title: Anesthesia-Induced Hypothermia Attenuates Early-Phase Blood-Brain Barrier Disruption but Not Infarct Volume following Cerebral Ischemia.
abstract: Blood-brain barrier (BBB) disruption is thought to facilitate the development of cerebral infarction after a stroke. In a typical stroke model (such as the one used in this study), the early phase of BBB disruption reaches a peak 6 h post-ischemia and largely recovers after 8-24 h, whereas the late phase of BBB disruption begins 48-58 h post-ischemia. Because cerebral infarct develops within 24 h after the onset of ischemia, and several therapeutic agents have been shown to reduce the infarct volume when administered at 6 h post-ischemia, we hypothesized that attenuating BBB disruption at its peak (6 h post-ischemia) can also decrease the infarct volume measured at 24 h. We used a mouse stroke model obtained by combining 120 min of distal middle cerebral arterial occlusion (dMCAo) with ipsilateral common carotid arterial occlusion (CCAo). This model produced the most reliable BBB disruption and cerebral infarction compared to other models characterized by a shorter duration of ischemia or obtained with dMCAO or CCAo alone. The BBB permeability was measured by quantifying Evans blue dye (EBD) extravasation, as this tracer has been shown to be more sensitive for the detection of early-phase BBB disruption compared to other intravascular tracers that are more appropriate for detecting late-phase BBB disruption. We showed that a 1 h-long treatment with isoflurane-anesthesia induced marked hypothermia and attenuated the peak of BBB disruption when administered 6 h after the onset of dMCAo/CCAo-induced ischemia. We also demonstrated that the inhibitory effect of isoflurane was hypothermia-dependent because the same treatment had no effect on ischemic BBB disruption when the mouse body temperature was maintained at 37°C. Importantly, inhibiting the peak of BBB disruption by hypothermia had no effect on the volume of brain infarct 24 h post-ischemia. In conclusion, inhibiting the peak of BBB disruption is not an effective neuroprotective strategy, especially in comparison to the inhibitors of the neuronal death signaling cascade; these, in fact, can attenuate the infarct volume measured at 24 h post-ischemia when administered at 6 h in our same stroke model.
authors.affiliation: Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan.|Department of Anesthesiology, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Yu-Cheng
authors.initials: YC
authors.lastname: Liu
authors.affiliation: Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan.
authors.forename: Yu-Da
authors.initials: YD
authors.lastname: Lee
authors.affiliation: Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan.
authors.forename: Hwai-Lee
authors.initials: HL
authors.lastname: Wang
authors.affiliation: Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan.|Department of Anesthesiology, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Kate Hsiurong
authors.initials: KH
authors.lastname: Liao
authors.affiliation: Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan.|Department of Anesthesiology, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Kuen-Bao
authors.initials: KB
authors.lastname: Chen
authors.affiliation: Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan.|Department of Anesthesiology, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Kin-Shing
authors.initials: KS
authors.lastname: Poon
authors.affiliation: Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan.
authors.forename: Yu-Ling
authors.initials: YL
authors.lastname: Pan
authors.affiliation: Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan.|Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan.|Translational Medicine Research Center, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Ted Weita
authors.identifier: http://orcid.org/0000-0002-6229-4134
authors.initials: TW
authors.lastname: Lai
mesh_terms: D000769:Anesthesia, Inhalation; D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D001157:Arterial Occlusive Diseases / Q000473:pathology / Q000503:physiopathology / Q000628:therapy; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000502:physiology; D001831:Body Temperature / Q000187:drug effects; D002545:Brain Ischemia / Q000150:complications / Q000503:physiopathology / Q000628:therapy*; D017536:Carotid Artery, Common / Q000473:pathology; D002544:Cerebral Infarction / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D007036:Hypothermia, Induced; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology / Q000503:physiopathology / Q000628:therapy; D007530:Isoflurane / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011897:Random Allocation; D015427:Reperfusion Injury / Q000517:prevention & control
chemical_list: D018685:Anesthetics, Inhalation; D007530:Isoflurane