Microglia: phagocyte and glia cell

Vilhardt, Frédérik

doi:10.1016/j.biocel.2004.06.010

Cited by 217 publications

(163 citation statements)

References 15 publications

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“…Importantly, there was no evidence of drug toxicity with even the highest doses of TRAM-34, i.e., there were no seizures or changes in feeding, activity, or behavior. The outcome of microglia activation can be complex and determined primarily by the factors they produce (for review, see Zielasek and Hartung, 1996;Nelson et al, 2002;Vilhardt, 2005). Together with our in vitro results showing an involvement of KCa3.1 channels in microglia iNOS induction, nitric oxide production, and p38 MAPK activation, the in vivo results suggest that KCa3.1 blockade likely acts by reducing production and/or secretion of soluble neurotoxic molecules in the retina.…”

Section: Kca3supporting

confidence: 60%

“…Microglia activate and migrate after retinal damage (Thanos and Richter, 1993) (for review, see Vilhardt, 2005), and inflammation has been implicated in the apoptotic degeneration of RGCs, which reaches 80 -90% by 2 weeks after axotomy (Koeberle and Ball, 1999;Bahr, 2000;Chen et al, 2002;Koeberle et al, 2004). First (Fig.…”

Section: Kca31 Blockade In Vivo Reduces Death Of Retinal Ganglion Cementioning

confidence: 99%

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The Ca²⁺-Activated K⁺ChannelKCNN4/KCa3.1 Contributes to Microglia Activation and Nitric Oxide-Dependent Neurodegeneration

Kaushal¹,

Koeberle²,

Wang³

et al. 2007

J. Neurosci.

207

233

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Brain damage and disease involve activation of microglia and production of potentially neurotoxic molecules, but there are no treatments that effectively target their harmful properties. We present evidence that the small-conductance Ca 2ϩ /calmodulin-activated K ϩ channel KCNN4/ KCa3.1/SK4/IK1 is highly expressed in rat microglia and is a potential therapeutic target for acute brain damage. Using a Transwell cell-culture system that allows separate treatment of the microglia or neurons, we show that activated microglia killed neurons, and this was markedly reduced by treating only the microglia with a selective inhibitor of KCa3.1 channels, triarylmethane-34 (TRAM-34). To assess the role of KCa3.1 channels in microglia activation and key signaling pathways involved, we exploited several fluorescence plate-reader-based assays. KCa3.1 channels contributed to microglia activation, inducible nitric oxide synthase upregulation, production of nitric oxide and peroxynitrite, and to consequent neurotoxicity, protein tyrosine nitration, and caspase 3 activation in the target neurons. Microglia activation involved the signaling pathways p38 mitogen-activated protein kinase (MAPK) and nuclear factor B (NF-B), which are important for upregulation of numerous proinflammatory molecules, and the KCa3.1 channels were functionally linked to activation of p38 MAPK but not NF-B. These in vitro findings translated into in vivo neuroprotection, because we found that degeneration of retinal ganglion cells after optic nerve transection was reduced by intraocular injection of TRAM-34. This study provides evidence that KCa3.1 channels constitute a therapeutic target in the CNS and that inhibiting this K ϩ channel might benefit acute and chronic neurodegenerative disorders that are caused by or exacerbated by inflammation.

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Section: Kca3supporting

confidence: 60%

Section: Kca31 Blockade In Vivo Reduces Death Of Retinal Ganglion Cementioning

confidence: 99%

The Ca²⁺-Activated K⁺ChannelKCNN4/KCa3.1 Contributes to Microglia Activation and Nitric Oxide-Dependent Neurodegeneration

Kaushal¹,

Koeberle²,

Wang³

et al. 2007

J. Neurosci.

207

233

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“…Activated microglia release several neurotoxic substances, including superoxide, nitric oxide, and metalloproteinases (Chao et al, 1992;Giulian et al, 1993;Hanisch, 2002;Vilhardt, 2005), and microglia activation is morphologically characterized by change to an amoeboid shape (Morioka et al, 1992;Lund et al, 1994;Kreutzberg, 1996). Several intercellular signals have been found to mediate microglial activation in ischemia, including zinc (Kauppinen et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

