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Updated: May 19, 2026
Induction of Acute Ischemic Stroke in Mice Using the Distal Middle Artery Occlusion Technique
Published on: December 15, 2023
Mice lacking the β2 adrenergic receptor have a unique genetic profile before and after focal brain ischaemia
Robin E White1, Curtis Palm2, Lijun Xu1
1*Department of Anesthesia, Stanford University, 300 Pasteur Drive, Grant Building S282, Stanford, CA 94305, U.S.A.
Abstract:
The role of the β2AR (β2 adrenergic receptor) after stroke is unclear as pharmacological manipulations of the β2AR have produced contradictory results. We previously showed that mice deficient in the β2AR (β2KO) had smaller infarcts compared with WT (wild-type) mice (FVB) after MCAO (middle cerebral artery occlusion), a model of stroke. To elucidate mechanisms of this neuroprotection, we evaluated changes in gene expression using microarrays comparing differences before and after MCAO, and differences between genotypes. Genes associated with inflammation and cell deaths were enriched after MCAO in both genotypes, and we identified several genes not previously shown to increase following ischaemia (Ccl9, Gem and Prg4). In addition to networks that were similar between genotypes, one network with a central core of GPCR (G-protein-coupled receptor) and including biological functions such as carbohydrate metabolism, small molecule biochemistry and inflammation was identified in FVB mice but not in β2KO mice. Analysis of differences between genotypes revealed 11 genes differentially expressed by genotype both before and after ischaemia. We demonstrate greater Glo1 protein levels and lower Pmaip/Noxa mRNA levels in β2KO mice in both sham and MCAO conditions. As both genes are implicated in NF-κB (nuclear factor κB) signalling, we measured p65 activity and TNFα (tumour necrosis factor α) levels 24 h after MCAO. MCAO-induced p65 activation and post-ischaemic TNFα production were both greater in FVB compared with β2KO mice. These results suggest that loss of β2AR signalling results in a neuroprotective phenotype in part due to decreased NF-κB signalling, decreased inflammation and decreased apoptotic signalling in the brain.
Insights
Mice lacking the beta-2 adrenergic receptor (β2AR) show reduced stroke damage. This neuroprotection is linked to decreased inflammation and cell death signaling pathways, suggesting a protective role for β2AR deficiency in stroke.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- The role of the beta-2 adrenergic receptor (β2AR) in stroke outcomes remains unclear due to conflicting research findings.
- Previous studies indicated that β2AR-deficient mice exhibit smaller infarct volumes after middle cerebral artery occlusion (MCAO), a stroke model.
Purpose of the Study:
- To elucidate the underlying mechanisms of neuroprotection observed in β2AR-deficient mice following stroke.
- To investigate the impact of β2AR deficiency on gene expression, inflammatory responses, and cell death signaling pathways post-ischemia.
Main Methods:
- Utilized microarray analysis to compare gene expression profiles between β2AR-deficient (β2KO) and wild-type (WT) mice before and after MCAO.
- Analyzed protein levels of Glo1 and mRNA levels of Pmaip/Noxa, key regulators in NF-κB signaling.
- Measured p65 activity and TNFα levels to assess NF-κB pathway activation and inflammation post-stroke.
Main Results:
- Gene expression analysis revealed distinct networks, including GPCR signaling and inflammation, in WT mice but not in β2KO mice post-MCAO.
- β2KO mice displayed higher Glo1 protein levels and lower Pmaip/Noxa mRNA levels compared to WT mice under both sham and MCAO conditions.
- MCAO induced greater p65 activation and TNFα production in WT mice than in β2KO mice, indicating reduced NF-κB signaling and inflammation in β2AR deficiency.
Conclusions:
- Loss of β2AR signaling confers a neuroprotective phenotype in the context of stroke.
- This neuroprotection is associated with diminished NF-κB signaling, reduced inflammation, and decreased apoptotic signaling in the brain.
- Targeting β2AR pathways may offer a therapeutic strategy for stroke treatment.
