The Pivotal Potentials of Scorpion Buthus Martensii Karsch-Analgesic-Antitumor Peptide in Pain Management and Cancer

Scorpion Buthus martensii Karsch -analgesic-antitumor peptide (BmK AGAP) has been used to treat diseases like tetanus, tuberculosis, apoplexy, epilepsy, spasm, migraine headaches, rheumatic pain, and cancer in China. AGAP is a distinctive long-chain scorpion toxin with a molecular mass of 7142 Da and composed of 66 amino acids cross-linked by four disulfide bridges. Voltage-gated sodium channels (VGSCs) are present in excitable membranes and partakes in essential roles in action potentials generation as compared to the significant function of voltage-gated calcium channels (VGCCs). A total of nine genes (Nav1.1–Nav1.9) have been recognized to encode practical sodium channel isoforms. Nav1.3, Nav1.7, Nav1.8, and Nav1.9 have been recognized as potential targets for analgesics. Nav1.8 and Nav1.9 are associated with nociception initiated by inflammation signals in the neuronal pain pathway, while Nav1.8 is fundamental for neuropathic pain at low temperatures. AGAP has a sturdy inhibitory influence on both viscera and soma pain. AGAP potentiates the effects of MAPK inhibitors on neuropathic as well as inflammation-associated pain. AGAP downregulates the secretion of phosphorylated p38, phosphorylated JNK, and phosphorylated ERK 1/2 in vitro. AGAP has an analgesic activity which may be an effective therapeutic agent for pain management because of its downregulation of PTX3 via NF-κB and Wnt/beta-catenin signaling pathway. In cancers like colon cancer, breast cancer, lymphoma, and glioma, rAGAP was capable of blocking the proliferation. Thus, AGAP is a promising therapy for these tumors. Nevertheless, research is needed with other tumors.

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Sodium Channel Nav1.3 Is Expressed by Polymorphonuclear Neutrophils during Mouse Heart and Kidney Ischemia InVivo and Regulates Adhesion, Transmigration, and Chemotaxis of Human and Mouse Neutrophils In Vitro

Anesthesiology ◽

10.1097/aln.0000000000002135 ◽

2018 ◽

Vol 128 (6) ◽

pp. 1151-1166 ◽

Cited By ~ 6

Author(s):

Marit Poffers ◽

Nathalie Bühne ◽

Christine Herzog ◽

Anja Thorenz ◽

Rongjun Chen ◽

...

Keyword(s):

Endothelial Cells ◽

Sodium Channel ◽

Sodium Channels ◽

Polymorphonuclear Neutrophils ◽

Human Neutrophils ◽

Mouse Heart ◽

Voltage Gated ◽

Voltage Gated Sodium Channels

Abstract Background Voltage-gated sodium channels generate action potentials in excitable cells, but they have also been attributed noncanonical roles in nonexcitable cells. We hypothesize that voltage-gated sodium channels play a functional role during extravasation of neutrophils. Methods Expression of voltage-gated sodium channels was analyzed by polymerase chain reaction. Distribution of Nav1.3 was determined by immunofluorescence and flow cytometry in mouse models of ischemic heart and kidney injury. Adhesion, transmigration, and chemotaxis of neutrophils to endothelial cells and collagen were investigated with voltage-gated sodium channel inhibitors and lidocaine in vitro. Sodium currents were examined with a whole cell patch clamp. Results Mouse and human neutrophils express multiple voltage-gated sodium channels. Only Nav1.3 was detected in neutrophils recruited to ischemic mouse heart (25 ± 7%, n = 14) and kidney (19 ± 2%, n = 6) in vivo. Endothelial adhesion of mouse neutrophils was reduced by tetrodotoxin (56 ± 9%, unselective Nav-inhibitor), ICA121431 (53 ± 10%), and Pterinotoxin-2 (55 ± 9%; preferential inhibitors of Nav1.3, n = 10). Tetrodotoxin (56 ± 19%), ICA121431 (62 ± 22%), and Pterinotoxin-2 (59 ± 22%) reduced transmigration of human neutrophils through endothelial cells, and also prevented chemotactic migration (n = 60, 3 × 20 cells). Lidocaine reduced neutrophil adhesion to 60 ± 9% (n = 10) and transmigration to 54 ± 8% (n = 9). The effect of lidocaine was not increased by ICA121431 or Pterinotoxin-2. Conclusions Nav1.3 is expressed in neutrophils in vivo; regulates attachment, transmigration, and chemotaxis in vitro; and may serve as a relevant target for antiinflammatory effects of lidocaine.

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Targeted Osmotic Lysis of Highly Invasive Breast Carcinomas Using Pulsed Magnetic Field Stimulation of Voltage-Gated Sodium Channels and Pharmacological Blockade of Sodium Pumps

Cancers ◽

10.3390/cancers12061420 ◽

2020 ◽

Vol 12 (6) ◽

pp. 1420

Author(s):

Dennis Paul ◽

Paul Maggi ◽

Fabio Del Piero ◽

Steven D. Scahill ◽

Kelly Jean Sherman ◽

...

