Combined use of spatial restraint stress and middle cerebral artery occlusion is a novel model of post-stroke depression in mice

Introduction: GPR124/TEM5 is an orphan G-protein coupled receptor (GPCR) with a large extracellular domain. We and others have previously demonstrated that GPR124 exerts CNS-specific angiogenesis regulation with knockout mice exhibiting embryonic lethality from hemorrhagic glomeruloid vascular malformations in forebrain and neural tube (c.f. Kuhnert et al., Science , Nov 12;330(6006):985-9 . (2010)). Hypothesis: GPR124 regulates adult angiogenesis and blood-brain barrier (BBB) integrity during homeostasis or after stroke. Methods: To bypass GPR124 embryonic lethality, we generated GPR124 conditional knockout (cko) mice allowing temporally-regulated deletion. Tamoxifen treatment of GPR124 flox/- ; ROSA-CreER mice versus GPR124 flox/+; ROSA-CreER littermate controls allowed GPR124 cko versus heterozygosity, respectively, in adult mice. GPR124 deletion was followed by analyses of microvascular structure and patterning and blood-brain barrier (BBB) integrity). GPR124 cko mice versus controls were also subjected to 60 minute middle cerebral artery occlusion (MCAO) and effects on stroke volume, survival and microvascular structure assessed. Results: GPR124 deletion in neonatal or adult mice was well-tolerated without impairment of postnatal vascular patterning, BBB maturation or BBB integrity. However, GPR124 cko mice subjected to the middle cerebral artery occlusion (MCAO) stroke model exhibited impaired survival and a profound microvascular hemorrhagic transformation that was confined to the infarct region relative to wild-type controls. GPR124 cko stroke vasculature also exhibited numerous cellular and architectural defects relative to controls that will be discussed. Conclusions: GPR124 deletion is well tolerated in adult mice but results in marked hemorrhagic transformation in the MCAO stroke model. GPR124 represents a novel receptor whose function is essential for cerebrovascular integrity in the post-stroke setting, with attendant therapeutic implications.

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Transient middle cerebral artery occlusion induces microglial priming in the lumbar spinal cord: a novel model of neuroinflammation

Journal of Neuroinflammation ◽

10.1186/1742-2094-5-29 ◽

2008 ◽

Vol 5 (1) ◽

pp. 29 ◽

Cited By ~ 15

Author(s):

Katie Moisse ◽

Ian Welch ◽

Tracy Hill ◽

Kathryn Volkening ◽

Michael J Strong

Keyword(s):

Spinal Cord ◽

Middle Cerebral Artery ◽

Middle Cerebral Artery Occlusion ◽

Cerebral Artery ◽

Artery Occlusion ◽

Lumbar Spinal Cord ◽

Lumbar Spinal ◽

Cerebral Artery Occlusion ◽

Novel Model

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Inadequate food and water intake determine mortality following stroke in mice

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x16660986 ◽

2016 ◽

Vol 37 (6) ◽

pp. 2084-2097 ◽

Cited By ~ 7

Author(s):

Athanasios Lourbopoulos ◽

Uta Mamrak ◽

Stefan Roth ◽

Matilde Balbi ◽

Joshua Shrouder ◽

...

Keyword(s):

Middle Cerebral Artery ◽

Middle Cerebral Artery Occlusion ◽

Water Intake ◽

Cerebral Artery ◽

Stroke Care ◽

Artery Occlusion ◽

Experimental Stroke ◽

Post Stroke ◽

Food And Water Intake ◽

Cerebral Artery Occlusion

Experimental stroke models producing clinically relevant functional deficits are often associated with high mortality. Because the mechanisms that underlie post-stroke mortality are largely unknown, results obtained using these models are often difficult to interpret, thereby limiting their translational potential. Given that specific forms of post-stroke care reduce mortality in patients, we hypothesized that inadequate food and water intake may underlie mortality following experimental stroke. C57BL/6 mice were subjected to 1 h of intraluminal filament middle cerebral artery occlusion. Nutritional support beginning on the second day after filament middle cerebral artery occlusion reduced the 14-day mortality rate from 59% to 15%. The surviving mice in the post-stroke support group had the same infarct size as non-surviving control mice, suggesting that post-stroke care was not neuroprotective and that inadequate food and/or water intake are the main reasons for filament middle cerebral artery occlusion–induced mortality. This notion was supported by the presence of significant hypoglycemia, ketonemia, and dehydration in control mice. Taken together, these data suggest that post–filament middle cerebral artery occlusion mortality in mice is not primarily caused by ischemic brain damage, but secondarily by inadequate food and/or water intake. Thus, providing nutritional support following filament middle cerebral artery occlusion greatly minimizes mortality bias and allows the study of long-term morphological and functional sequelae of stroke in mice.

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