Alterations in metabolism and gap junction expression may determine the role of astrocytes as “good samaritans” or executioners

Farahani, Reza Masteri; Pina-Benabou, M. H.; Kyrozis, Andreas; Siddiq, Ayesha; Barradas, Penha C.; Chiu, Fung‐Chow; Cavalcante, Leny A.; Lai, James C. K.; Stanton, Patric K.; Rozental, Renato

doi:10.1002/glia.20213

Cited by 77 publications

(59 citation statements)

References 101 publications

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“…This topic, which has been reviewed in detail elsewhere, 134,135 is beyond the scope of the present review. It is nonetheless worth pointing out that carbenoxolone, a gap junction inhibitor, reduces neuronal death in focal and global models of ischemia in adult and neonatal rodents.…”

Section: Astrocytes Cx43 Adenosine and Neuroprotectionmentioning

confidence: 99%

Targeting Astrocytes for Stroke Therapy

2010

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Summary: Stroke remains a major health problem and is a leading cause of death and disability. Past research and neurotherapeutic clinical trials have targeted the molecular mechanisms of neuronal cell death during stroke, but this approach has uniformly failed to reduce stroke-induced damage or to improve functional recovery. Beyond the intrinsic molecular mechanisms inducing neuronal death during ischemia, survival and function of astrocytes is absolutely required for neuronal survival and for functional recovery after stroke. Many functions of astrocytes likely improve neuronal viability during stroke. For example, uptake of glutamate and release of neurotrophins enhances neuronal viability during ischemia. Under certain conditions, however, astrocyte function may compromise neuronal viability. For example, astrocytes may produce inflammatory cytokines or toxic mediators, or may release glutamate. The only clinical neurotherapeutic trial for stroke that specifically targeted astrocyte function focused on reducing release of S-100␤ from astrocytes, which becomes a neurotoxin when present at high levels. Recent work also suggests that astrocytes, beyond their influence on cell survival, also contribute to angiogenesis, neuronal plasticity, and functional recovery in the several days to weeks after stroke. If these delayed functions of astrocytes could be targeted for enhancing stroke recovery, it could contribute importantly to improving stroke recovery. This review focuses on both the positive and the negative influences of astrocytes during stroke, especially as they may be targeted for translation to human trials.

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Section: Astrocytes Cx43 Adenosine and Neuroprotectionmentioning

confidence: 99%

Targeting Astrocytes for Stroke Therapy

2010

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“…The apoptosis of retinal neurosensory cells, which occurs during ischemia, is thought to be through open gap junctions, propagated by the "bystander effect" [4].…”

Section: Introductionmentioning

confidence: 99%

“…The gap junction "bystander effect" occurs when a dying cell delivers a cellular apoptotic signal such as high Ca +2 or ATP to an adjacent cell through open gap junctions which, in turn, causes spread of the death signal [4]. The process is well-documented in brain ischemia [10][11][12].…”

Section: Introductionmentioning

confidence: 99%

Protection of retinal cells from ischemia by a novel gap junction inhibitor

Das¹,

Lin²,

Jena³

et al. 2008

Biochemical and Biophysical Research Communications

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Retinal cells which become ischemic will pass apoptotic signal to adjacent cells, resulting in the spread of damage. This occurs through open gap junctions. A class of novel drugs, based on primaquine (PQ), was tested for binding to connexin 43 using simulated docking studies. A novel drug has been synthesized and tested for inhibition of gap junction activity using R28 neuro-retinal cells in culture. Four drugs were initially compared to mefloquine, a known gap junction inhibitor. The drug with optimal inhibitory activity, PQ1, was tested for inhibition and was found to inhibit dye transfer by 70% at 10 μM. Retinal ischemia was produced in R28 cells using cobalt chloride as a chemical agent. This resulted in activation of caspase-3 which was prevented by the PQ1 gap junction inhibitor. Results demonstrate that novel gap junction inhibitors may provide a means to prevent retinal damage during ischemia.

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“…Inhibition of gap junctions prevents cell death (Farahani et al, 2005;de Pina-Benabou et al, 2005;Krysko et al, 2005). We, for the first time, show that PKCγ C1B mutations have a negative effect on endogenous wild type PKCγ.…”

Section: Discussionmentioning

confidence: 65%

“…Loss of control of gap junctions by PKCγ, ie., no PKCγ phosphorylation of Cx50 in PKCγ knockout lenses, causes PKCγ knockout lenses to be more susceptible to oxidative stress-induced cataracts in the mouse (Lin et al, 2006). Inhibition of gap junctions prevents cell death (Farahani et al, 2005;de Pina-Benabou et al, 2005;Krysko et al, 2005). It is apparent that control of gap junctions is essential for lens cell survival.…”

Section: Introductionmentioning

confidence: 99%

Protein kinase C γ mutations in the C1B domain cause caspase-3-linked apoptosis in lens epithelial cells through gap junctions

Lin

Shanks

Prakash

et al. 2007

Experimental Eye Research

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Failure to control oxidative stress is closely related to aging and to a diverse range of human diseases. We have reported that protein kinase C γ (PKCγ) acts as a primary oxidative stress sensor in the lens. PKCγ has a Zn-finger C1B stress switch domain, residues 101-150. Mutation, H101Y, in the C1B domain of PKCγ proteins causes a failure of the PKCγ oxidative stress response (Lin and Takemoto (2005) (100 μM, 3 h) activated a caspase-3 apoptotic pathway in the lens epithelial cells but was more severe in cells expressing PKCγ mutations. The presence of 18α-glycyrrhetinic acid (AGA), an inhibitor of gap junctions, decreased Cx43 and Cx50 protein levels and gap junction plaque number. This reduction in gap junctions by AGA resulted in inhibition of H 2 O 2 -induced apoptosis. Our results demonstrate that there is a dominant negative effect of PKCγ C1B mutations on endogenous PKCγ which results in loss of control of gap junctions. Modeled structures suggest that the severity of C1B mutation effects may be related to extent of loss of C1B structure. Mutations in the C1B domain of PKCγ result in increased apoptosis in lens epithelial cells. This can be prevented by a gap junction inhibitor. Thus, propagation of apoptosis from cellto-cell in lens epithelial cells may be through open gap junctions. The control of gap junctions requires PKCγ.

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Alterations in metabolism and gap junction expression may determine the role of astrocytes as “good samaritans” or executioners

Cited by 77 publications

References 101 publications

Targeting Astrocytes for Stroke Therapy

Targeting Astrocytes for Stroke Therapy

Protection of retinal cells from ischemia by a novel gap junction inhibitor

Protein kinase C γ mutations in the C1B domain cause caspase-3-linked apoptosis in lens epithelial cells through gap junctions

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