Postischemic brain injury is attenuated in mice lacking the β2-adrenergic receptor

Ru Quan Han, Yi Bing Ouyang, Lijun Xu, Rani Agrawal, Andrew J. Patterson, Rona G. Giffard

Research output: Contribution to journalArticle

52 Citations (Scopus)

Abstract

BACKGROUND:: Several β-adrenergic receptor (βAR) antagonists have been shown to have neuroprotective effects against cerebral ischemia. However, clenbuterol, a β2AR agonist, was shown to have neuroprotective activity by increasing nerve growth factor expression. We used β2AR knockout mice and a β2 selective antagonist to test the effect of loss of β2ARs on outcome from transient focal cerebral ischemia. METHODS:: Ischemia was induced by the intraluminal suture method, for 60 min of middle cerebral artery occlusion (MCAO) followed by 24 h reperfusion. Neurological score was determined at 24 h reperfusion and infarct size was determined by cresyl violet or 2,3,5-triphenyltetrazolium chloride staining. β2AR knockout mice and wild-type congenic FVB/N controls were studied, as well as 2 groups of wild type mice given either ICI 118,551 (0.2 mg/kg) or 0.9% saline intraperitoneally 30 min before MCAO (n = 10 per group). Changes in expression of heat shock protein (Hsp)72 after ischemia were examined by immunohistochemistry and western blots. RESULTS:: Compared with wild type littermates, infarct volume was decreased by 22.3% in β2AR knockout mice (39.7 ± 10.7 mm vs 51.0 ± 11.4 mm, n = 10/group, P = 0.034) after 60 min of MCAO followed by 24 h reperfusion. Pretreatment with a β2AR selective antagonist, ICI 118,551, also decreased infarct size significantly, by 25.1%, compared with the saline control (32.8 ± 11.9 mm vs 43.8 ± 10.3 mm, n = 10/group, P = 0.041). Neurological scores were also significantly improved in mice lacking the β2AR or pretreated with ICI 118,551. After cerebral ischemia, total levels of Hsp72 and the number of Hsp72 immunopositive cells were greater in mice lacking β2 AR. CONCLUSION:: Brain injury is reduced and neurological outcome improved after MCAO in mice lacking the β2AR, or in wild type mice pretreated with a selective β2AR antagonist. This is consistent with a shift away from prosurvival signaling to prodeath signaling in the presence of β2AR activation in cerebral ischemia. Protection is associated with higher levels of Hsp72, a known antideath protein. The effect of β2AR signaling in the setting of cerebral ischemia is complex and warrants further study.

Original languageEnglish (US)
Pages (from-to)280-287
Number of pages8
JournalAnesthesia and analgesia
Volume108
Issue number1
DOIs
StatePublished - Jan 2009

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Brain Injuries
Adrenergic Receptors
Middle Cerebral Artery Infarction
Brain Ischemia
Knockout Mice
Reperfusion
Ischemia
HSP72 Heat-Shock Proteins
Clenbuterol
Adrenergic Antagonists
Transient Ischemic Attack
Neuroprotective Agents
Nerve Growth Factor
Sutures
Western Blotting
Immunohistochemistry
Staining and Labeling
ICI 118551
Proteins

ASJC Scopus subject areas

  • Anesthesiology and Pain Medicine

Cite this

Han, R. Q., Ouyang, Y. B., Xu, L., Agrawal, R., Patterson, A. J., & Giffard, R. G. (2009). Postischemic brain injury is attenuated in mice lacking the β2-adrenergic receptor. Anesthesia and analgesia, 108(1), 280-287. https://doi.org/10.1213/ane.0b013e318187ba6b

Postischemic brain injury is attenuated in mice lacking the β2-adrenergic receptor. / Han, Ru Quan; Ouyang, Yi Bing; Xu, Lijun; Agrawal, Rani; Patterson, Andrew J.; Giffard, Rona G.

In: Anesthesia and analgesia, Vol. 108, No. 1, 01.2009, p. 280-287.

Research output: Contribution to journalArticle

Han, RQ, Ouyang, YB, Xu, L, Agrawal, R, Patterson, AJ & Giffard, RG 2009, 'Postischemic brain injury is attenuated in mice lacking the β2-adrenergic receptor', Anesthesia and analgesia, vol. 108, no. 1, pp. 280-287. https://doi.org/10.1213/ane.0b013e318187ba6b
Han, Ru Quan ; Ouyang, Yi Bing ; Xu, Lijun ; Agrawal, Rani ; Patterson, Andrew J. ; Giffard, Rona G. / Postischemic brain injury is attenuated in mice lacking the β2-adrenergic receptor. In: Anesthesia and analgesia. 2009 ; Vol. 108, No. 1. pp. 280-287.
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AU - Patterson, Andrew J.

AU - Giffard, Rona G.

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N2 - BACKGROUND:: Several β-adrenergic receptor (βAR) antagonists have been shown to have neuroprotective effects against cerebral ischemia. However, clenbuterol, a β2AR agonist, was shown to have neuroprotective activity by increasing nerve growth factor expression. We used β2AR knockout mice and a β2 selective antagonist to test the effect of loss of β2ARs on outcome from transient focal cerebral ischemia. METHODS:: Ischemia was induced by the intraluminal suture method, for 60 min of middle cerebral artery occlusion (MCAO) followed by 24 h reperfusion. Neurological score was determined at 24 h reperfusion and infarct size was determined by cresyl violet or 2,3,5-triphenyltetrazolium chloride staining. β2AR knockout mice and wild-type congenic FVB/N controls were studied, as well as 2 groups of wild type mice given either ICI 118,551 (0.2 mg/kg) or 0.9% saline intraperitoneally 30 min before MCAO (n = 10 per group). Changes in expression of heat shock protein (Hsp)72 after ischemia were examined by immunohistochemistry and western blots. RESULTS:: Compared with wild type littermates, infarct volume was decreased by 22.3% in β2AR knockout mice (39.7 ± 10.7 mm vs 51.0 ± 11.4 mm, n = 10/group, P = 0.034) after 60 min of MCAO followed by 24 h reperfusion. Pretreatment with a β2AR selective antagonist, ICI 118,551, also decreased infarct size significantly, by 25.1%, compared with the saline control (32.8 ± 11.9 mm vs 43.8 ± 10.3 mm, n = 10/group, P = 0.041). Neurological scores were also significantly improved in mice lacking the β2AR or pretreated with ICI 118,551. After cerebral ischemia, total levels of Hsp72 and the number of Hsp72 immunopositive cells were greater in mice lacking β2 AR. CONCLUSION:: Brain injury is reduced and neurological outcome improved after MCAO in mice lacking the β2AR, or in wild type mice pretreated with a selective β2AR antagonist. This is consistent with a shift away from prosurvival signaling to prodeath signaling in the presence of β2AR activation in cerebral ischemia. Protection is associated with higher levels of Hsp72, a known antideath protein. The effect of β2AR signaling in the setting of cerebral ischemia is complex and warrants further study.

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