Mechanisms of Injury‐Induced Calcium Entry into Peripheral Nerve Myelinated Axons: Role of Reverse Sodium‐Calcium Exchange

Lehning, Ellen J.; Doshi, Renu; Isaksson, Norman; Stys, Peter K.; LoPachin, Richard M.

doi:10.1046/j.1471-4159.1996.66020493.x

Cited by 76 publications

(40 citation statements)

References 28 publications

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“…It has been demonstrated using in-vitro optic nerve, tibial nerve myelinated axons and dorsal roots that anoxic injury to the nerve is associated with Ca 2ϩ loading via reverse operation of the Na ϩ /Ca 2ϩ exchanger due to anoxia-induced depolarization and Na ϩ influx. 39,41,42) Furthermore, Na ϩ /Ca 2ϩ exchange inhibitors such as bepridil, benzamil and dichlorobenzamil significantly protected the optic nerve from anoxic injury. Acrylamide-induced distal axon degeneration has also been linked to activation of reverse mode operation of the Na ϩ /Ca 2ϩ exchanger with axonal Ca 2ϩ entry in exchange for Na ϩ .…”

Section: Discussionmentioning

confidence: 92%

“…The high density of sodium-calcium exchanger (the canine cardiac type I) has been demonstrated in the peripheral myelinated mammalian axons with glial and axonal localization. 39,40) However, the detailed characterization of Na ϩ /Ca 2ϩ exchanger including its various subtypes on the peripheral nerves has not been documented. It has been demonstrated using in-vitro optic nerve, tibial nerve myelinated axons and dorsal roots that anoxic injury to the nerve is associated with Ca 2ϩ loading via reverse operation of the Na ϩ /Ca 2ϩ exchanger due to anoxia-induced depolarization and Na ϩ influx.…”

Section: Discussionmentioning

confidence: 99%

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Ameliorative Potential of Pralidoxime in Tibial and Sural Nerve Transection-Induced Neuropathic Pain in Rats

Kaur

Jaggi

Singh

2010

Biological & Pharmaceutical Bulletin

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The present study was designed to investigate the ameliorative potential of pralidoxime in tibial and sural nerve transection-induced neuropathy in rats. Tibial and sural nerve transection was performed by sectioning tibial and sural nerve portions (2 mm) of the sciatic nerve, and leaving the common peroneal nerve intact. The pinprick, acetone, hot and cold tail immersion tests were performed to assess the degree of motor functions, mechanical hyperalgesia, cold allodynia, heat and cold hyperalgesia respectively. Biochemically, the tissue thio-barbituric acid reactive species (TBARS), super-oxide anion contents (the markers of oxidative stress) and total calcium levels were measured. Tibial sural nerve transection resulted in the development of mechanical hyperalgesia, cold allodynia, heat and cold hyperalgesia along with the rise in oxidative stress and calcium levels. However, administration of pralidoxime (10, 20 mg/kg intraperitoneally (i.p.)) for 14 d attenuated tibial and sural nerve transection-induced cold allodynia, mechanical, hot and cold hyperalgesia. Furthermore, pralidoxime also attenuated tibial and sural nerve transection induced increase in oxidative stress and calcium levels. It may be concluded that pralidoxime has ameliorative potential in attenuating the painful neuropathic state associated with tibial and sural nerve transection, which may possibly be attributed to decrease in oxidative stress and calcium levels.

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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Ameliorative Potential of Pralidoxime in Tibial and Sural Nerve Transection-Induced Neuropathic Pain in Rats

Kaur

Jaggi

Singh

2010

Biological & Pharmaceutical Bulletin

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“…Fine-caliber distal axons are especially sensitive to small changes in sodium channel activity due to high input resistance, short electrotonic and diffusional length constant, and high surface-to-volume ratio (28,29). Persistent sodium current in myelinated CNS and PNS axons can trigger injurious, Ca 2+ -importing reverse Na/Ca exchange (30,31). I228M Na v 1.7 mutant channels, found in a patient with painful neuropathy, reduce the length of DRG neurites in vitro, whereas blockade of sodium channels, and of reverse Na/Ca exchange, are protective of axons expressing mutant, but not wild-type channels, suggesting that activity of mutant channels and reverse Na/Ca exchange contribute to axonal injury in this model (32).…”

