Simvastatin Attenuates Neurogenetic Damage and Improves Neurocongnitive Deficits Induced by Isoflurane in Neonatal Rats

Abstract

Background/Aims: Isoflurane inhibited neurogenesis and induced subsequent neurocognitive deficits in developing brain. Simvastatin exerts neuroprotection in a wide range of brain injury models. In the present study, we investigated whether simvastatin could attenuate neurogenetic inhibition and cognitive deficits induced by isoflurane exposure in neonatal rats. Methods: Sprague-Dawley rats at postnatal day (PND) 7 and neural stem cells (NSCs) were treated with either gas mixture, isoflurane, or simvastatin 60 min prior to isoflurane exposure, respectively. The rats were decapitated at PND 8 and PND 10 for detection of neurogenesis in the subventricular zone (SVZ) and subgranular zone (SGZ) of the hippocampus by immunostaining. NSC proliferation, viability and apoptosis were assessed by immunohistochemistry, CCK-8 and TUNEL, respectively. The protein expressions of caspase-3, p-Akt and p-GSK-3β both in vivo and vitro were assessed by western blotting. Cognitive functions were assessed by Morris Water Maze test and context fear conditioning test at the adult. Results: Isoflurane exposure inhibited neurogenesis in the SVZ and SGZ, decreased NSC proliferation and viability, promoted NSC apoptosis and led to late cognitive deficits. Furthermore, isoflurane increased caspase-3 expression and decreased protein expressions of p-Akt and p-GSK-3β both in vivo and in vitro. Pretreatment with simvastatin attenuated isoflurane-elicited changes in NSCs and cognitive function. Co-treatment with LY294002 reversed the effect of simvastatin on NSCs in vitro. Conclusion: We for the first time showed that simvastatin, by upregulating Akt/GSK-3β signaling pathway, alleviated isoflurane-induced neurogenetic damage and neurocognitive deficits in developing rat brain.

L-Theanine Attenuates Isoflurane-Induced Injury in Neural Stem Cells and Cognitive Impairment in Neonatal Mice

“…However, there is still lack of data on isoflurane-induced NSC injury. In the present study, we showed that isoflurane exposure (3.4%, 6 h) inhibited neurogenesis by decreasing NSC proliferation and viability as well as increasing NSC apoptosis, which is consistent with the previous studies 28,29) . Additional, we also demonstrated that 3 consecutive day's isoflurane exposure on neonatal mice induced late cognitive deficits in adult, which supported the previous studies [11][12][13][14][15] .…”

“…As a main anabolism pathway in cellular signal transduction, Akt/GSK-3β signaling pathway plays an importantly mediated role in cell survival, proliferation, apoptosis and metabolism 36) . Akt/GSK-3β pathway is involved in isoflurane-induced neurogenesis inhibition and cognitive impairment 28) . There are also similar studies on other anesthetics such sevoflurane and ketamine 27,37,38) .…”

“…Glycogen synthase kinase 3β (GSK-3β), a serine/threonine kinase, is highly expressed in the developing brain and can be phosphorylated at serine 9 by Akt (protein kinase B). It has been reported that activation of the Akt/GSK-3β signaling pathway is involved in the protection of several brain injury models such as traumatic brain injury, Alzheimer's disease, ischemia/reperfusion-induced myocardial apoptosis, and anesthetic-induced neurotoxcity [25][26][27][28] . As it remains unclear whether and how L-theanine attenuates isoflurane-induced neurotoxicity in NSCs, in the present study we investigated the neuroprotective effects of L-theanine on isoflurane-caused injury in NSCs in vitro and cognitive impairment in young mice, and proposed that Akt/GSK-3β might be involved in this process.…”

Emulsified isoflurane alleviates rat islet beta cell RIN-m5F apoptosis induced by glucose via inhibiting endoplasmic reticulum stress

“…Isoflurane is an isomeride of enflurane, which was commonly used in inhalation anesthesia. But, isoflurane can induce neurogenetic damage and neurocognitive disorder, even accelerate the process of Alzheimer's disease [17][18][19].With a view to the adverse effects of inhalational anesthetic compare to intravenous anesthetic. EIso was manufactured by West China Hospital of Sichuan University, which liquid isoflurane was mixed with intralipid at the final concentration of 8% (v/v).…”

Genistein attenuates cognitive deficits and neuroapoptosis in hippocampus induced by ketamine exposure in neonatal rats

“…At P57, rats were subjected to fear conditioning test as described previously (Wang et al., 2018). Briefly, the test was composed of two days.…”