title: Isoflurane induced cognitive impairment in aged rats through hippocampal calcineurin/NFAT signaling.
abstract: Calcineurin (CaN) over-activation constrains synaptic plasticity and memory formation. Upon CaN activation, NFAT imports into the nucleus and guides its downstream genes, which also affect neuronal and synaptic function. Aberrant CaN/NFAT signaling involves in neurotoxicity and cognitive impairment in neurological disorders such as Alzheimer's disease, but its role in postoperative cognitive dysfunction (POCD) remains uninvestigated. Inhaled anesthetic isoflurane facilitates the development of POCD, and the present study investigated the role of CaN/NFAT signaling in isoflurane induced cognitive impairment of aged rats, and the therapeutic effects of CaN inhibitor cyclosporine A (CsA). The results indicated that hippocampal CaN activity increased and peaked at 6 h after isoflurane exposure, and NFAT, especially NFATc4, imported into the nucleus following CaN activation. Furthermore, phamacological inhibition of CaN by CsA markedly attenuated isoflurane induced aberrant CaN/NFATc4 signaling in the hippocampus, and rescued relevant spatial learning and memory impairment of aged rats. Overall, the study suggests hippocampal CaN/NFAT signaling as the upstream mechanism of isoflurane induced cognitive impairment, and provides potential therapeutic target and possible treatment methods for POCD.
authors.affiliation: Department of Anesthesiology, Peking University Third Hospital, Beijing 100191, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Ni
authors.affiliation: Department of Anesthesiology, Peking University Third Hospital, Beijing 100191, China.
authors.forename: Zhengqian
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Anesthesiology, Peking University Third Hospital, Beijing 100191, China.
authors.forename: Min
authors.initials: M
authors.lastname: Qian
authors.affiliation: Department of Anesthesiology, Peking University Third Hospital, Beijing 100191, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Anesthesiology, Peking University Third Hospital, Beijing 100191, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Anesthesiology, Peking University Third Hospital, Beijing 100191, China. Electronic address: puthmzk@163.com.
authors.forename: Xiangyang
authors.initials: X
authors.lastname: Guo
mesh_terms: D000375:Aging / Q000523:psychology*; D000818:Animals; D019703:Calcineurin / Q000378:metabolism*; D003072:Cognition Disorders / Q000139:chemically induced* / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D007530:Isoflurane / Q000633:toxicity; D008297:Male; D050778:NFATC Transcription Factors / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction
chemical_list: D050778:NFATC Transcription Factors; D007530:Isoflurane; D019703:Calcineurin
keywords: Calcineurin; Cognitive impairment; Cyclosporine A; Isoflurane; Nuclear factor of activated T-cells