Neuroprotection after Transient Global Cerebral Ischemia in Wlds Mutant Mice

The Wlds mouse mutant demonstrates a remarkable phenotype of delayed axonal and synaptic degeneration after nerve lesion. In this study, the authors tested the hypothesis that expression of Wld protein is neuroprotective in an in vivo mouse model of global cerebral ischemia. This model is associated with selective neuronal degeneration in specific brain regions such as the caudate nucleus and CA2 hippocampal pyramidal cell layer. The extent of neuronal damage was quantified in Wlds compared to wild-type mice after an identical episode of global cerebral ischemia. The results demonstrated a significant and marked reduction in the extent of neuronal damage in Wlds as compared to wild-type C57Bl/6 mice. In the caudate nucleus, Wld expression significantly reduced the percentage of ischemic neuronal damage after global ischemia (Wlds, 27.7 ± 16.8%; wild-type mice, 58.7 ± 32.3%; P = 0.036). Similarly, in the CA2 pyramidal cell layer, there was a significant reduction of neuronal damage in the Wlds mice as compared to wild-type mice after ischemia (Wlds, 17.7 ± 23.0%; wild-type mice, 41.9 ± 28.0%; P < 0.023). Thus, these results clearly demonstrate that the Wld gene confers substantial neuroprotection after cerebral ischemia, and suggest a new role to that previously described for Wlds.

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Estrogen is Neuroprotective via an Apolipoprotein E—Dependent Mechanism in a Mouse Model of Global Ischemia

Journal of Cerebral Blood Flow & Metabolism ◽

10.1097/01.wcb.0000037991.07114.4e ◽

2002 ◽

Vol 22 (10) ◽

pp. 1189-1195 ◽

Cited By ~ 31

Author(s):

Karen Horsburgh ◽

I. Mhairi Macrae ◽

Hilary Carswell

Keyword(s):

Cerebral Ischemia ◽

Apolipoprotein E ◽

Caudate Nucleus ◽

Pyramidal Cell ◽

Cell Layer ◽

Neuronal Damage ◽

Global Ischemia ◽

Pyramidal Cell Layer ◽

17Β Estradiol ◽

Deficient Mice

Estrogen can ameliorate brain damage in experimental models of focal cerebral ischemia. In vitro, estrogen increases levels of apolipoprotein E (apoE), which also has neuroprotective effects in brain injury. The authors tested the hypotheses that physiologically relevant levels of 17β-estradiol are neuroprotective in global cerebral ischemia and that neuroprotection is mediated via apoE. In the first study, subcutaneous implants of 17β-estradiol were tested in female C57Bl/6J mice (ovariectomized and nonovariectomized) and plasma levels measured by radioimmunoassay to validate that physiologically relevant levels could be achieved. In the second study, female C57Bl/6J and apoE-deficient mice were ovariectomized and implanted with 17β-estradiol or placebo pellet. Two weeks later, transient global ischemia was induced by bilateral carotid artery occlusion and the mice killed after 72 hours. Ischemic and normal neurons were counted in the caudate nucleus and CA1 pyramidal cell layer and the percentage of neuronal damage was compared between the treated groups. In C57Bl/6J mice, there was less neuronal damage in the 17β-estradiol-treated group compared with placebo group in the caudate nucleus (15 ± 20% versus 39 ± 27%, P = 0.02) and in the CA1 pyramidal cell layer (1.8 ± 2% versus 10 ± 14%, P = 0.08). In contrast, neuronal damage was not significantly different between the 17β-estradiol and placebo groups in apoE-deficient mice in the caudate nucleus (47 ± 35% versus 53 ± 29%, P = 0.7) or in the CA1 pyramidal cell layer (24 ± 19% versus 24 ± 19%, P = 1.0). The data indicate a neuroprotective role for estrogen in global ischemia, the mechanism of which is apoE-dependent.

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Targeting Expression of hsp70i to Discrete Neuronal Populations Using the Lmo-1 Promoter: Assessment of the Neuroprotective Effects of hsp70i In vivo and In vitro

Journal of Cerebral Blood Flow & Metabolism ◽

10.1097/00004647-200108000-00010 ◽

2001 ◽

Vol 21 (8) ◽

pp. 972-981 ◽

Cited By ~ 40

Author(s):

Stephen Kelly ◽

Alison Bieneman ◽

Karen Horsburgh ◽

David Hughes ◽

Michael V. Sofroniew ◽

...

