N58A Exerts Analgesic Effect on Trigeminal Neuralgia by Regulating the MAPK Pathway and Tetrodotoxin-Resistant Sodium Channel.
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ABSTRACT:
SUBMITTER: Li CL
PROVIDER: S-EPMC8157219 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundVoltage-gated sodium channels (Nav) mediate neuronal action potentials. Tetrodotoxin inhibits all Nav isoforms, but Nav1.8 and Nav1.9 are relatively tetrodotoxin-resistant (TTX-r) compared to other isoforms. Nav1.8 is highly expressed in dorsal root ganglion neurons and is functionally linked to nociception, but the sensitivity of TTX-r isoforms to inhaled anesthetics is unclear.MethodsThe sensitivities of heterologously expressed rat TTX-r Nav1.8 and endogenous tetrodotoxin-sensitive (TTX-s) Nav to the prototypic inhaled anesthetic isoflurane were tested in mammalian ND7/23 cells using patch-clamp electrophysiology.ResultsFrom a holding potential of -70 mV, isoflurane (0.53 +/- 0.06 mM, 1.8 minimum alveolar concentration at 24 degrees C) reduced normalized peak Na current (INa) of Nav1.8 to 0.55 +/- 0.03 and of endogenous TTX-s Nav to 0.56 +/- 0.06. Isoflurane minimally inhibited INa from a holding potential of -140 mV. Isoflurane did not affect voltage-dependence of activation, but it significantly shifted voltage-dependence of steady-state inactivation by -6 mV for Nav1.8 and by -7 mV for TTX-s Nav. IC50 values for inhibition of peak INa were 0.67 +/- 0.06 mM for Nav1.8 and 0.66 +/- 0.09 mM for TTX-s Nav; significant inhibition occurred at clinically relevant concentrations as low as 0.58 minimum alveolar concentration. Isoflurane produced use-dependent block of Nav1.8; at a stimulation frequency of 10 Hz, 0.56 +/- 0.08 mM isoflurane reduced INa to 0.64 +/- 0.01 versus 0.78 +/- 0.01 for control.ConclusionIsoflurane inhibited the tetrodotoxin-resistant isoform Nav1.8 with potency comparable to that for endogenous tetrodotoxin-sensitive Nav isoforms, indicating that sensitivity to inhaled anesthetics is conserved across diverse Nav family members. Block of Nav1.8 in dorsal root ganglion neurons could contribute to the effects of inhaled anesthetics on peripheral nociceptive mechanisms.
| S-EPMC2756082 | biostudies-literature
Project description:Voltage-gated sodium channels (VGSCs) play an important role in the control of membrane excitability. We previously reported that the excitability of nociceptor was increased by hypotonic stimulation. The present study tested the effect of hypotonicity on tetrodotoxin-sensitive sodium current (TTX-S current) in cultured trigeminal ganglion (TG) neurons. Our data show that after hypotonic treatment, TTX-S current was increased. In the presence of hypotonicity, voltage-dependent activation curve shifted to the hyperpolarizing direction, while the voltage-dependent inactivation curve was not affected. Transient Receptor Potential Vanilloid 4 receptor (TRPV4) activator increased TTX-S current and hypotonicity-induced increase was markedly attenuated by TRPV4 receptor blockers. We also demonstrate that inhibition of PKC attenuated hypotonicity-induced inhibition, whereas PKA system was not involved in hypotonic-response. We conclude that hypotonic stimulation enhances TTX-S current, which contributes to hypotonicity-induced nociception. TRPV4 receptor and PKC intracellular pathway are involved in the increase of TTX-S current by hypotonicity.