EAAC1 Gene Deletion Alters Zinc Homeostasis and Exacerbates Neuronal Injury after Transient Cerebral Ischemia

Won¹,

Yoo²,

Brennan³

et al. 2010

J. Neurosci.

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EAAC1 is a neuronal glutamate and cysteine transporter. EAAC1 uptake of cysteine provides substrate for neuronal glutathione synthesis, which plays a key role in both antioxidant defenses and intracellular zinc binding. Here we evaluated the role of EAAC1 in neuronal resistance to ischemia. EAAC1 Ϫ/Ϫ mice subjected to transient cerebral ischemia exhibited twice as much hippocampal neuronal death as wild-type mice and a corresponding increase in microglial activation. EAAC1 Ϫ/Ϫ mice also had elevated vesicular and cytosolic zinc concentrations in hippocampal CA1 neurons and an increased zinc translocation to postsynaptic neurons after ischemia. Treatment of the EAAC1 Ϫ/Ϫ mice with N-acetyl cysteine restored neuronal glutathione concentrations and normalized basal zinc levels in the EAAC1 Ϫ/Ϫ mice. Treatment of the EAAC1 Ϫ/Ϫ mice with either N-acetyl cysteine or with zinc chelators reduced ischemia-induced zinc translocation, superoxide production, and neuron death. These findings suggest that cysteine uptake by EAAC1 is important for zinc homeostasis and neuronal antioxidant function under ischemic conditions.

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“…Microglial cells also have relevance to neuronal function in various types of brain injury and disease, such as ischemic trauma and AD. Activation of microglia under pathological conditions results in their transformation to amoeboid morphology, migration toward the site of injury/damage, and release of neuroactive compounds that can have either neurotoxic or neuroprotective effects [171,172]. In vivo two-photon imaging revealed that resting microglia make brief but direct contacts with synapses without undergoing complete transformation/activation associated with a pathological phenotype [173,174].…”

Section: Glial-neuronal Interactions Involving P2y 2 Receptorsmentioning

confidence: 99%

Neuroprotective roles of the P2Y2 receptor

Weisman

Ajit

Garrad

et al. 2012

Purinergic Signalling

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Microglia: phagocyte and glia cell

Cited by 217 publications

References 15 publications

The Ca²⁺-Activated K⁺ChannelKCNN4/KCa3.1 Contributes to Microglia Activation and Nitric Oxide-Dependent Neurodegeneration

The Ca²⁺-Activated K⁺ChannelKCNN4/KCa3.1 Contributes to Microglia Activation and Nitric Oxide-Dependent Neurodegeneration

EAAC1 Gene Deletion Alters Zinc Homeostasis and Exacerbates Neuronal Injury after Transient Cerebral Ischemia

Neuroprotective roles of the P2Y2 receptor

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Microglia: phagocyte and glia cell

Cited by 217 publications

References 15 publications

The Ca2+-Activated K+ChannelKCNN4/KCa3.1 Contributes to Microglia Activation and Nitric Oxide-Dependent Neurodegeneration

The Ca2+-Activated K+ChannelKCNN4/KCa3.1 Contributes to Microglia Activation and Nitric Oxide-Dependent Neurodegeneration

EAAC1 Gene Deletion Alters Zinc Homeostasis and Exacerbates Neuronal Injury after Transient Cerebral Ischemia

Neuroprotective roles of the P2Y2 receptor

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The Ca²⁺-Activated K⁺ChannelKCNN4/KCa3.1 Contributes to Microglia Activation and Nitric Oxide-Dependent Neurodegeneration

The Ca²⁺-Activated K⁺ChannelKCNN4/KCa3.1 Contributes to Microglia Activation and Nitric Oxide-Dependent Neurodegeneration