabetic neuropathy involves the polyol pathway, advanced glycation end products, oxidative stress, protein kinase C activation, neurotrophism, and hypoxia. Experimental studies with respect to oxidative stress and Ca2+ signaling, inhibitor roles of antioxidants in diabetic neuropathic pain are also summarized in the review. We hypothesize that deficits in insulin, triggers alterations of sensory neurone phenotype that are critical for the development of abnormal Ca2+ homeostasis and oxidative stress and associated mitochondrial dysfunction. The transient receptor potential channels are a large family of proteins with six main subfamilies. The sheer number of different TRPs with distinct functions supports the statement that these channels are involved in a wide range of processes ranging in diabetic neuropathic pain and it seems that the TRPC, TRPM and TRPV groups are mostly responsible from diabetic neuropathic pain. In conclusion, the accumulating evidence implicating Ca2+ dysregulation and over production of oxidative stress products in diabetic neuropathic pains, along with recent advances in understanding of genetic variations in cation channels such as TRP channels, makes modulation of neuronal Ca2+ handling an increasingly viable approach for therapeutic interventions against the painful and degenerative aspects of many diabetic neuropathies.

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Abbreviations

2-APB:

Aminoethoxydiphenylborane

HEK:

Human embryonic kidney

IGF:

Insulin growth factor

NGF:

Nerve growth factor

NMDA:

N-methyl-d-asparate

NO:

Nitric oxide

PKA:

Protein kinase A

PKC:

Protein kinase C

RAGE:

Advanced glycation end-products

ROS:

Reactive oxygen species

SERCA:

Sarcoendoplasmic reticulum Ca2+-ATPase

STZ:

Streptozotocin

TCA:

Tricarboxylic acid

TRP:

Transient receptor potential

TRPV1:

Transient receptor potential vanilloid 1

VDCC:

Voltage-dependent Ca2+ channels

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  1. Department of Biophysics, Medical Faculty, Süleyman Demirel University, 32260, Isparta, Turkey

    Mustafa Nazıroğlu, Döndü Merve Dikici & Şeyda Dursun

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  1. Mustafa Nazıroğlu
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  2. Döndü Merve Dikici
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Correspondence to Mustafa Nazıroğlu.

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Nazıroğlu, M., Dikici, D.M. & Dursun, Ş. Role of Oxidative Stress and Ca2+ Signaling on Molecular Pathways of Neuropathic Pain in Diabetes: Focus on TRP Channels. Neurochem Res 37, 2065–2075 (2012). https://doi.org/10.1007/s11064-012-0850-x

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