| S-EPMC3094255 | biostudies-literature
Project description:BackgroundTrigeminal neuralgia (TN) can have a significant impact on wellbeing and quality of life. Limited data exist for treatments that improve TN pain acutely, within 24 h of administration. This systematic review aims to identify effective treatments that acutely relieve TN exacerbations.MethodsWe searched Medline and Cochrane Central Register of Controlled Trials (CENTRAL) for relevant English language publications. The reference list for all articles was searched for other relevant publications. All studies that satisfied the following PICO criteria were included: (i) Population-adults with acute exacerbation of primary TN symptoms; (ii) Intervention-any medication or intervention with the primary goal of pain relief within 24 h; (iii) Comparator-usual medical care, placebo, sham or active treatment; (iv) Outcome-more than 50% reduction in pain intensity within 24 h of administration.ResultsOf 431 studies, 17 studies were identified that reported immediate results of acute treatment in TN. The evidence suggests that the following interventions may be beneficial: local anaesthetic, mainly lidocaine (ophthalmic, nasal or oral mucosa, trigger point injection, i.v. infusion, nerve block); anticonvulsant, phenytoin or fosphenytoin (i.v. infusion); serotonin agonist, sumatriptan (s.c. injection, nasal). Other referenced interventions with very limited evidence include N-methyl-d-aspartate receptor antagonist (magnesium sulphate infusion) and botulinum toxin (trigger point injection).ConclusionsSeveral treatment options exist that may provide fast and safe relief of TN. Future studies should report on outcomes within 24 h to improve knowledge of the acute analgesic TN treatments.
| S-EPMC6676170 | biostudies-literature
Project description:ATP-binding cassette subfamily G member 2 (ABCG2) is a member of the ABC transporter superfamily proteins, which has been implicated in the development of multidrug resistance (MDR) in cancer, apart from its physiological role to remove toxic substances out of the cells. The diverse range of substrates of ABCG2 includes many antineoplastic agents such as topotecan, doxorubicin and mitoxantrone. ABCG2 expression has been reported to be significantly increased in some solid tumors and hematologic malignancies, correlated to poor clinical outcomes. In addition, ABCG2 expression is a distinguishing feature of cancer stem cells, whereby this membrane transporter facilitates resistance to the chemotherapeutic drugs. To enhance the chemosensitivity of cancer cells, attention has been focused on MDR modulators. In this study, we investigated the effect of a tetrodotoxin-resistant sodium channel blocker, A-803467 on ABCG2-overexpressing drug selected and transfected cell lines. We found that at non-toxic concentrations, A-803467 could significantly increase the cellular sensitivity to ABCG2 substrates in drug-resistant cells overexpressing either wild-type or mutant ABCG2. Mechanistic studies demonstrated that A-803467 (7.5 ?M) significantly increased the intracellular accumulation of [(3)H]-mitoxantrone by inhibiting the transport activity of ABCG2, without altering its expression levels. In addition, A-803467 stimulated the ATPase activity in membranes overexpressed with ABCG2. In a murine model system, combination treatment of A-803467 (35 mg/kg) and topotecan (3 mg/kg) significantly inhibited the tumor growth in mice xenografted with ABCG2-overexpressing cancer cells. Our findings indicate that a combination of A-803467 and ABCG2 substrates may potentially be a novel therapeutic treatment in ABCG2-positive drug resistant cancers.
| S-EPMC4770772 | biostudies-literature
Project description:Tetrodotoxin (TTX) is used to distinguish between two classes of voltage-gated sodium channel (VGSC)--TTX sensitive (TTXS) and TTX resistant (TTXR). The resistance of TTXR VGSCs is thought to result from a low binding affinity of TTX, although at high TTX concentrations channel block does occur. Here, we show that, at concentrations below those which produce block, TTX can bind to TTXR VGSCs.Whole-cell voltage clamp recordings were made from dissociated rat dorsal root ganglion neurones that expressed both TTXS and TTXR sodium currents. Voltage-gated calcium currents were blocked by 10 microM extracellular lanthanum chloride. TTXS, but not TTXR, current was suppressed by using a holding potential of -50 mV, and the effect of TTX on the isolated TTXR current was explored.Extracellular application of 0.5 microM TTX produced a 40% increase in TTXR current amplitude, a negative shift in the voltage-dependence of current activation (approximately -8 mV) and inactivation (approximately -10 mV) and increased rates of current activation and inactivation. The effect of TTX on current amplitude was dose-dependent (EC50 = 364 nM). Removal of lanthanum prevented the effect of TTX on TTXR current amplitude, whereas reducing extracellular calcium did not.The findings are consistent with an interpretation that TTX relieves a tonic block of the TTXR VGSC by lanthanum. We conclude that TTX binds to the TTXR VGSC at low concentrations, without blocking it. This appears to be the first demonstration of a clear distinction between binding affinity and blocking potency of a channel-blocking agent.
