Characterization of long-term functional outcome in a murine model of mild brain ischemia

Balkaya, Mustafa; Kröber, Jan; Gertz, Karen; Peruzzaro, Sarah; Endres, Matthias

doi:10.1016/j.jneumeth.2012.12.021

Cited by 104 publications

(103 citation statements)

References 25 publications

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“…Rotarod test is used to assess motor ability where the longer latency to fall represents better motor function. 20 There was no difference before ischemia (113.2 ± 8.3 seconds NS versus 115.8 ± 11.9 seconds ketones). At 24 hours after ischemia, the latency to fall decreased in both groups, but to a much lesser degree in the treatment group (91.7 ± 6.7 seconds versus 69.0 ± 7.2 seconds NS, Figure 1B).…”

Section: Ketones Improved Neurologic Function By Reducing Infarct Volumementioning

confidence: 85%

Sirtuin 3 Mediates Neuroprotection of Ketones against Ischemic Stroke

Yin

Han

Tang

et al. 2015

J Cereb Blood Flow Metab

125

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Stroke is one of the leading causes of death. Growing evidence indicates that ketone bodies have beneficial effects in treating stroke, but their underlying mechanism remains unclear. Our previous study showed ketone bodies reduced reactive oxygen species by using NADH as an electron donor, thus increasing the NAD + /NADH ratio. In this study, we investigated whether mitochondrial NAD + -dependent Sirtuin 3 (SIRT3) could mediate the neuroprotective effects of ketone bodies after ischemic stroke. We injected mice with either normal saline or ketones (beta-hydroxybutyrate and acetoacetate) at 30 minutes after ischemia induced by transient middle cerebral artery (MCA) occlusion. We found that ketone treatment enhanced mitochondria function, reduced oxidative stress, and therefore reduced infarct volume. This led to improved neurologic function after ischemia, including the neurologic score and the performance in Rotarod and open field tests. We further showed that ketones' effects were achieved by upregulating NAD + -dependent SIRT3 and its downstream substrates forkhead box O3a (FoxO3a) and superoxide dismutase 2 (SOD2) in the penumbra region since knocking down SIRT3 in vitro diminished ketones' beneficial effects. These results provide us a foundation to develop novel therapeutics targeting this SIRT3-FoxO3a-SOD2 pathway.

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Section: Ketones Improved Neurologic Function By Reducing Infarct Volumementioning

confidence: 85%

Sirtuin 3 Mediates Neuroprotection of Ketones against Ischemic Stroke

Yin

Han

Tang

et al. 2015

J Cereb Blood Flow Metab

125

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“…Next we investigated whether EC-targeted HSP27 overexpression leads to long-term functional improvements in stroke mice. Commonly used neurobehavioral tests for assessing neurological deficits of mice show different patterns and time course of spontaneous recovery in stroke animals (23)(24)(25). To comprehensively evaluate sensorimotor functions after stroke, a battery of four different behavioral tests was performed on WT, N-HSP27, and EC-HSP27 mice before and up to 21 d after tFCI ( Fig.…”

Section: Ec-specific Overexpression Of Hsp27 Ameliorates Bbb Disruptionmentioning

confidence: 99%

Endothelium-targeted overexpression of heat shock protein 27 ameliorates blood–brain barrier disruption after ischemic brain injury

Shi

Jiang

Zhang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

121

144

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The damage borne by the endothelial cells (ECs) forming the blood–brain barrier (BBB) during ischemic stroke and other neurological conditions disrupts the structure and function of the neurovascular unit and contributes to poor patient outcomes. We recently reported that structural aberrations in brain microvascular ECs—namely, uncontrolled actin polymerization and subsequent disassembly of junctional proteins, are a possible cause of the early onset BBB breach that arises within 30–60 min of reperfusion after transient focal ischemia. Here, we investigated the role of heat shock protein 27 (HSP27) as a direct inhibitor of actin polymerization and protectant against BBB disruption after ischemia/reperfusion (I/R). Using in vivo and in vitro models, we found that targeted overexpression of HSP27 specifically within ECs—but not within neurons—ameliorated BBB impairment 1–24 h after I/R. Mechanistically, HSP27 suppressed I/R-induced aberrant actin polymerization, stress fiber formation, and junctional protein translocation in brain microvascular ECs, independent of its protective actions against cell death. By preserving BBB integrity after I/R, EC-targeted HSP27 overexpression attenuated the infiltration of potentially destructive neutrophils and macrophages into brain parenchyma, thereby improving long-term stroke outcome. Notably, early poststroke administration of HSP27 attached to a cell-penetrating transduction domain (TAT-HSP27) rapidly elevated HSP27 levels in brain microvessels and ameliorated I/R-induced BBB disruption and subsequent neurological deficits. Thus, the present study demonstrates that HSP27 can function at the EC level to preserve BBB integrity after I/R brain injury. HSP27 may be a therapeutic agent for ischemic stroke and other neurological conditions involving BBB breakdown.

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“…Mild focal ischemia in the mouse causing severe striatal SNL sometimes associated with small infarcts also leads to subtle, although long-lasting, sensorimotor deficits, 91,92 as well as cognitive changes including deficits in strategy switching, 93 and long-term neuropsychiatric sequelae such as anxious and hyperactive phenotype. 46 The clinical correlates of SNL are difficult to address because in the vast majority of patients there is an associated infarct, albeit small, in most.…”

Section: Animal Modelsmentioning

confidence: 99%

Selective Neuronal Loss in Ischemic Stroke and Cerebrovascular Disease

Baron

Yamauchi

Fujioka

et al. 2013

J Cereb Blood Flow Metab

Self Cite

207

208

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As a sequel of brain ischemia, selective neuronal loss (SNL)-as opposed to pannecrosis (i.e. infarction)-is attracting growing interest, particularly because it is now detectable in vivo. In acute stroke, SNL may affect the salvaged penumbra and hamper functional recovery following reperfusion. Rodent occlusion models can generate SNL predominantly in the striatum or cortex, showing that it can affect behavior for weeks despite normal magnetic resonance imaging. In humans, SNL in the salvaged penumbra has been documented in vivo mainly using positron emission tomography and 11 C-flumazenil, a neuronal tracer validated against immunohistochemistry in rodent stroke models. Cortical SNL has also been documented using this approach in chronic carotid disease in association with misery perfusion and behavioral deficits, suggesting that it can result from chronic or unstable hemodynamic compromise. Given these consequences, SNL may constitute a novel therapeutic target. Selective neuronal loss may also develop at sites remote from infarcts, representing secondary 'exofocal' phenomena akin to degeneration, potentially related to poststroke behavioral or mood impairments again amenable to therapy. Further work should aim to better characterize the time course, behavioral consequences-including the impact on neurological recovery and contribution to vascular cognitive impairment-association with possible causal processes such as microglial activation, and preventability of SNL.

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Characterization of long-term functional outcome in a murine model of mild brain ischemia

Cited by 104 publications

References 25 publications

Sirtuin 3 Mediates Neuroprotection of Ketones against Ischemic Stroke

Sirtuin 3 Mediates Neuroprotection of Ketones against Ischemic Stroke

Endothelium-targeted overexpression of heat shock protein 27 ameliorates blood–brain barrier disruption after ischemic brain injury

Selective Neuronal Loss in Ischemic Stroke and Cerebrovascular Disease

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