Abstract
Purpose: Isoflurane could induce cognitive impairment and activate caspase-3. However, the mechanism of action is unclear and target interventions are unavailable. The present study examined the potential protective function of hydrogen sulfide (H2S) against isoflurane-induced cognitive impairment.Methods: Effects of NaHS (5 mg/kg) on cognitive impairment induced by isoflurane (1.4% for 2 h) were assessed using a fear-conditioning test in a group of 8-month old mice. H4 human neuroglioma cells, which were transfected with upregulated human amyloid precursor protein were treated for 3 or 6 h with 2% isoflurane, in the presence of 100-μM NaHS in the mice. A group of mice treated with normal saline in place of the NaHS in each case served as control. Western blotting, fluorescence assay, and a mitochondrial swelling assay were employed to observe the results of caspase-3 activation, mitochondrial dysfunction, and ROS and ATP levels.Results: NaHS significantly mitigated isoflurane-induced cognitive impairment in mice. In cultured cells, NaHS reduced caspase-3 activation, ROS, mitochondria membrane reduction, mitochondrial permeability transition pore opening, and cellular ATP level. NaHS could ameliorate cognitiveimpariment induced by isoflurane through inhibiting caspase-3 activation, oxidative stress, and mitochondrial dysfunction.Conclusion: These results indicate that hydrogen sulfide (H2S) has potential protective function against isoflurane-induced cognitive impairment. Further investigation of NaHS as an intervention to attenuate anesthesia-associated neurotoxicity is vital.
 Keywords: Hydrogen sulfide, isoflurane-cognition，fear conditioning，neurotoxicity
Highlights
Alzheimer’s disease (AD) is a prevailing reason for dementia in adults [1]
Another study indicated that people in the middle age without cognitive impairment are more likely to have rapid cognitive decline after surgery and anesthesia [5]
NaHS ameliorates cognitive impairment induced by isoflurane
Summary
Alzheimer’s disease (AD) is a prevailing reason for dementia in adults [1]. Symptoms typically start at age of 60 years and might involve memory loss, failure in performing daily activities, and personality change. The evidence so far shows that exposure to general anesthetics could interact with AD-associated pathological mechanisms, and promote the progression of AD [2]. A case-control study in China established that anesthesia during surgery is associated with the risk of dementia [4]. Another study indicated that people in the middle age without cognitive impairment are more likely to have rapid cognitive decline after surgery and anesthesia [5]. Several other studies failed to establish this association in anesthesia and dementia [6,7,8]. It was previously reported that isoflurane might promote caspase-3 activation [9], increase amyloid beta-protein (Aβ) level in the brain [10,11,12], and impair learning and memory [13]. The mechanism on how isoflurane enhances caspase activation is not completely understood, but may result from increased levels of ROS, mitochondrial dysfunction and decreased ATP level [14,15]
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