| S-EPMC2527855 | biostudies-other
Project description:BackgroundClassic trigeminal neuralgia (TN) is caused by vessels compressing the trigeminal nerve root entry zone. The cause is usually impingement of the superior cerebellar artery, anterior inferior cerebellar artery, or a vein. Other rare causes have been reported including aneurysmal compression, skull base tumors, and vascular malformations. An enlarged suprameatal tubercle (EST) as a cause of TN has not yet been described.Case presentationWe report the first case of 37 year old female patient presented with severe TN involving the three branches of trigeminal nerve who failed medical treatment and underwent multiple balloon compression for left TN with minimal improvement. The severity of pain was assessed using Barrow Neurological Institute (BNI) pain intensity score. Patient had brain MRI with CISS sequence and CT scan for the brain. After careful revision of her imaging studies, patient found to have prominent and heavily calcified left supra meatal tubercle. Her preoperative BNI score was 5.Patient had left retrosigmoid craniotomy and drilling of left suprameatal tubercle. No other structures were seen in contact with left trigeminal nerve root entry zone. Patient had significant improvement on her pain, postoperative BNI score was 1 until the last follow-up 4 years.ConclusionEST is a rare cause of TGN and should be suspected as the offending compressing structure when no other causes seen on imaging studies.
| S-EPMC8141507 | biostudies-literature
Project description:ObjectiveTo compare complete neuroendoscopic and microscopic microvascular decompression (MVD) in primary trigeminal neuralgia (PTN) and their impacts on the microstructure of the trigeminal nerve.MethodsEighty-seven PTN patients admitted in our hospital from July 2017 to December 2019 were selected for this prospective study and divided into the endoscopic group (n=45) (complete neuroendoscopic MVD) and the microscope group (n=42) (microscopic MVD) according to the treatment method each patient underwent. All the patients underwent MRI scanning, and the fractional anisotropy (FA) scores and the apparent diffusion coefficient (ADC) values of the neurovascular compression (NVC) sites were measured. The operation times, the treatment efficacy, the microstructural changes in the trigeminal nerve, the complications, and the recurrence and mortality rates at one year after the operations were compared.ResultsThe endoscopic group observed a superior therapeutic effect compared with the microscope group one year after the surgeries (P=0.046). After the surgeries, the endoscopic group observed a greater increase in their FA values and a larger decline in their ADC values than the microscope group did (P=0.014, 0.015, 0.011, 0.002). The complication rate in the endoscopic group was 11.11%, and the complication rate in the microscopic group was 30.95% (P=0.022). One year after the surgeries, we found a lower recurrence rate in the endoscopic group (P=0.001). The perforator vessels from the offending vessel to the outlet area of the durmedulla, the distances between the front edge of the bone window and the inner surfaces of the petrous part of the temporal bone ≥ the distance between the duration ≥ the duration of conventional MVD were independent risk factors for complications after MVD in the hemifacial spasm patients (P=0.001, 0.037, 0.023, 0.005).ConclusionComplete neuroendoscopic MV yields better long-term treatment outcomes than microscopic MVD, and it is more effective at improving the microstructure of the trigeminal nerve and has fewer postoperative complications.
