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.

Repurposed molecules for antiepileptogenesis: Missing an opportunity to prevent epilepsy?

“…Short-duration treatments with isoflurane during or shortly after SE in the kainate or paraoxon models of epileptogenesis attenuated BBB breakdown, glial activation, and neuroinflammation, reduced neuronal damage, abolished epileptiform activity, and reduced the incidence of late epilepsy. 96 The vasoprotective effect of isoflurane has also been shown in rodent models of stroke [97][98][99] and in subarachnoid hemorrhage. 100 Thus, preclinical data suggest isoflurane as a promising antiepileptogenic, vasoprotective, and neuroprotective agent in specific patient populations, including SE and severe traumatic or ischemic brain injuries that require general anesthesia.…”

New Concept in Stroke Diagnosis

“…To establish a model of cerebral ischemia characterized by both a robust BBB disruption and a sizable infarct volume, mice should be subjected to a distal MCAo (dMCAo). The greatest infarct volume can be produced by 120 min of ischemic time induced by dMCAo + ipsilateral [51]. Compared to other protocols, this method also will produce the greatest unilateral increase in BBB permeability.…”

Developing a standardized system of exposure and intervention endpoints for isoflurane in preclinical stroke models

“…The BBB normally protects against cytokine induced inflammation by preventing passage of inflammatory cells or plasma proteins into the brain 38. In ischemic stroke, deterioration of the BBB occurs with the attenuation of tight-junction proteins 3839. With isoflurane treatment, a reduction of the early BBB disruption was reported in cerebral ischemia 39.…”

“…In ischemic stroke, deterioration of the BBB occurs with the attenuation of tight-junction proteins 3839. With isoflurane treatment, a reduction of the early BBB disruption was reported in cerebral ischemia 39. Therefore, the maintained BBB after isoflurane exposure correlates with increased neuroprotection after cerebral ischemia 39.…”

“…With isoflurane treatment, a reduction of the early BBB disruption was reported in cerebral ischemia 39. Therefore, the maintained BBB after isoflurane exposure correlates with increased neuroprotection after cerebral ischemia 39. BBB is composed of vascular endothelial cells that are degraded by matrix metalloproteinase-9 14.…”