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Stephen G Waxman - One of the best experts on this subject based on the ideXlab platform.
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virus mediated knockdown of Nav1.3 in dorsal root ganglia of stz induced diabetic rats alleviates tactile allodynia
Molecular Medicine, 2015Co-Authors: Omar Abdel Samad, Sulayman D Dibhajj, Stephen G WaxmanAbstract: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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virus mediated shrna knockdown of Nav1.3 in rat dorsal root ganglion attenuates nerve injury induced neuropathic pain
Molecular Therapy, 2013Co-Authors: Omar Abdel Samad, Edmund Foster, Sulayman D Dibhajj, Xiaoyang Cheng, Stephen G WaxmanAbstract:Neuropathic pain is a chronic condition that is often refractory to treatment with available therapies and thus an unmet medical need. We have previously shown that the voltage-gated Sodium Channel Nav1.3 is upregulated in peripheral and central nervous system (CNS) of rats following nerve injury, and that it contributes to nociceptive neuron hyperexcitability in neuropathic conditions. To evaluate the therapeutic potential of peripheral Nav1.3 knockdown at a specific segmental level, we constructed adeno-associated viral (AAV) vector expressing small hairpin RNA against rat Nav1.3 and injected it into lumbar dorsal root ganglion (DRG) of rats with spared nerve injury (SNI). Our data show that direct DRG injection provides a model that can be used for proof-of-principle studies in chronic pain with respect to peripheral delivery route of gene transfer constructs, high transduction efficiency, flexibility in terms of segmental localization, and limited behavioral effects of the surgical procedure. We show that knockdown of Nav1.3 in lumbar 4 (L4) DRG results in an attenuation of nerve injury-induced mechanical allodynia in the SNI model. Taken together, our studies support the contribution of peripheral Nav1.3 to pain in adult rats with neuropathic pain, validate Nav1.3 as a target, and provide validation for this approach of AAV-mediated peripheral gene therapy.
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multiple Sodium Channel isoforms and mitogen activated protein kinases are present in painful human neuromas
Annals of Neurology, 2008Co-Authors: Joel A Black, Stephen G Waxman, Lone Nikolajsen, Karsten Kroner, Troels S JensenAbstract:Objective Although axons within neuromas have been shown to produce inappropriate spontaneous ectopic discharges, the molecular basis for pain in patients with neuromas is still not fully understood. Because Sodium Channels are known to play critical roles in neuronal electrogenesis and hyperexcitability, we examined the expression of all the neuronal voltage-gated Sodium Channels (Nav1.1, Nav1.2, Nav1.3, Nav1.6, Nav1.7, Nav1.8, and Nav1.9) within human painful neuromas. We also examined the expression of two mitogen-activated protein (MAP) kinases, activated p38 and extracellular signal-regulated kinases 1 and 2 (ERK1/2), which are known to contribute to chronic pain, within these human neuromas. Methods We used immunocytochemical methods with specific antibodies to Sodium Channels Nav1.1, Nav1.2, Nav1.3, Nav1.6, Nav1.7, Nav1.8, and Nav1.9, and to activated MAP kinases p38 and ERK1/2 to study by confocal microscopy control and painful neuroma tissue from five patients with well-documented pain. Results We demonstrate upregulation of Sodium Channel Nav1.3, as well as Nav1.7 and Nav1.8, in blind-ending axons within human painful neuromas. We also demonstrate upregulation of activated p38 and ERK1/2 MAP kinases in axons within these neuromas. Interpretation These results demonstrate that multiple Sodium Channel isoforms (Nav1.3, Nav1.7, and Nav1.8), as well as activated p38 and ERK1/2 MAP kinases, are expressed in painful human neuromas, indicating that these molecules merit study as possible therapeutic targets for the treatment of pain associated with traumatic neuromas. Ann Neurol 2008;64:644–653
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Contactin Associates with Sodium Channel Nav1.3 in Native Tissues and Increases Channel Density at the Cell Surface
The Journal of Neuroscience, 2004Co-Authors: Bhaval S. Shah, Sulayman D Dib-hajj, Anthony M. Rush, Joel A Black, Lynda Tyrrell, Stephen G WaxmanAbstract:The upregulation of voltage-gated Sodium Channel Nav1.3 has been linked to hyperexcitability of axotomized dorsal root ganglion (DRG) neurons, which underlies neuropathic pain. However, factors that regulate delivery of Nav1.3 to the cell surface are not known. Contactin/F3, a cell adhesion molecule, has been shown to interact with and enhance surface expression of Sodium Channels Nav1.2 and Nav1.9. In this study we show that contactin coimmunoprecipitates with Nav1.3 from postnatal day 0 rat brain where this Channel is abundant, and from human embryonic kidney (HEK) 293 cells stably transfected with Nav1.3 (HEK-Nav1.3). Purified GST fusion proteins of the N and C termini of Nav1.3 pull down contactin from lysates of transfected HEK 293 cells. Transfection of HEK-Nav1.3 cells with contactin increases the amplitude of the current threefold without changing the biophysical properties of the Channel. Enzymatic removal of contactin from the cell surface of cotransfected cells does not reduce the elevated levels of the Nav1.3 current. Finally, we show that, similar to Nav1.3, contactin is upregulated in axotomized DRG neurons and accumulates within the neuroma of transected sciatic nerve. We propose that the upregulation of contactin and its colocalization with Nav1.3 in axotomized DRG neurons may contribute to the hyper-excitablity of the injured neurons.
