Isoflurane/nitrous oxide anesthesia induces increases in NMDA receptor subunit NR2B protein expression in the aged rat brain

Abstract

Postoperative cognitive dysfunction, POCD, afflicts a large number of elderly surgical patients following surgery with general anesthesia. Mechanisms of POCD remain unclear. N-methyl-D-aspartate (NMDA) receptors, critical in learning and memory, that display protein expression changes with age are modulated by inhalation anesthetics. The aim of this study was to identify protein expression changes in NMDA receptor subunits and downstream signaling pathways in aged rats that demonstrated anesthesia-induced spatial learning impairments. Three-month-old and 18-month-old male Fischer 344 rats were randomly assigned to receive 1.8% isoflurane/70 % nitrous oxide (N2O) anesthesia for 4h or no anesthesia. Spatial learning was assessed at 2 weeks and 3 months post-anesthesia in Morris water maze. Hippocampal and cortical protein lysates of 18-month-old rats were immunoblotted for activated caspase 3, NMDA receptor subunits, and extracellular-signal regulated kinase (ERK) 1/2. In a separate experiment, Ro 25-6981 (0.5mg/kg dose) was administered by I.P. injection before anesthesia to 18-month-old rats. Immunoblotting of NR2B was performed on hippocampal protein lysates. At 3 months post-anesthesia, rats treated with anesthesia at 18-months-old demonstrated spatial learning impairment corresponding to acute and long-term increases in NR2B protein expression and a reduction in phospho-ERK1/2 in the hippocampus and cortex. Ro 25-6981 pretreatment attenuated the increase in acute NR2B protein expression. Our findings suggest a role for disruption of NMDA receptor mediated signaling pathways in the hippocampus and cortex of rats treated with isoflurane/ N2O anesthesia at 18-months-old, leading to spatial learning deficits in these animals. A potential therapeutic intervention for anesthesia associated cognitive deficits is discussed.

Identification of a Novel Rat NR2B Subunit Gene Promoter Region Variant and Its Association with Microwave-Induced Neuron Impairment

“…The activity of these receptors is important in long-term neuronal potentiation, a cellular process thought to underlie memory formation [57,58]. Overactivity of NMDA receptors is toxic and results in neuronal death brought about by excessive intracellular calcium accumulation and a subsequent cascade of events, which may involve activation of intracellular hydrolases or an apoptotic genetic program [59,60]. Therefore, the more effect of T allele in the binding abilities with the transcript factor, the transcriptional activity, NR2B mRNA, and protein expressions might aggravate the injury of PC12 cells induced by microwave radiation.…”

Endoplasmic reticulum stress pathway mediates isoflurane-induced neuroapoptosis and cognitive impairments in aged rats

“…Inhalation anesthetics such as isoflurane have been widely used in recent years in clinical and research practices. There is no clear clinical evidence to indicate the link between anesthesia and cognitive deficits, however, a growing body of preclinical evidence supports the view that exposure to general anesthetics may contribute to POCD [6][7][8]. The phenomenon is receiving increasing attention.…”

Fixing Hearts and Protecting Minds

“…49 Many of these studies have been conducted in young animals, but anesthesiainduced alteration to neural pathways has also been associated with memory impairment in aged rats. 50 Other features have been described. For example, hypoxic challenge would normally be moderated by the capacity of the brain to autoregulate its own blood supply and also through astrocyte-derived upregulation of hypoxia-protective factors (eg, via hypoxiainducible factor pathway).…”