β3, a novel auxiliary subunit for the voltage gated sodium channel is upregulated in sensory neurones following streptozocin induced diabetic neuropathy in rat

Shah, Bhaval S.; Gonzalez, Maria; Bramwell, S.; Pinnock, R.D.; Lee, Kevin; Dixon, A. R.

doi:10.1016/s0304-3940(01)01976-0

Cited by 49 publications

(27 citation statements)

References 22 publications

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“…Increased hyperalgesia, as reported here and previously (18,19,21), has been associated with increased spontaneous firing of nociceptive neurons (39) due to upregulation of ␤ 3 and tetrodotoxin-resistant voltage-gated Na ϩ channels in small nociceptive and A␦ DRG neurons (40,41). This will inevitably result in increased Na ϩ influx as demonstrated by increased Na ϩ current densities and a shift in steady-state inactivation in diabetic dorsal root ganglia (41).…”

Section: Discussionsupporting

confidence: 72%

Apoptotic Stress Is Counterbalanced by Survival Elements Preventing Programmed Cell Death of Dorsal Root Ganglions in Subacute Type 1 Diabetic BB/Wor Rats

2005

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Several groups have reported apoptosis of dorsal root ganglion (DRG) cells as a prominent feature of diabetic polyneuropathy (DPN), although this has been controversial. Here, we examined subacute (4-month) type 1 diabetic BB/Wor rats with respect to sensory nerve functions, DRG and sural nerve morphometry, pro-and antiapoptotic proteins, and the expression of neurotrophic factors and their receptors. Sensory nerve conduction velocity was reduced by 13% and was accompanied by significant hyperalgesia. The numbers of DRG neurons including substance P-and calcitonin gene-related peptide-positive neurons were not altered, although they showed significant atrophy. Sural nerve morphometry showed decreased numbers of myelinated and unmyelinated fibers. Active caspase-3 and Bax expressions were increased, whereas antiapoptotic Bcl-xl and heat shock protein (HSP) 27 expressions in DRGs were increased. Nerve growth factor (NGF) contents in sciatic nerves and the expression of NGF receptor TrkA in DRGs were decreased. Immunohistochemistry showed increased numbers of active caspase-3-, HSP70-, and HSP27-positive neurons. Examinations of DRGs revealed no structural evidence of apoptosis but rather progressive hydropic degenerative changes. We conclude that apoptotic stress is induced in DRGs but is counterbalanced by survival elements in subacute type 1 diabetic BB/Wor rats and that distal nerve fiber loss reflects a dying-back phenomenon caused by impaired neurotrophic support. Diabetes 54: 3288 -3295, 2005 D iabetic polyneuropathy (DPN) is the most common late complication of diabetes and shows an increasing prevalence. Like other diabetes complications, DPN has been ascribed to hyperglycemia and subsequent metabolic abnormalities, particularly oxidative stress. Although other factors contribute to its development, such as insulin and C-peptide deficiencies and consequent deprivation of neurotrophic support (1), these have received less attention. Several investigators have reported neuronal apoptosis in relatively acute (2-to 3-month) streptozotocin-induced diabetes (STZ-D) in rats, sometimes exceeding 30% of dorsal root ganglion (DRG) cells as a contributing factor to DPN (2-4), while others have reported no significant neuronal loss in DRGs even after 12 months of STZ-D (5,6). The validity of major programmed cell death can be disputed, since the magnitude of reported apoptotic neuronal death does not correlate with a corresponding loss of axonal extensions in the peripheral nerve of the STZ-D rat. In contrast to the STZ-D rat, the spontaneously type 1 diabetic BB/Wor rat develops progressive sensory nerve fiber loss (7), as in humans, which therefore could reflect loss of parent DRG cells.Apoptotic phenomena occur in pancreatic ␤-cells in type 1 diabetes (8), in diabetic retinopathy (9), and in hippocampal neurons in primary diabetic encephalopathy (10,11). Programmed cell death is believed to result from hyperglycemia-induced mitochondrial dysfunction (4,12) and depletion of antiapoptotic trophic factors like IGFs, i...

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Section: Discussionsupporting

confidence: 72%

Apoptotic Stress Is Counterbalanced by Survival Elements Preventing Programmed Cell Death of Dorsal Root Ganglions in Subacute Type 1 Diabetic BB/Wor Rats

2005

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“…Thus, in our previous gene therapy study we chose to verify the functional efficacy of the Nav1.3 knockdown construct in HEK293 cells, in which we definitively attributed changes in current density to the Nav1.3 isoform (13,30). In the present study using the same construct, we showed a decrease in Nav1.3 mRNA expression in DRG tissues following viral transduction of approximately 50% of L4-L5 DRG neurons and concomitant reductions of both dorsal horn neuron hyperexcitability and tactile allodynia.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have shown that levels of Nav1.3 increase in DRG neurons of streptozotocin (STZ)-induced diabetic models of neuropathic pain (12). Thus, it has been posited that Nav1.3 upregulation within DRG neurons in diabetes contributes to hyperactivity of nociceptive circuits and neuropathic pain (13). Here, we hypothesize that knockdown of Nav1.3 will reduce neuropathic pain in painful diabetic neuropathy.…”