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upregulation of Sodium Channel Nav1.3 and functional involvement in neuronal hyperexcitability associated with central neuropathic pain after spinal cord injury
The Journal of Neuroscience, 2003Co-Authors: Bryan C Hains, Joel A Black, Joshua P Klein, Carl Y Saab, Matthew J Craner, Stephen G WaxmanAbstract:Spinal cord injury (SCI) can result in hyperexcitability of dorsal horn neurons and central neuropathic pain. We hypothesized that these phenomena are consequences, in part, of dysregulated expression of voltage-gated Sodium Channels. Because the rapidly repriming TTX-sensitive Sodium Channel Nav1.3 has been implicated in peripheral neuropathic pain, we investigated its role in central neuropathic pain after SCI. In this study, adult male Sprague Dawley rats underwent T9 spinal contusion injury. Four weeks after injury when extracellular recordings demonstrated hyperexcitability of L3-L5 dorsal horn multireceptive nociceptive neurons, and when pain-related behaviors were evident, quantitative RT-PCR, in situ hybridization, and immunocytochemistry revealed an upregulation of Nav1.3 in dorsal horn nociceptive neurons. Intrathecal administration of antisense oligodeoxynucleotides (ODNs) targeting Nav1.3 resulted in decreased expression of Nav1.3 mRNA and protein, reduced hyperexcitability of multireceptive dorsal horn neurons, and attenuated mechanical allodynia and thermal hyperalgesia after SCI. Expression of Nav1.3 protein and hyperexcitability in dorsal horn neurons as well as pain-related behaviors returned after cessation of antisense delivery. Responses to normally noxious stimuli and motor function were unchanged in SCI animals administered Nav1.3 antisense, and administration of mismatch ODNs had no effect. These results demonstrate for the first time that Nav1.3 is upregulated in second-order dorsal horn sensory neurons after nervous system injury, showing that SCI can trigger changes in Sodium Channel expression, and suggest a functional link between Nav1.3 expression and neuronal hyperexcitability associated with central neuropathic pain.
Omar Abdel Samad - One of the best experts on this subject based on the ideXlab platform.
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virus mediated knockdown of Nav1.3 in dorsal root ganglia of stz induced diabetic rats alleviates tactile allodynia
Molecular Medicine, 2015Co-Authors: Omar Abdel Samad, Sulayman D Dibhajj, Stephen G WaxmanAbstract: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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virus mediated shrna knockdown of Nav1.3 in rat dorsal root ganglion attenuates nerve injury induced neuropathic pain
Molecular Therapy, 2013Co-Authors: Omar Abdel Samad, Edmund Foster, Sulayman D Dibhajj, Xiaoyang Cheng, Stephen G WaxmanAbstract:Neuropathic pain is a chronic condition that is often refractory to treatment with available therapies and thus an unmet medical need. We have previously shown that the voltage-gated Sodium Channel Nav1.3 is upregulated in peripheral and central nervous system (CNS) of rats following nerve injury, and that it contributes to nociceptive neuron hyperexcitability in neuropathic conditions. To evaluate the therapeutic potential of peripheral Nav1.3 knockdown at a specific segmental level, we constructed adeno-associated viral (AAV) vector expressing small hairpin RNA against rat Nav1.3 and injected it into lumbar dorsal root ganglion (DRG) of rats with spared nerve injury (SNI). Our data show that direct DRG injection provides a model that can be used for proof-of-principle studies in chronic pain with respect to peripheral delivery route of gene transfer constructs, high transduction efficiency, flexibility in terms of segmental localization, and limited behavioral effects of the surgical procedure. We show that knockdown of Nav1.3 in lumbar 4 (L4) DRG results in an attenuation of nerve injury-induced mechanical allodynia in the SNI model. Taken together, our studies support the contribution of peripheral Nav1.3 to pain in adult rats with neuropathic pain, validate Nav1.3 as a target, and provide validation for this approach of AAV-mediated peripheral gene therapy.
Sulayman D Dibhajj - One of the best experts on this subject based on the ideXlab platform.