Keyword(s):

Cerebral Ischemia ◽

Transgenic Mice ◽

Caudate Nucleus ◽

Neuronal Damage ◽

Global Cerebral Ischemia ◽

Specific Gene ◽

Wild Type ◽

Neuroprotective Effects ◽

Bilateral Carotid

Transgenic technology provides a powerful means of studying gene regulation and specific gene function with complex mammalian systems. In this study, the authors exploited the specific and discrete neuronal expression pattern mediated by promoter 1 of the Lmo-1 gene to study the neuroprotective effects of the inducible form of heat shock protein 70kD (hsp70i) in primary hippocampal cultures in a mouse model of global cerebral ischemia. Targeting expression of hsp70i to hippocampal neurons protected these cells significantly from toxic levels of glutamate and oxidative stress (for example, exposure to 10 μmol/L free iron produced a 26% increase in lactate dehydrogenase release from neurons cultured from wild-type mice, but a 7% increase in neurons cultured from hsp70i transgenic mice). Bilateral carotid occlusion (25 minutes) produced significantly less neuronal damage in the caudate nucleus and posterior thalamus in hsp70i transgenic mice than in wild-type littermates (for example, 21% ± 9.3% and 12.5% ± 9.0% neuronal damage in lateral caudate nucleus of wild-type and hsp70i transgenic mice, respectively, P < 0.05). The current study highlights the utility of targeted expression of transgenes of interest in cerebral ischemia and demonstrates that expression of hsp70i alone is sufficient to mediate the protection of primary neurons from denaturing stress and that expression of human hsp70i in vivo plays crucial role in determining the fate of neurons after ischemic challenge.

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Intraventricular Infusion of Apolipoprotein E Ameliorates Acute Neuronal Damage after Global Cerebral Ischemia in Mice

Journal of Cerebral Blood Flow & Metabolism ◽

10.1097/00004647-200003000-00003 ◽

2000 ◽

Vol 20 (3) ◽

pp. 458-462 ◽

Cited By ~ 55

Author(s):

Karen Horsburgh ◽

James McCulloch ◽

Margaret Nilsen ◽

Eileen McCracken ◽

Charles Large ◽

...

Keyword(s):

Cerebral Ischemia ◽

Apolipoprotein E ◽

Marked Reduction ◽

Cell Layer ◽

Neuronal Damage ◽

Global Cerebral Ischemia ◽

Wild Type ◽

Anti Oxidant ◽

Intraventricular Infusion ◽

Deficient Mice

The ability of intraventricular infusion of apolipoprotein E (apoE) to reduce neuronal damage after global cerebral ischemia was investigated in apoE-deficient and wild-type mice. ApoE (5 μg/mL lipid-conjugated derived from human plasma; 1 μL/h, continuous infusion) significantly reduced neuronal damage in the caudate nucleus and CA2 pyramidal cell layer by approximately 50% in apoE-deficient mice after global ischemia compared to vehicle infusion. In wild-type mice infused with apoE, there was a trend for ischemic neuronal damage to be reduced. ApoE-infused mice had a marked reduction in 4-hydroxynonenal immunoreactivity, as a marker of lipid peroxidation. The results show that the presence of apoE at or after the time of injury can be neuroprotective, possibly via an anti-oxidant mechanism.

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A Model of Global Cerebral Ischemia in C57 BL/6 Mice

Journal of Cerebral Blood Flow & Metabolism ◽

10.1097/01.wcb.0000096063.84070.c1 ◽

2004 ◽

Vol 24 (2) ◽

pp. 151-158 ◽

Cited By ~ 69

Author(s):

Ichiro Yonekura ◽

Nobutaka Kawahara ◽

Hirofumi Nakatomi ◽

Kazuhide Furuya ◽

Takaaki Kirino

Keyword(s):

Cerebral Ischemia ◽

Genetic Background ◽

Neuronal Degeneration ◽

Neuronal Damage ◽

Neuronal Injury ◽

Genetically Engineered ◽

Global Cerebral Ischemia ◽

Vessel Occlusion ◽

Bilateral Carotid ◽

The Mean

A reproducible model of global cerebral ischemia in mice is essential for elucidating the molecular mechanism of ischemic neuronal injury. Such a model is particularly important in the mouse because many genetically engineered mutant animals are available. In C57BL/6 and SV129/EMS mice, we evaluated a three-vessel occlusion model. Occlusion of the basilar artery with a miniature clip was followed by bilateral carotid occlusion. The mean cortical cerebral blood flow was reduced to less than 10% of the preischemic value, and the mean anoxic depolarization was attained within 1 minute. In C57BL/6 mice, there was CA1 hippocampal neuronal degeneration 4 days after ischemia. Neuronal damage depended upon ischemic duration: the surviving neuronal count was 78.5 ± 8.5% after 8-minute ischemia and 8.4 ± 12.7% after 14-minute ischemia. In SV129/EMS mice, similar neuronal degeneration was not observed after 14-minute ischemia. The global ischemia model in C57BL/6 mice showed high reproducibility and consistent neuronal injury in the CA1 sector, indicating that comparison of ischemic outcome between wild-type and mutant mice could provide meaningful data using the C57BL/6 genetic background. Strain differences in this study highlight the need for consideration of genetic background when evaluating ischemia experiments in mice.

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