N-type Calcium Channel in the Pathogenesis of Experimental Autoimmune Encephalomyelitis*

Tokuhara, Naoki; Namiki, Kana; Uesugi, Mai; Miyamoto, Chihiro; Ohgoh, Makoto; Ido, Katsutoshi; Yoshinaga, Takashi; Yamauchi, Toshihiko; Kuromitsu, Junro; Kimura, Sadao; Miyamoto, Naokazu; Kasuya, Yoshitoshi

doi:10.1074/jbc.m109.089805

Cited by 30 publications

(27 citation statements)

References 49 publications

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“…Recent studies have shown that the inhibition of N-type voltage-gated calcium channels reduced the severity of EAE neurological symptoms and decreased demyelination and infiltration areas [50,51]. The authors indicated microglia/macrophages as the principal effectors of this improvement, demonstrating that inhibition of these voltage-gated calcium channels regulates microglial activation.…”

Section: Discussionmentioning

confidence: 99%

Oral administration of the KATP channel opener diazoxide ameliorates disease progression in a murine model of multiple sclerosis

Virgili¹,

Espinosa-Parrilla²,

Mancera³

et al. 2011

J Neuroinflammation

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BackgroundMultiple Sclerosis (MS) is an acquired inflammatory demyelinating disorder of the central nervous system (CNS) and is the leading cause of nontraumatic disability among young adults. Activated microglial cells are important effectors of demyelination and neurodegeneration, by secreting cytokines and others neurotoxic agents. Previous studies have demonstrated that microglia expresses ATP-sensitive potassium (KATP) channels and its pharmacological activation can provide neuroprotective and anti-inflammatory effects. In this study, we have examined the effect of oral administration of KATP channel opener diazoxide on induced experimental autoimmune encephalomyelitis (EAE), a mouse model of MS.MethodsAnti-inflammatory effects of diazoxide were studied on lipopolysaccharide (LPS) and interferon gamma (IFNγ)-activated microglial cells. EAE was induced in C57BL/6J mice by immunization with myelin oligodendrocyte glycoprotein peptide (MOG35-55). Mice were orally treated daily with diazoxide or vehicle for 15 days from the day of EAE symptom onset. Treatment starting at the same time as immunization was also assayed. Clinical signs of EAE were monitored and histological studies were performed to analyze tissue damage, demyelination, glial reactivity, axonal loss, neuronal preservation and lymphocyte infiltration.ResultsDiazoxide inhibited in vitro nitric oxide (NO), tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) production and inducible nitric oxide synthase (iNOS) expression by activated microglia without affecting cyclooxygenase-2 (COX-2) expression and phagocytosis. Oral treatment of mice with diazoxide ameliorated EAE clinical signs but did not prevent disease. Histological analysis demonstrated that diazoxide elicited a significant reduction in myelin and axonal loss accompanied by a decrease in glial activation and neuronal damage. Diazoxide did not affect the number of infiltrating lymphocytes positive for CD3 and CD20 in the spinal cord.ConclusionTaken together, these results demonstrate novel actions of diazoxide as an anti-inflammatory agent, which might contribute to its beneficial effects on EAE through neuroprotection. Treatment with this widely used and well-tolerated drug may be a useful therapeutic intervention in ameliorating MS disease.

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Section: Discussionmentioning

confidence: 99%

Oral administration of the KATP channel opener diazoxide ameliorates disease progression in a murine model of multiple sclerosis

Virgili¹,

Espinosa-Parrilla²,

Mancera³

et al. 2011

J Neuroinflammation

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“…Tokuhara and coworkers compared the clinical and pathological evolution of EAE in knockout mice for N-type channel pore forming subunit Ca V 2.2 (α 1B ) and in their wild type littermates [239]. As expected, the neurological symptoms and the spinal cord lesions were less severe in knockout than in wild type mice [239]. Also perilesional inflammation was less severe in knockout mice.…”

Section: Introductionmentioning

confidence: 96%

“…Also, the N-type channel blocker ω-conotoxin GVIA protects Norway rats from EAE-induced optic neuritis [238]. Tokuhara and coworkers compared the clinical and pathological evolution of EAE in knockout mice for N-type channel pore forming subunit Ca V 2.2 (α 1B ) and in their wild type littermates [239]. As expected, the neurological symptoms and the spinal cord lesions were less severe in knockout than in wild type mice [239].…”

Section: Introductionmentioning

confidence: 99%

The Changing Landscape of Voltage-Gated Calcium Channels in Neurovascular Disorders and in Neurodegenerative Diseases

Cataldi

2013

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It is a common belief that voltage-gated calcium channels (VGCC) cannot carry toxic amounts of Ca2+ in neurons. Also, some of them as L-type channels are essential for Ca2+-dependent regulation of prosurvival gene-programs. However, a wealth of data show a beneficial effect of drugs acting on VGCCs in several neurodegenerative and neurovascular diseases. In the present review, we explore several mechanisms by which the “harmless” VGCCs may become “toxic” for neurons. These mechanisms could explain how, though usually required for neuronal survival, VGCCs may take part in neurodegeneration. We will present evidence showing that VGCCs can carry toxic Ca2+ when: a) their density or activity increases because of aging, chronic hypoxia or exposure to β-amyloid peptides or b) Ca2+-dependent action potentials carry high Ca2+ loads in pacemaker neurons. Besides, we will examine conditions in which VGCCs promote neuronal cell death without carrying excess Ca2+. This can happen, for instance, when they carry metal ions into the neuronal cytoplasm or when a pathological decrease in their activity weakens Ca2+-dependent prosurvival gene programs. Finally, we will explore the role of VGCCs in the control of nonneuronal cells that take part to neurodegeneration like those of the neurovascular unit or of microglia.

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“…The mechanism of MS has often been studied using an animal model, EAE, that resembles the pathology of human MS (2). It is thought to be mediated in part by myelin-specific lymphocytes, and it shows infiltration of activated peripheral inflammatory cells into the CNS, attack of myelin by the immune system or cell death of oligodendrocytes, and axonal damage (3)(4)(5). Hence, to better understand the mechanism of the signs of EAE, EAE is characterized into two phases, an immune-mediated process and a neurodegenerative process (1).…”

Section: Multiple Sclerosis (Ms)mentioning

confidence: 99%

Mechanism for p38α-mediated Experimental Autoimmune Encephalomyelitis

Namiki

Matsunaga

Yoshioka

et al. 2012

Journal of Biological Chemistry

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Background: p38 signaling pathway plays a key role in inflammatory diseases. Results: A single copy disruption of the p38␣ gene or a p38␣ inhibitor markedly reduced the pathogenesis of EAE by decreasing IL-17 production. Conclusion: p38␣ regulates the pathogenesis of EAE through transcriptional regulation of IL-17 production. Significance: Anti-p38␣ strategy achieves therapeutic benefit for the treatment of multiple sclerosis.

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N-type Calcium Channel in the Pathogenesis of Experimental Autoimmune Encephalomyelitis*

Cited by 30 publications

References 49 publications

Oral administration of the KATP channel opener diazoxide ameliorates disease progression in a murine model of multiple sclerosis

Oral administration of the KATP channel opener diazoxide ameliorates disease progression in a murine model of multiple sclerosis

The Changing Landscape of Voltage-Gated Calcium Channels in Neurovascular Disorders and in Neurodegenerative Diseases

Mechanism for p38α-mediated Experimental Autoimmune Encephalomyelitis

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