| S-EPMC8661214 | biostudies-literature
Project description:Natural selection often produces convergent changes in unrelated lineages, but the degree to which such adaptations occur via predictable genetic paths is unknown. If only a limited subset of possible mutations is fixed in independent lineages, then it is clear that constraint in the production or function of molecular variants is an important determinant of adaptation. We demonstrate remarkably constrained convergence during the evolution of resistance to the lethal poison, tetrodotoxin, in six snake species representing three distinct lineages from around the globe. Resistance-conferring amino acid substitutions in a voltage-gated sodium channel, Na(v)1.4, are clustered in only two regions of the protein, and a majority of the replacements are confined to the same three positions. The observed changes represent only a small fraction of the experimentally validated mutations known to increase Na(v)1.4 resistance to tetrodotoxin. These results suggest that constraints resulting from functional tradeoffs between ion channel function and toxin resistance led to predictable patterns of evolutionary convergence at the molecular level. Our data are consistent with theoretical predictions and recent microcosm work that suggest a predictable path is followed during an adaptive walk along a mutational landscape, and that natural selection may be frequently constrained to produce similar genetic outcomes even when operating on independent lineages.
| S-EPMC3311348 | biostudies-literature
Project description:Growth differentiation factor 15 (GDF-15) is a member of the transforming growth factor-β superfamily. It is widely distributed in the central and peripheral nervous systems. Whether and how GDF-15 modulates nociceptive signaling remains unclear. Behaviorally, we found that peripheral GDF-15 significantly elevated nociceptive response thresholds to mechanical and thermal stimuli in naïve and arthritic rats. Electrophysiologically, we demonstrated that GDF-15 decreased the excitability of small-diameter dorsal root ganglia (DRG) neurons. Furthermore, GDF-15 concentration-dependently suppressed tetrodotoxin-resistant sodium channel Nav1.8 currents, and shifted the steady-state inactivation curves of Nav1.8 in a hyperpolarizing direction. GDF-15 also reduced window currents and slowed down the recovery rate of Nav1.8 channels, suggesting that GDF-15 accelerated inactivation and slowed recovery of the channel. Immunohistochemistry results showed that activin receptor-like kinase-2 (ALK2) was widely expressed in DRG medium- and small-diameter neurons, and some of them were Nav1.8-positive. Blockade of ALK2 prevented the GDF-15-induced inhibition of Nav1.8 currents and nociceptive behaviors. Inhibition of PKA and ERK, but not PKC, blocked the inhibitory effect of GDF-15 on Nav1.8 currents. These results suggest a functional link between GDF-15 and Nav1.8 in DRG neurons via ALK2 receptors and PKA associated with MEK/ERK, which mediate the peripheral analgesia of GDF-15.
| S-EPMC8423960 | biostudies-literature
Project description:The trigeminal nerve is the largest of all cranial nerves. It has three branches that provide the main sensory innervation of the anterior two-thirds of the head and face. Trigeminal neuralgia (TN) is characterized by sudden, severe, brief, and stabbing recurrent episodes of facial pain in one or more branches of the trigeminal nerve. Pain attacks can occur spontaneously or can be triggered by non-noxious stimuli, such as talking, eating, washing the face, brushing teeth, shaving, a light touch or even a cool breeze. In addition to pain attacks, a proportion of the patients also experience persistent background pain, which along with autonomic signs and prolonged disease duration, represent predictors of worse treatment outcomes. It is now widely accepted that the presence of a neurovascular compression at the trigeminal root entry zone is an anatomic abnormality with a high correlation with classical TN. However, TN may be related to other etiologies, thus presenting different and/or additional features. Since the 1960s, the anticonvulsant carbamazepine is the drug of choice for TN treatment. Although anti-epileptic drugs are commonly used to treat neuropathic pain in general, the efficacy of carbamazepine has been largely limited to TN. Carbamazepine, however, is associated with dose-limiting side-effects, particularly with prolonged usage. Thus, a better understanding and new treatment options are urgently warranted for this rare, but excruciating disease.
| S-EPMC7324879 | biostudies-literature