Keyword(s):

Sodium Channels ◽

Electrical Current ◽

Normal Breast ◽

Voltage Gated ◽

Voltage Gated Sodium Channels ◽

Reduce Tumor Growth ◽

Osmotic Lysis ◽

Stimulation Of

Concurrent activation of voltage-gated sodium channels (VGSCs) and blockade of Na+ pumps causes a targeted osmotic lysis (TOL) of carcinomas that over-express the VGSCs. Unfortunately, electrical current bypasses tumors or tumor sections because of the variable resistance of the extracellular microenvironment. This study assesses pulsed magnetic fields (PMFs) as a potential source for activating VGSCs to initiate TOL in vitro and in vivo as PMFs are unaffected by nonconductive tissues. In vitro, PMFs (0–80 mT, 10 msec pulses, 15 pps for 10 min) combined with digoxin-lysed (500 nM) MDA-MB-231 breast cancer cells stimulus-dependently. Untreated, stimulation-only, and digoxin-only control cells did not lyse. MCF-10a normal breast cells were also unaffected. MDA-MB-231 cells did not lyse in a Na+-free buffer. In vivo, 30 min of PMF stimulation of MDA-MB-231 xenografts in J/Nu mice or 4T1 homografts in BALB/c mice, concurrently treated with 7 mg/kg digoxin reduced tumor size by 60–100%. Kidney, spleen, skin and muscle from these animals were unaffected. Stimulation-only and digoxin-only controls were similar to untreated tumors. BALB/C mice with 4T1 homografts survived significantly longer than mice in the three control groups. The data presented is evidence that the PMFs to activate VGSCs in TOL provide sufficient energy to lyse highly malignant cells in vitro and to reduce tumor growth of highly malignant grafts and improve host survival in vivo, thus supporting targeted osmotic lysis of cancer as a possible method for treating late-stage carcinomas without compromising noncancerous tissues.

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Development of the 1,2,4-triazole-based anticonvulsant drug candidates acting on the voltage-gated sodium channels. Insights from in-vivo, in-vitro, and in-silico studies

European Journal of Pharmaceutical Sciences ◽

10.1016/j.ejps.2018.12.018 ◽

2019 ◽

Vol 129 ◽

pp. 42-57 ◽

Cited By ~ 14

Author(s):

Barbara Kaproń ◽

Jarogniew J. Łuszczki ◽

Anita Płazińska ◽

Agata Siwek ◽

Tadeusz Karcz ◽

...

Keyword(s):

Sodium Channels ◽

In Silico ◽

Anticonvulsant Drug ◽

Voltage Gated ◽

Drug Candidates ◽

Voltage Gated Sodium Channels ◽

In Silico Studies

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Polarized localization of voltage-gated Na+ channels is regulated by concerted FGF13 and FGF14 action

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1521194113 ◽

2016 ◽

Vol 113 (19) ◽

pp. E2665-E2674 ◽

Cited By ~ 33

Author(s):

Juan Lorenzo Pablo ◽

Chaojian Wang ◽

Matthew M. Presby ◽

Geoffrey S. Pitt

Keyword(s):

Action Potential ◽

Hippocampal Neurons ◽

Single Point ◽

Point Mutations ◽

Surface Expression ◽

Voltage Gated ◽

Voltage Gated Sodium Channels ◽

Action Potential Initiation ◽

Potential Initiation

Clustering of voltage-gated sodium channels (VGSCs) within the neuronal axon initial segment (AIS) is critical for efficient action potential initiation. Although initially inserted into both somatodendritic and axonal membranes, VGSCs are concentrated within the axon through mechanisms that include preferential axonal targeting and selective somatodendritic endocytosis. How the endocytic machinery specifically targets somatic VGSCs is unknown. Here, using knockdown strategies, we show that noncanonical FGF13 binds directly to VGSCs in hippocampal neurons to limit their somatodendritic surface expression, although exerting little effect on VGSCs within the AIS. In contrast, homologous FGF14, which is highly concentrated in the proximal axon, binds directly to VGSCs to promote their axonal localization. Single-point mutations in FGF13 or FGF14 abrogating VGSC interaction in vitro cannot support these specific functions in neurons. Thus, our data show how the concerted actions of FGF13 and FGF14 regulate the polarized localization of VGSCs that supports efficient action potential initiation.