Section: Discussionmentioning

confidence: 99%

Gain-of-function Na _v 1.8 mutations in painful neuropathy

Faber

Lauria²,

Merkies³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

397

301

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Painful peripheral neuropathy often occurs without apparent underlying cause. Gain-of-function variants of sodium channel Na v 1.7 have recently been found in ∼30% of cases of idiopathic painful small-fiber neuropathy. Here, we describe mutations in Na v 1.8, another sodium channel that is specifically expressed in dorsal root ganglion (DRG) neurons and peripheral nerve axons, in patients with painful neuropathy. Seven Na v 1.8 mutations were identified in 9 subjects within a series of 104 patients with painful predominantly small-fiber neuropathy. Three mutations met criteria for potential pathogenicity based on predictive algorithms and were assessed by voltage and current clamp. Functional profiling showed that two of these three Na v 1.8 mutations enhance the channel's response to depolarization and produce hyperexcitability in DRG neurons. These observations suggest that mutations of Na v 1.8 contribute to painful peripheral neuropathy.dorsal root ganglia | patch clamp P ainful peripheral neuropathy involving small-diameter nociceptive nerve fibers represents a significant public health challenge (1); in about one-half of cases, no cause can be identified (1). Faber et al. (2) recently described gain-of-function variants (single amino acid substitutions) in sodium channel Na v 1.7, which is abundantly expressed in spinal sensory [dorsal root ganglion (DRG)] neurons and their axons (3) in nearly 30% of patients with biopsy-confirmed, painful small-fiber neuropathy (SFN) and no other apparent cause. These variants increase the excitability of DRG neurons, providing an explanation for pain in these patients. Molecular substrates for pain in the remaining SFN patients remain unknown. Here, we describe gain-of-function mutations in Na v 1.8, another sodium channel that is specifically expressed in DRG neurons and peripheral nerve axons, in human subjects with painful neuropathy, including a father-son pair. These mutations alter gating properties of the channel in a proexcitatory manner and increase the excitability of DRG neurons. These genetic and functional observations suggest that Na v 1.8 mutations contribute to pain in some peripheral neuropathies.

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“…It has been hypothesized that the energy depletion following hypoxia or ischemia results in failure of Na + /K + ATPase and activation of sodium channels, which augments axoplasmic Na + concentrations. This, in turn, causes the reversal of Na + /Ca 2+ exchanger (NCX) activity, thus increasing calcium levels (48). Moreover, calcium influx through sodium channels further augments axoplasmic calcium concentrations (12).…”

Section: Discussionmentioning

confidence: 99%

Plasma membrane calcium ATPase deficiency causes neuronal pathology in the spinal cord: a potential mechanism for neurodegeneration in multiple sclerosis and spinal cord injury

et al. 2004

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Dysfunction and death of spinal cord neurons are critical determinants of neurological deficits in various pathological conditions, including multiple sclerosis (MS) and spinal cord injury. Yet, the molecular mechanisms underlying neuronal/axonal damage remain undefined. Our previous studies raised the possibility that a decrease in the levels of plasma membrane calcium ATPase isoform 2 (PMCA2), a major pump extruding calcium from neurons, promotes neuronal pathology in the spinal cord during experimental autoimmune encephalomyelitis (EAE), an animal model of MS, and after spinal cord trauma. However, the causal relationship between alterations in PMCA2 levels and neuronal injury was not well established. We now report that inhibition of PMCA activity in purified spinal cord neuronal cultures delays calcium clearance, increases the number of nonphosphorylated neurofilament H (SMI-32) immunoreactive cells, and induces swelling and beading of SMI-32-positive neurites. These changes are followed by activation of caspase-3 and neuronal loss. Importantly, the number of spinal cord motor neurons is significantly decreased in PMCA2-deficient mice and the deafwaddler 2J , a mouse with a functionally null mutation in the PMCA2 gene. Our findings suggest that a reduction in PMCA2 level or activity leading to delays in calcium clearance may cause neuronal damage and loss in the spinal cord.Keywords autoimmune disease; ATP2B2; excitotoxicity; cytoskeleton Neuronal and axonal dysfunction and loss have increasingly received attention as important contributors to neural decline in various central nervous system (CNS) disorders, including MS and spinal cord trauma. MS is a CNS disease that may initially show a relapsing-remitting course but finally leads to permanent neurological impairment (1,2). Classically, demyelination of structurally intact axons was considered to be the main cause of clinical symptoms and neural deficits in MS. However, recent studies indicate that axonal dysfunction is already evident at the earliest clinical stages of MS, and axonal transection or loss may be the cause of persistent, irreversible disability at later phases of the disease when remissions no longer occur (3-5).

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Mechanisms of Injury‐Induced Calcium Entry into Peripheral Nerve Myelinated Axons: Role of Reverse Sodium‐Calcium Exchange

Abstract: To investigate the route of axonal Ca

Cited by 76 publications

References 28 publications

Ameliorative Potential of Pralidoxime in Tibial and Sural Nerve Transection-Induced Neuropathic Pain in Rats

Ameliorative Potential of Pralidoxime in Tibial and Sural Nerve Transection-Induced Neuropathic Pain in Rats

Gain-of-function Na _v 1.8 mutations in painful neuropathy

Plasma membrane calcium ATPase deficiency causes neuronal pathology in the spinal cord: a potential mechanism for neurodegeneration in multiple sclerosis and spinal cord injury

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Mechanisms of Injury‐Induced Calcium Entry into Peripheral Nerve Myelinated Axons: Role of Reverse Sodium‐Calcium Exchange

Abstract: To investigate the route of axonal Ca

Cited by 76 publications

References 28 publications

Ameliorative Potential of Pralidoxime in Tibial and Sural Nerve Transection-Induced Neuropathic Pain in Rats

Ameliorative Potential of Pralidoxime in Tibial and Sural Nerve Transection-Induced Neuropathic Pain in Rats

Gain-of-function Na v 1.8 mutations in painful neuropathy

Plasma membrane calcium ATPase deficiency causes neuronal pathology in the spinal cord: a potential mechanism for neurodegeneration in multiple sclerosis and spinal cord injury

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Product

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Gain-of-function Na _v 1.8 mutations in painful neuropathy