Isoflurane delays the development of early brain injury after subarachnoid hemorrhage through sphingosine-related pathway activation in mice*

Abstract

Objective Isoflurane, a volatile anesthetic agent, has been recognized for its potential neuroprotective properties and has antiapoptotic effects. We examined whether isoflurane posttreatment is protective against early brain injury (EBI) after subarachnoid hemorrhage (SAH) and determined whether this effect needs sphingosine-related pathway activation. Design Controlled in vivo laboratory study. Setting Animal research laboratory. Subjects 179 eight-week-old male CD-1 mice weighing 30 to 38 g. Interventions SAH was induced in mice by endovascular perforation. Animals were randomly assigned to sham-operated, SAH-vehicle, and SAH+2% isoflurane. Neurobehavioral function and brain edema were evaluated at 24 and 72 hours. The expression of sphingosine kinase (SphK), phosphorylated Akt (p-Akt) and cleaved caspase-3 was determined by Western blotting and immunofluorescence. Neuronal cell death was examined by terminal deoxynucleotidyl transferase-mediated uridine 5′-triphosphate-biotin nick end-labeling staining. Effects of a SphK inhibitor DMS, or a sphingosine 1 phosphate receptor inhibitor VPC23019 on isoflurane’s protective action against post-SAH EBI were also examined. Measurements and Main Results Isoflurane significantly improved neurobehavioral function and brain edema at 24 hours but not 72 hours after SAH. At 24 hours, isoflurane attenuated neuronal cell death in the cortex, associated with an increase in SphK1 and p-Akt, and a decrease in cleaved caspase-3. The beneficial effects of isoflurane were abolished by DMS and VPC23019. Conclusions Isoflurane posttreatment delays the development of post-SAH EBI through antiapoptotic mechanisms including sphingosine-related pathway activation, implying its use for anesthesia during acute aneurysm surgery or intervention.

Cerebroprotection by salvianolic acid B after experimental subarachnoid hemorrhage occurs via Nrf2- and SIRT1-dependent pathways

“…First, we used two different anesthetic drugs—chloral hydrate and isoflurane—to anesthetize the animals. Previous studies reported that isoflurane might reduce brain inflammation and delay the development of brain injury after SAH [65,66]. However, isoflurane is a very common and safe anesthetic drug and is widely used for mouse anesthesia.…”

Controversies and evolving new mechanisms in subarachnoid hemorrhage

“…The endovascular puncture SAH model has also been produced in the mouse, though it is technically more challenging (Kamii et al, 1999). Recently, the therapeutic effect of potential drug candidates against EBI has been examined on the mouse endovascular puncture model (Altay et al, 2012a). The advantage of a mouse SAH model would be the option to use transgenic mice, which is becoming the preferred research tool for gene-specific silencing in vivo .…”

Isoflurane post-conditioning protects primary cultures of cortical neurons against oxygen and glucose deprivation injury via upregulation of Slit2/Robo1

“…In a rat model of hepatic ischemic reperfusion injury, isoflurane also showed protective effect by reducing the protein expression of caspase 3 (Ko et al, 2013). In a mouse model of subarachnoid hemorrhage, isoflurane (2%) post-conditioning reduced cleaved caspase-3 expression at 24 hours (Altay et al, 2012). The effect of isoflurane on the expression of the active fragment of caspase 3 in our OGD/R model suggests that isoflurane can attenuate apoptosis in primary cultured rat cortical neurons.…”