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Conserved Expression of Nav1.7 and Nav1.8 Contribute to the Spontaneous and Thermally Evoked Excitability in IL-6 and NGF-Sensitized Adult Dorsal Root Ganglion Neurons In Vitro

Bioengineering ◽

10.3390/bioengineering7020044 ◽

2020 ◽

Vol 7 (2) ◽

pp. 44

Author(s):

Rahul R. Atmaramani ◽

Bryan J. Black ◽

June Bryan de la Peña ◽

Zachary T. Campbell ◽

Joseph J. Pancrazio

Keyword(s):

Sodium Channels ◽

Sensory Neurons ◽

Inflammatory Pain ◽

Dorsal Root Ganglion Neurons ◽

Electrode Arrays ◽

Voltage Gated ◽

Voltage Gated Sodium Channels ◽

Ganglion Neurons

Sensory neurons respond to noxious stimuli by relaying information from the periphery to the central nervous system via action potentials driven by voltage-gated sodium channels, specifically Nav1.7 and Nav1.8. These channels play a key role in the manifestation of inflammatory pain. The ability to screen compounds that modulate voltage-gated sodium channels using cell-based assays assumes that key channels present in vivo is maintained in vitro. Prior electrophysiological work in vitro utilized acutely dissociated tissues, however, maintaining this preparation for long periods is difficult. A potential alternative involves multi-electrode arrays which permit long-term measurements of neural spike activity and are well suited for assessing persistent sensitization consistent with chronic pain. Here, we demonstrate that the addition of two inflammatory mediators associated with chronic inflammatory pain, nerve growth factor (NGF) and interleukin-6 (IL-6), to adult DRG neurons increases their firing rates on multi-electrode arrays in vitro. Nav1.7 and Nav1.8 proteins are readily detected in cultured neurons and contribute to evoked activity. The blockade of both Nav1.7 and Nav1.8, has a profound impact on thermally evoked firing after treatment with IL-6 and NGF. This work underscores the utility of multi-electrode arrays for pharmacological studies of sensory neurons and may facilitate the discovery and mechanistic analyses of anti-nociceptive compounds.

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In vitro assessment of the effect of methylene blue on voltage-gated sodium channels and action potentials in rat hippocampal CA1 pyramidal neurons

NeuroToxicology ◽

10.1016/j.neuro.2010.07.001 ◽

2010 ◽

Vol 31 (6) ◽

pp. 724-729 ◽

Cited By ~ 2

Author(s):

Yinguo Zhang ◽

Jingxia Zhao ◽

Tao Zhang ◽

Zhuo Yang

Keyword(s):

Methylene Blue ◽

Sodium Channels ◽

Action Potentials ◽

Pyramidal Neurons ◽

Voltage Gated ◽

Ca1 Pyramidal Neurons ◽

Voltage Gated Sodium Channels ◽

Hippocampal Ca1 ◽

In Vitro Assessment

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Gain of function of sporadic/familial hemiplegic migraine-causing SCN1A mutations: Use of an optimized cDNA

Cephalalgia ◽

10.1177/0333102418788336 ◽

2018 ◽

Vol 39 (4) ◽

pp. 477-488 ◽

Cited By ~ 6

Author(s):

Sara Bertelli ◽

Raffaella Barbieri ◽

Michael Pusch ◽

Paola Gavazzo

Keyword(s):

Sodium Channels ◽

Headache Disorder ◽

Familial Hemiplegic Migraine ◽

Optimization Strategy ◽

Gain Of Function ◽

Hemiplegic Migraine ◽

Efficient Manner ◽

Voltage Gated ◽

Voltage Gated Sodium Channels

Introduction Familial hemiplegic migraine 3 is an autosomal dominant headache disorder associated with aura and transient hemiparesis, caused by mutations of the neuronal voltage-gated sodium channel Nav1.1. While a gain-of function phenotype is generally assumed to underlie familial hemiplegic migraine, this has not been fully explored. Indeed, a major obstacle in studying in vitro neuronal sodium channels is the difficulty in propagating and mutagenizing expression plasmids containing their cDNAs. The aim of this work was to study the functional effect of two previously uncharacterized hemiplegic migraine causing mutations, Leu1670Trp (L1670W) and Phe1774Ser (F1774S). Methods A novel SCN1A containing-plasmid was designed in silico and synthesized, and migraine mutations were inserted in this background. Whole-cell patch clamp was performed to investigate the functional properties of mutant Nav1.1 transiently expressed in Human Embryonic Kidney 293 cells. Results and conclusions We generated an optimized Nav1.1 expression plasmid that was extremely simple to handle and used the novel plasmid to study the functional effects of two migraine mutations. We observed that L1670W, but not F1774S, reduced current density and that both mutations led to a dramatic increase in persistent sodium currents, a depolarizing shift of the steady state-inactivation voltage-dependence, and a faster recovery from inactivation. The results are consistent with a major gain-of function effect underlying familial hemiplegic migraine 3. Our optimization strategy will help to characterize in an efficient manner the effect in vitro of mutations of neuronal voltage-gated sodium channels.

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