Anesthesia-Induced Hypothermia Attenuates Early-Phase Blood-Brain Barrier Disruption but Not Infarct Volume following Cerebral Ischemia

PLoS One. 2017 Jan 24;12(1):e0170682. doi: 10.1371/journal.pone.0170682. eCollection 2017.

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.

MeSH terms

  • Anesthesia, Inhalation*
  • Anesthetics, Inhalation / pharmacology*
  • Animals
  • Arterial Occlusive Diseases / pathology
  • Arterial Occlusive Diseases / physiopathology
  • Arterial Occlusive Diseases / therapy
  • Blood-Brain Barrier* / drug effects
  • Blood-Brain Barrier* / physiology
  • Body Temperature / drug effects
  • Brain Ischemia / complications
  • Brain Ischemia / physiopathology
  • Brain Ischemia / therapy*
  • Carotid Artery, Common / pathology
  • Cerebral Infarction / etiology
  • Cerebral Infarction / pathology
  • Cerebral Infarction / prevention & control*
  • Disease Models, Animal
  • Hypothermia, Induced*
  • Infarction, Middle Cerebral Artery / pathology
  • Infarction, Middle Cerebral Artery / physiopathology
  • Infarction, Middle Cerebral Artery / therapy
  • Isoflurane / pharmacology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Random Allocation
  • Reperfusion Injury / prevention & control

Substances

  • Anesthetics, Inhalation
  • Isoflurane

Grant support

This study was supported by research grants from the China Medical University Hospital (DMR-102-062), the Taiwan Ministry of Science and Technology (MOST105-2320-B-039-007), and the National Health Research Institutes (NHRI-EX105-10412NC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.