Sevoflurane postconditioning against cerebral ischemic neuronal injury is abolished in diet-induced obesity: Role of brain mitochondrial KATP channels

Abstract

Abstract. Obesity is associated with increased infarct volumes and adverse outcomes following ischemic stroke. However, its effect on anesthetic postconditioning-induced neuroprotection has not been investigated. The present study examined the effect of sevoflurane postconditioning on focal ischemic brain injury in diet-induced obesity. Sprague-Dawley rats were fed a high-fat diet (HF; 45% kcal as fat) for 12 weeks to develop obesity syndrome. Rats fed a low-fat diet (LF; 10% kcal as fat) served as controls. The HF or LF-fed rats were subjected to focal cerebral ischemia for 60 min, followed by 24 h of reperfusion. Postconditioning was performed by exposure to sevoflurane for 15 min immediately at the onset of reperfusion. The involvement of the mitochondrial K ATP (mitoK ATP ) channel was analyzed by the administration of a selective inhibitor of 5-hydroxydecanoate (5-HD) prior to sevoflurane postconditioning or by administration of diazoxide (DZX), a mitoK ATP channel opener, instead of sevoflurane. The cerebral infarct volume, neurological score and motor coordination were evaluated 24 h after reperfusion. The HF-fed rats had larger infarct volumes, and lower neurological scores than the LF-fed rats and also failed to respond to neuroprotection by sevoflurane or DZX. By contrast, sevoflurane and DZX reduced the infarct volumes and improved the neurological scores and motor coordination in the LF-fed rats. Pretreatment with 5-HD inhibited sevoflurane-induced neuroprotection in the LF-fed rats, whereas it had no effect in the HF-fed rats. Molecular studies demonstrated that the expression of Kir6.2, a significant mitoK ATP channel component, was reduced in the brains of the HF-fed rats compared with the LF-fed rats. The results of this study indicate that diet-induced obesity eliminates the ability of anesthetic sevoflurane postconditioning to protect the brain against cerebral ischemic neuronal injury, most likely due to an impaired brain mitoK ATP channel.

Mitochondrial dysfunction induces NLRP3 inflammasome activation during cerebral ischemia/reperfusion injury

“…Rats were randomly divided into six groups: the sham-operation group (sham), the sham + diazoxide group, the 6 h after reperfusion group (I/R 6 h), the I/R 6 h + diazoxide group, the 24 h after reperfusion group (I/R 24 h), and the I/R 24 h + diazoxide group. The diazoxide was treated at 10 mg/kg intraperitoneally after reperfusion immediately as the previous studies [ 11 , 12 ]. The diazoxide was dissolved in sterile 0.1 M NaOH solution, and diluted with saline to the concentration of 0.02 N NaOH solution before being used.…”

Obesity and stroke: Can we translate from rodents to patients?

“…57 Worse stroke outcome has also been confirmed in diet-induced models in which animals become obese due to being fed a high-fat diet. These detrimental effects of a high-fat diet have been observed in rat, 58,61,65,73,82,93 mouse 60,64,66,88 and gerbil 62,63,94 models of diet-induced obesity. A variety of models of cerebral ischaemia have also been used in these studies, including transient and permanent occlusion of the middle cerebral artery, common carotid artery ligation and exposure to a low-oxygen environment.…”

Sevoflurane post-conditioning attenuates traumatic brain injury-induced neuronal apoptosis by promoting autophagy via the PI3K/AKT signaling pathway

“…These factors make it a viable anesthetic for neurosurgery. 12 – 14 Previous studies have shown that sevoflurane post-conditioning improves neurological function following ischemia reperfusion, as well as protects neurons by inhibiting the production of oxygen free radicals, which prevents intracellular calcium and excitatory amino acid overload, while stabilizing neuron membranes. 13 Sevoflurane post-conditioning also increases nerve function by suppressing inflammation via protein kinase B (AKT) regulation.…”