Reversal of Rotenone-Induced Dysfunction of Astrocytic Connexin43 by Opening Mitochondrial ATP-Sensitive Potassium Channels

Zhang, Shu; Liang, Rui; Zhou, Fang; Huang, Xu; Ding, Jingzhong; Hu, Gang

doi:10.1007/s10571-010-9560-6

Cited by 24 publications

(22 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In astrocytes, diazoxide exerts a neuroprotective effect by different mechanisms, including the facilitation of glutamate uptake [52] and amelioration of mitochondrial and connexin 43 dysfunction [53]. We also observed a decrease in nitrite production and inflammatory cytokines release in primary cultures that included both astrocytes and microglia and a decrease of GFAP reactivity in the gray matter of diazoxide treated EAE mice.…”

Section: Discussionmentioning

confidence: 82%

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

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 82%

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

View full text Add to dashboard Cite

show abstract

“…Wang, et al, 2005b,Wang, et al, 2004,S. Wang, et al, 2005,Wang, et al, 2006,Yang, et al, 2004,Yang, et al, 2005,Yang, et al, 2009,Zhang, et al, 2011,Zhou, et al, 2007). Other experimental results reported for iptakalim in mammals include beneficial neurochemical effects that may help to combat depression or psychoses (Lu, et al, 2014,Volf, et al, 2012).…”

Section: Abcc9 In the Brainmentioning

confidence: 99%

ABCC9/SUR2 in the brain: Implications for hippocampal sclerosis of aging and a potential therapeutic target

Nelson

Jicha

Wang

et al. 2015

Ageing Research Reviews

View full text Add to dashboard Cite

The ABCC9 gene and its polypeptide product, SUR2, are increasingly implicated in human neurologic disease, including prevalent diseases of the aged brain. SUR2 proteins are a component of the ATP-sensitive potassium (“KATP”) channel, a metabolic sensor for stress and/or hypoxia that has been shown to change in aging. The KATP channel also helps regulate the neurovascular unit. Most brain cell types express SUR2, including neurons, astrocytes, oligodendrocytes, microglia, vascular smooth muscle, pericytes, and endothelial cells. Thus it is not surprising that ABCC9 gene variants are associated with risk for human brain diseases. For example, Cantu syndrome is a result of ABCC9 mutations; we discuss neurologic manifestations of this genetic syndrome. More common brain disorders linked to ABCC9 gene variants include hippocampal sclerosis of aging (HS-Aging), sleep disorders, and depression. HS-Aging is a prevalent neurological disease with pathologic features of both neurodegenerative (aberrant TDP-43) and cerebrovascular (arteriolosclerosis) disease. As to potential therapeutic intervention, the human pharmacopeia features both SUR2 agonists and antagonists, so ABCC9/SUR2 may provide a “druggable target”, relevant perhaps to both HS-Aging and Alzheimer’s disease. We conclude that more work is required to better understand the roles of ABCC9/SUR2 in the human brain during health and disease conditions.

show abstract

“…However, some authors registered inhibited expression of astrocytic Cx43 and gap junction permeability in astrocytes in rotenone models of Parkinson's disease. Moreover, rotenone-induced dysfunction of astrocytic Cx43 can be reversed by opening mitochondrial ATP-sensitive potassium channels (iptakalim and diazoxide) resulting in prevention of astrocyte apoptosis (Zhang et al, 2010). Thus, we believe that Cx43-CD38 functional coupling in astrocytes significantly contribute to controlling energy homeostasis in astroglial and neuronal cells.…”

Section: Wwwintechopencommentioning

confidence: 96%

Alteration of Neuron-Glia Interactions in Neurodegeneration: Molecular Biomarkers and Therapeutic Strategy

Салмина¹,

Петрова²,

Таранушенко³

et al. 2011

Neurodegenerative Diseases - Processes, Prevention, Protection and Monitoring

View full text Add to dashboard Cite

Reversal of Rotenone-Induced Dysfunction of Astrocytic Connexin43 by Opening Mitochondrial ATP-Sensitive Potassium Channels

Cited by 24 publications

References 50 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

ABCC9/SUR2 in the brain: Implications for hippocampal sclerosis of aging and a potential therapeutic target

Alteration of Neuron-Glia Interactions in Neurodegeneration: Molecular Biomarkers and Therapeutic Strategy

Contact Info

Product

Resources

About