Neuroprotective activity of tamoxifen in permanent focal ischemia

Kimelberg, Harold K.; Jin, Yiqiang; Charniga, Carol; Feustel, Paul J.

doi:10.3171/jns.2003.99.1.0138

Cited by 81 publications

(66 citation statements)

References 32 publications

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“…Anion channel blockers L644,711 and tamoxifen reduced mortality rates and strongly decreases the infarction size in several ischemia models [26][27][28][29]. 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].…”

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

confidence: 78%

“…Apparently, VRAC is functionally important for Cl − accumulation and pathological cell swelling during exposure to excitotoxins, as well as for cell volume recovery when excitotoxins are removed [21]. In vivo, two VRAC blockers, Merck compound L644,711 and tamoxifen, potently protect brain tissue against ischemic damage in animal models of focal transient and permanent ischemia [26][27][28][29]. However, as discussed in the next section, the protective actions of VRAC blockers are not restricted to preventing pathological cell swelling, but also involve other mechanisms.…”

Section: Introduction: Overview Of Ischemic Brain Damagementioning

confidence: 99%

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

Mongin

2007

Pathophysiology

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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.

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

confidence: 78%

Section: Introduction: Overview Of Ischemic Brain Damagementioning

confidence: 99%

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

Mongin

2007

Pathophysiology

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“…Tamoxifen at both 5 and 10 mg/kg given 3 hours post initiation of ischemia was as effective a neuroprotectant as when it was administered simultaneously with ischemia (Kimelberg et al, 2000(Kimelberg et al, ,2003. To see whether this protection correlated with antioxidant activity under the same conditions we tested the antioxidant effects of 5 mg/kg tamoxifen given 3 hours after initiation of ischemia as measured by effects on isoprostane appearance.…”

Section: Antioxidant Activity Of Tamoxifenmentioning

confidence: 99%

“…Since ICI 182,780 has been shown not to penetrate the BBB ( Wade et al, 1993), we administered it intravaneously and intracisternally, thus testing whether tamoxifen induced neuroprotection involves an action on either peripheral or central estrogen receptors (Hurn and Brass, 2003). In this case we gave tamoxifen at the time of the occlusion and ICI 182,780 just prior to tamoxifen, since we assume that there is no time-dependent change in mechanism as the amount of protection is the same within this time window (Kimelberg et al, 2000(Kimelberg et al, ,2003. A novel finding in this study therefore, is that tamoxifen's protection persists when administered with either intravenous injection or intracisternal injection of pure ER blocker, ICI 182,780, in the rMCAo model in rats.…”

Section: Actions Of Tamoxifen On Estrogen Receptorsmentioning

confidence: 99%

“…We have previously shown that tamoxifen, a drug widely used in the treatment of breast cancer (MacGregor and Jordan, 1998), and also used at higher doses in brain cancers (Pollack et al, 1997), reduces infarct size by more than 80% in both the reversible (Kimelberg et al, 2000) and permanent (Kimelberg et al, 2003) middle cerebral artery occlusion models in the rat.…”

Section: Introductionmentioning

confidence: 99%

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

Zhang

Milatović²,

Aschner³

et al. 2007

Experimental Neurology

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We have previously shown that tamoxifen can induce marked neuroprotection after middle cerebral artery occlusion (MCAo) in rats and have described two possible mechanisms of action: namely inhibition of EAA release and inhibition of nNOS activity. In this study we tested other potential mechanisms. Namely, agonist action at estrogen receptors and an antioxidative action. Tamoxifentreated rats had significantly improved neurobehavioral deficit scores after 24 hours and showed ∼75% reduced infarct volumes. These were unaffected by ICI 182,780 (a high affinity and pure receptor antagonist) administered intravenously, or intracisternally to avoid possible lack of brain penetration, 15 minutes before intravenous administration of tamoxifen. In rats subjected to 2 hours MCAo followed by 22 hours reperfusion, a 1.8-fold and 2.9-fold increase of F 2 -IsoPs and F 4 neuroprostanes, respectively, as relatively stable markers of oxidative damage, were measured in the ischemic hemisphere compared with the corresponding contralateral hemisphere or sham controls. Tamoxifen given at 3 hours after the start of ischemia reduced the IsoPs and NeuroPs to sham control levels, and also inhibited their production by chemically induced lipid peroxidation in brain homogenates. These data are consistent with at least part of tamoxifen's marked neuroprotection in focal cerebral ischemic injury being due to its antioxidant activity but not by an acute action on estrogen receptors (212 words).

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Astrocytic swelling in cerebral ischemia as a possible cause of injury and target for therapy

Kimelberg

2005

Glia

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In this viewpoint article, I summarize data showing that the astrocytic swelling that occurs early after the acute CNS pathologies ischemia and traumatic brain injury is damaging. We have proposed that one reason may be the release of excitatory amino acids (EAA) via volume-activated anion channels (VRACs) that are activated by such swelling. This release could be a target for therapy, which could involve blocking the astrocytic swelling or the release mechanisms. The transport mechanisms likely causing the early astrocytic swelling are therefore summarized. In terms of targeting the release mechanisms, we have found a potent inhibitor of VRACs, tamoxifen, to be strongly neuroprotective in focal ischemia with a therapeutic window of 3 h after initiation of the ischemia. The question, however, of whether neuroprotection by tamoxifen can be solely attributed to VRAC inhibition in astrocytes has yet to be resolved.

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Neuroprotective activity of tamoxifen in permanent focal ischemia

Cited by 81 publications

References 32 publications

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

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

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

Astrocytic swelling in cerebral ischemia as a possible cause of injury and target for therapy

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