Neuroprotection by tamoxifen in focal cerebral ischemia is not mediated by an agonist action at estrogen receptors but is associated with antioxidant activity

Zhang, Yonghua; Milatović, Dejan; Aschner, Michael; Feustel, Paul J.; Kimelberg, Harold K.

doi:10.1016/j.expneurol.2007.01.015

Cited by 80 publications

(63 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Nonetheless, although tamoxifen counteracts astrocyte swelling, it has other prominent effects, and recent work suggests that it likely reduces stroke volume primarily through its ability to reduce ROS. 53 Inflammation and hypoxia influence glutamate homeostasis by altering astrocyte function…”

Section: Astrocytes Edema and Volume Regulation In Strokementioning

confidence: 99%

Targeting Astrocytes for Stroke Therapy

2010

View full text Add to dashboard Cite

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.

show abstract

Section: Astrocytes Edema and Volume Regulation In Strokementioning

confidence: 99%

Targeting Astrocytes for Stroke Therapy

2010

View full text Add to dashboard Cite

show abstract

“…Importantly, tamoxifen has an extended therapeutic window of up to 3 hrs after initiation of ischemia, which is comparable with tissue plasminogen activator, the only drug used to treat human stroke [2,11,27]. However, the specificity of the effects of tamoxifen have to be verified with more selective VRAC blockers because it may protect brain tissue via non-VRAC related mechanisms, such as inhibition of neuronal nitric oxide synthase or due to its antioxidant properties [73,74].…”

Section: Volume-regulated Anion Channels and The Reversed Mode Of Glumentioning

confidence: 99%

Disruption of ionic and cell volume homeostasis in cerebral ischemia: The perfect storm

Mongin

2007

Pathophysiology

View full text Add to dashboard Cite

The mechanisms of brain tissue damage in stroke are strongly linked to the phenomenon of excitotoxicity, which is defined as damage or death of neural cells due to excessive activation of receptors for the excitatory neurotransmitters glutamate and aspartate. Under physiological conditions, ionotropic glutamate receptors mediate the processes of excitatory neurotransmission and synaptic plasticity. In ischemia, sustained pathological release of glutamate from neurons and glial cells causes prolonged activation of these receptors, resulting in massive depolarization and cytoplasmic Ca 2+ overload. The NMDA subtype of glutamate receptors is particularly important as it represents the main initial route for the Ca 2+ influx. High cytoplasmic levels of Ca 2+ activate many degradative processes that, depending on the metabolic status, cause immediate or delayed death of neural cells. This traditional view has been expanded by a number of observations that implicate Cl − channels and several types of non-channel transporter proteins, such as the Na + ,K + ,2Cl − cotransporter, Na + /H + exchanger, and Na + /Ca 2+ exchanger, in the development of glutamate toxicity. Some of these ion transporters increase tissue damage by promoting pathological cell swelling and necrotic cell death, while others contribute to a long term accumulation of cytoplasmic Ca 2+ . This brief review is aimed at illustrating how the dysregulation of various ion transport processes combine in a 'perfect storm' that disrupts neural ionic homeostasis and culminates in the irreversible damage and death of neural cells. The clinical relevance of individual transporters as targets for therapeutic intervention in stroke is also briefly discussed.

show abstract

“…Reversible middle cerebral artery occlusion was performed as described by Longa et al (Longa et al, 1989), as used previously in our laboratory Zhang et al, 2005;2007). The suture was left in place for 2 hours and then slowly withdrawn.…”

Section: Middle Cerebral Artery Occlusionmentioning

confidence: 99%

DCPIB, a specific inhibitor of volume regulated anion channels (VRACs), reduces infarct size in MCAo and the release of glutamate in the ischemic cortical penumbra

Zhang

Feustel

et al. 2008

Experimental Neurology

Self Cite

113

View full text Add to dashboard Cite

Previous studies have indicated that volume regulated anion channels (VRACs) may be involved in the pathology of the ischemic brain cortical penumbra due to activation of VRAC-mediated excitatory amino-acid (EAA) release. To assess this we had studied neuroprotection and EAA release inhibition by a potent VRAC inhibitor, tamoxifen. However, tamoxifen inhibits several other neurodamaging processes. In the present study we use an ethacrynic acid derivative, 4-(2-butyl-6, 7-dichloro-2-cyclopentyl-indan-1-on-5-yl) oxobutyric acid (DCPIB), that has recently been shown to be a specific antagonist of volume regulated anion channels (VRAC), to measure the extent of neuroprotection provided and thus to better assess the role of VRAC-mediated release of excitatory amino acids in an intraluminal suture, reversible middle cerebral artery occlusion (rMCAO) model in adult rats. Rats given DCPIB intracisternally had significantly better neurobehavioral scores after 24 hours and showed significantly reduced infarct volumes. Mean infarct volumes were 208.0 (SD = 38.3) mm 3 for the vehicle groups, compared with 68.5 (SD = 22.7) mm 3 for intracisternally DCPIBtreated groups (p=0.02, Mann-Whitney test), a reduction of around 75%. However, a 500-fold higher dose of DCPIB given intravenously did not reduce infarct volume or improve behavior. The microdialysis study demonstrated statistically significant reduced brain extracellular fluid glutamate when DCPIB was present in the probe. Thus DCPIB, a specific inhibitor of VRACs, given i.c. provides strong neuroprotection in brain ischemia, but it appears to not cross the blood brain barrier as it is not effective when given i.v. These experiments support the hypothesis that EAA released via VRACs contributes to later ischemic-induced damage.

show abstract

Neuroprotection by tamoxifen in focal cerebral ischemia is not mediated by an agonist action at estrogen receptors but is associated with antioxidant activity

Cited by 80 publications

References 36 publications

Targeting Astrocytes for Stroke Therapy

Targeting Astrocytes for Stroke Therapy

Disruption of ionic and cell volume homeostasis in cerebral ischemia: The perfect storm

DCPIB, a specific inhibitor of volume regulated anion channels (VRACs), reduces infarct size in MCAo and the release of glutamate in the ischemic cortical penumbra

Contact Info

Product

Resources

About