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virus mediated knockdown of Nav1.3 in dorsal root ganglia of stz induced diabetic rats alleviates tactile allodynia
Molecular Medicine, 2015Co-Authors: Omar Abdel Samad, Sulayman D Dibhajj, Stephen G WaxmanAbstract: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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virus mediated shrna knockdown of Nav1.3 in rat dorsal root ganglion attenuates nerve injury induced neuropathic pain
Molecular Therapy, 2013Co-Authors: Omar Abdel Samad, Edmund Foster, Sulayman D Dibhajj, Xiaoyang Cheng, Stephen G WaxmanAbstract:Neuropathic pain is a chronic condition that is often refractory to treatment with available therapies and thus an unmet medical need. We have previously shown that the voltage-gated Sodium Channel Nav1.3 is upregulated in peripheral and central nervous system (CNS) of rats following nerve injury, and that it contributes to nociceptive neuron hyperexcitability in neuropathic conditions. To evaluate the therapeutic potential of peripheral Nav1.3 knockdown at a specific segmental level, we constructed adeno-associated viral (AAV) vector expressing small hairpin RNA against rat Nav1.3 and injected it into lumbar dorsal root ganglion (DRG) of rats with spared nerve injury (SNI). Our data show that direct DRG injection provides a model that can be used for proof-of-principle studies in chronic pain with respect to peripheral delivery route of gene transfer constructs, high transduction efficiency, flexibility in terms of segmental localization, and limited behavioral effects of the surgical procedure. We show that knockdown of Nav1.3 in lumbar 4 (L4) DRG results in an attenuation of nerve injury-induced mechanical allodynia in the SNI model. Taken together, our studies support the contribution of peripheral Nav1.3 to pain in adult rats with neuropathic pain, validate Nav1.3 as a target, and provide validation for this approach of AAV-mediated peripheral gene therapy.
Ryan Doan - One of the best experts on this subject based on the ideXlab platform.
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Sodium Channel scn3a Nav1.3 regulation of human cerebral cortical folding and oral motor development
Neuron, 2018Co-Authors: Richard S Smith, Connor J Kenny, Ahram Jang, Taehwan Shin, Allen Y Chen, Jennifer N. Partlow, Vijay S Ganesh, Sean R Hill, Rebeca Borgesmonroy, Ryan DoanAbstract:Summary Channelopathies are disorders caused by abnormal ion Channel function in differentiated excitable tissues. We discovered a unique neurodevelopmental Channelopathy resulting from pathogenic variants in SCN3A, a gene encoding the voltage-gated Sodium Channel Nav1.3. Pathogenic Nav1.3 Channels showed altered biophysical properties including increased persistent current. Remarkably, affected individuals showed disrupted folding (polymicrogyria) of the perisylvian cortex of the brain but did not typically exhibit epilepsy; they presented with prominent speech and oral motor dysfunction, implicating SCN3A in prenatal development of human cortical language areas. The development of this disorder parallels SCN3A expression, which we observed to be highest early in fetal cortical development in progenitor cells of the outer subventricular zone and cortical plate neurons and decreased postnatally, when SCN1A (NaV1.1) expression increased. Disrupted cerebral cortical folding and neuronal migration were recapitulated in ferrets expressing the mutant Channel, underscoring the unexpected role of SCN3A in progenitor cells and migrating neurons.
Jian Wang - One of the best experts on this subject based on the ideXlab platform.
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MiR-30b Attenuates Neuropathic Pain by Regulating Voltage-Gated Sodium Channel Nav1.3 in Rats
Frontiers in Molecular Neuroscience, 2017Co-Authors: Songxue Su, Jinping Shao, Qingzan Zhao, Lei Li, Xuemei Chen, Bo Xu, Jian WangAbstract:Nav1.3 is a tetrodotoxin-sensitive isoform among voltage-gated Sodium Channels that are closely associated with neuropathic pain. It can be up-regulated following nerve injury, but its biological function remains uncertain. MicroRNAs (miRNAs) are endogenous non-coding RNAs that can regulate post-transcriptional gene expression by binding with their target mRNAs. Using Target Scan software, we discovered that SCN3A is the major target of miR-30b, and we then determined whether miR-30b regulated the expression of Nav1.3 by transfecting miR-30b agomir through the stimulation of TNF-α or by transfecting miR-30b antagomir in primary dorsal root ganglion (DRG) neurons. The spinal nerve ligation (SNL) model was used to determine the contribution of miR-30b to neuropathic pain, to evaluate changes in Nav1.3 mRNA and protein expression, and to understand the sensitivity of rats to mechanical and thermal stimuli. Our results showed that miR-30b agomir transfection down-regulated Nav1.3 mRNA stimulated with TNF-α in primary DRG neurons. Moreover, miR-30b overexpression significantly attenuated neuropathic pain induced by SNL, with decreases in the expression of Nav1.3 mRNA and protein both in DRG neurons and spinal cord. Activation of Nav1.3 caused by miR-30b antagomir was identified. These data suggest that miR-30b is involved in the development of neuropathic pain, probably by regulating the expression of Nav1.3, and might be a novel therapeutic target for neuropathic pain.