Section: Introductionmentioning

confidence: 85%

Virus-Mediated Knockdown of Nav1.3 in Dorsal Root Ganglia of STZ-Induced Diabetic Rats Alleviates Tactile Allodynia

Tan

Samad

Dib‐Hajj

et al. 2015

Mol Med

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Diabetic neuropathic pain affects a substantial number of people and represents a major public health problem. Available clinical treatments for diabetic neuropathic pain remain only partially effective and many of these treatments carry the burden of side effects or the risk of dependence. The misexpression of sodium channels within nociceptive neurons contributes to abnormal electrical activity associated with neuropathic pain. Voltage-gated sodium channel Nav1.3 produces tetrodotoxin-sensitive sodium currents with rapid repriming kinetics and has been shown to contribute to neuronal hyperexcitability and ectopic firing in injured neurons. Suppression of Nav1.3 activity can attenuate neuropathic pain induced by peripheral nerve injury. Previous studies have shown that expression of Nav1.3 is upregulated in dorsal root ganglion (DRG) neurons of diabetic rats that exhibit neuropathic pain. Here, we hypothesized that viral-mediated knockdown of Nav1.3 in painful diabetic neuropathy would reduce neuropathic pain. We used a validated recombinant adeno-associated virus (AAV)-shRNA-Nav1.3 vector to knockdown expression of Nav1.3, via a clinically applicable intrathecal injection method. Three weeks following vector administration, we observed a significant rate of transduction in DRGs of diabetic rats that concomitantly reduced neuronal excitability of dorsal horn neurons and reduced behavioral evidence of tactile allodynia. Taken together, these findings offer a novel gene therapy approach for addressing chronic diabetic neuropathic pain.

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“…This is particularly relevant given the binding of gabapentin and pregabalin to this channel in mediating analgesia during neuropathic pain (39). Other specific ion channels linked to diabetic neuropathic pain not examined here include Cav3.2 T-type calcium channels and several sodium channels: Nav1.3 (upregulation), Nav1.7 (upregulation, increased tyrosine phosphorylation), Nav1.6 and Nav1.8 (both downregulated but with increased serine/threonine phosphorylation; Nav 1.6 also had increased tyrosine phosphorylation) (40), Nav1.9 (upregulated), and ␤3 (upregulated) (41,42).…”

Section: Discussionmentioning

confidence: 99%

Distal Degenerative Sensory Neuropathy in a Long-Term Type 2 Diabetes Rat Model

et al. 2008

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OBJECTIVE-Peripheral neuropathy associated with type 2 diabetes (DPN) is not widely modeled. We describe unique features of DPN in type 2 diabetic Zucker diabetic fatty (ZDF) rats.RESEARCH DESIGN AND METHODS-We evaluated the structural, electrophysiological, behavioral, and molecular features of DPN in ZDF rats and littermates over 4 months of hyperglycemia. The status of insulin signaling transduction molecules that might be interrupted in type 2 diabetes and selected survival-, stress-, and pain-related molecules was emphasized in dorsal root ganglia (DRG) sensory neurons.RESULTS-ZDF rats developed slowing of motor sciatic-tibial and sensory sciatic digital conduction velocity and selective mechanical allodynia with preserved thermal algesia. Diabetic sural axons, preserved in number, developed atrophy, but there was loss of large-calibre dermal and small-calibre epidermal axons. In diabetic rats, insulin signal transduction pathways in lumbar DRGs were preserved or had trends toward upregulation: mRNA levels of insulin receptor ␤-subunit (IR␤), insulin receptor substrate (IRS)-1, and IRS-2. The numbers of neurons expressing IR␤ protein were also preserved. There were trends toward early rises of mRNA levels of heat shock protein 27 (HSP27), the ␣2␦1 calcium channel subunit, and phosphatidylinositol 3-kinase in diabetes. Others were unchanged, including nuclear factor-B (NF-B; p50/p105) and receptor for advanced glycosylation endproducts (RAGE) as was the proportion of neurons expressing HSP27, NF-B, and RAGE protein.CONCLUSIONS-ZDF type 2 diabetic rats develop a distal degenerative sensory neuropathy accompanied by a selective long-term pain syndrome. Neuronal insulin signal transduction molecules are preserved.

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β3, a novel auxiliary subunit for the voltage gated sodium channel is upregulated in sensory neurones following streptozocin induced diabetic neuropathy in rat

Cited by 49 publications

References 22 publications

Apoptotic Stress Is Counterbalanced by Survival Elements Preventing Programmed Cell Death of Dorsal Root Ganglions in Subacute Type 1 Diabetic BB/Wor Rats

Apoptotic Stress Is Counterbalanced by Survival Elements Preventing Programmed Cell Death of Dorsal Root Ganglions in Subacute Type 1 Diabetic BB/Wor Rats

Virus-Mediated Knockdown of Nav1.3 in Dorsal Root Ganglia of STZ-Induced Diabetic Rats Alleviates Tactile Allodynia

Distal Degenerative Sensory Neuropathy in a Long-Term Type 2 Diabetes Rat Model

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