Sodium channels contribute to microglia/macrophage activation and function in EAE and MS

Craner, Matthew; Damarjian, Tina G.; Liu, Shujun; Hains, Bryan C.; Lo, Albert; Black, Joel A.; Newcombe, J; Cuzner, M. L.; Waxman, Stephen G.

doi:10.1002/glia.20112

Cited by 239 publications

(207 citation statements)

References 57 publications

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“…Recently, it was demonstrated that the sodium channel antagonist lamotrigine was effective in protecting axons from exposure to NO (43) and might suppress the activation of innate immune cells, in particular microglia and their migratory activity in MS patients. However, the drug failed in clinical trials because it did not prevent brain atrophy later in disease (42,45). Nimodipine already has been demonstrated to restore cognitive function (10)(11)(12).…”

Section: Discussionmentioning

confidence: 99%

Nimodipine fosters remyelination in a mouse model of multiple sclerosis and induces microglia-specific apoptosis

Schampel

Volovitch

Koeniger

et al. 2017

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

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Despite continuous interest in multiple sclerosis (MS) research, there is still a lack of neuroprotective strategies, because the main focus has remained on modulating the immune response. Here we performed in-depth analysis of neurodegeneration in experimental autoimmune encephalomyelitis (EAE) and in in vitro studies regarding the effect of the well-established L-type calcium channel antagonist nimodipine. Nimodipine treatment attenuated clinical EAE and spinal cord degeneration and promoted remyelination. Surprisingly, we observed calcium channel-independent effects on microglia, resulting in apoptosis. These effects were cell-type specific and irrespective of microglia polarization. Apoptosis was accompanied by decreased levels of nitric oxide (NO) and inducible NO synthase (iNOS) in cell culture as well as decreased iNOS and reactive oxygen species levels in EAE. In addition, increased numbers of Olig2 + APC + oligodendrocytes were detected. Overall, nimodipine application seems to generate a favorable environment for regenerative processes and therefore could be a treatment option for MS, because it combines features of immunomodulation with beneficial effects on neuroregeneration.M ultiple sclerosis (MS) is the most prevalent neurological disease of the CNS in young adults and is characterized by inflammation, demyelination, and axonal pathology (1) that result in multiple neurological and cognitive deficits (1-3). Intensive MS research studies have investigated modulating the immune system (4). Common therapeutic strategies are effective in slowing disease progression and attenuating the symptoms, but they cannot cure the disease. The option of preventing neurodegeneration early on would be a valuable addendum to customary treatment (4). Here we suggest that application of nimodipine could be an elegant way to target both neuroinflammation and neurodegeneration. The dihydropyridine nimodipine is commonly known as a 1.2 voltagegated L-type calcium channel antagonist and is used to treat hypertension and other cardiovascular diseases (5, 6). It also is used to prevent vasospasms after subarachnoidal hemorrhage (5) because of its high affinity for the CNS (7-9). Current research trials are examining its effects on brain injury, epilepsy, cognitive performance, and behavioral effects (6,7,10,11). Its influence on oxidative stress, neuronal survival, synaptic plasticity, and aging also are being investigated, especially within the hippocampus (10, 12). In addition, it was recently shown that the risk of suffering from Parkinson's disease was decreased under treatment with dihydropyridines (13). These studies suggest that nimodipine might have beneficial effects in MS as well, although its role in neurodegenerative diseases that are mediated by inflammatory events has not been well established (6). So far, nimodipine-mediated effects in the CNS have been claimed to result mainly from the modulation of neuronal activity, and studies on the potential effects of nimodipine on (micro)glia have not yet been conduct...

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Section: Discussionmentioning

confidence: 99%

Nimodipine fosters remyelination in a mouse model of multiple sclerosis and induces microglia-specific apoptosis

Schampel

Volovitch

Koeniger

et al. 2017

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

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“…Expression of the sodium channel Na v 16 is upregulated on activated microglia and macrophages in EAE and MS. Microglia from knockout mice deficient in Na v 16 had attenuated phagocytic function (Craner et al, 2005). Persistent activation of sodium channels has been demonstrated to trigger axonal injury (Craner et al, 2004).…”

Section: Do Other Factors Cause Inflammation And/or Neurodegenerationmentioning

confidence: 99%

Inflammation, demyelination, neurodegeneration and neuroprotection in the pathogenesis of multiple sclerosis

Peterson¹,

Fujinami²

2007

Journal of Neuroimmunology

166

104

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Although axonal loss has been observed in demyelinated multiple sclerosis (MS) lesions, there has been a major focus on understanding mechanisms of demyelination. However, identification of markers for axonal damage and development of new imaging techniques has enabled detection of subtle changes in axonal pathology and revived interest in the neurodegenerative component of MS. Axonal loss is generally accepted as the main determinant of permanent clinical disability. However, the role of axonal loss early in disease or during relapsing-remitting disease is still under investigation, as are the interactions and interdependency between inflammation, demyelination, neurodegeneration and neuroprotection in the pathogenesis of MS.

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“…NaV1.6 has a less clear functional role in macrophages. Unlike NaV1.5, NaV1.6 is also expressed in unprimed human macrophages and in unprimed and primed mouse macrophages and microglia (7,8). Many invasive neoplastic cell lines also express voltage-gated sodium channels, which may regulate their ability to metastasize (9).…”

mentioning

confidence: 99%

Regulation of Podosome Formation in Macrophages by a Splice Variant of the Sodium Channel SCN8A

Carrithers

Chatterjee

Carrithers

et al. 2009

Journal of Biological Chemistry

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103

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Voltage-gated sodium channels initiate electrical signaling in excitable cells such as muscle and neurons. They also are expressed in non-excitable cells such as macrophages and neoplastic cells. Previously, in macrophages, we demonstrated expression of SCN8A, the gene that encodes the channel NaV1.6, and intracellular localization of NaV1.6 to regions near F-actin bundles, particularly at areas of cell attachment. Here we show that a splice variant of NaV1.6 regulates cellular invasion through its effects on podosome and invadopodia formation in macrophages and melanoma cells. cDNA sequence analysis of SCN8A from THP-1 cells, a human monocyte-macrophage cell line, confirmed the expression of a full-length splice variant that lacks exon 18. Immunoelectron microscopy demonstrated NaV1.6-positive staining within the electron dense podosome rosette structure. Pharmacologic antagonism with tetrodotoxin (TTX) in differentiated THP-1 cells or absence of functional NaV1.6 through a naturally occurring mutation (med) in mouse peritoneal macrophages inhibited podosome formation. Agonistmediated activation of the channel with veratridine caused release of sodium from cationic vesicular compartments, uptake by mitochondria, and mitochondrial calcium release through the Na/Ca exchanger. Invasion by differentiated THP-1 and HTB-66 cells, an invasive melanoma cell line, through extracellular matrix was inhibited by TTX. THP-1 invasion also was inhibited by small hairpin RNA knockdown of SCN8A. These results demonstrate that a variant of NaV1.6 participates in the control of podosome and invadopodia formation and suggest that intracellular sodium release mediated by NaV1.6 may regulate cellular invasion of macrophages and melanoma cells.

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Sodium channels contribute to microglia/macrophage activation and function in EAE and MS

Cited by 239 publications

References 57 publications

Nimodipine fosters remyelination in a mouse model of multiple sclerosis and induces microglia-specific apoptosis

Nimodipine fosters remyelination in a mouse model of multiple sclerosis and induces microglia-specific apoptosis

Inflammation, demyelination, neurodegeneration and neuroprotection in the pathogenesis of multiple sclerosis

Regulation of Podosome Formation in Macrophages by a Splice Variant of the Sodium Channel SCN8A

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