Long-term potentiation (LTP), a sustained enhancement of synaptic efficacy that is produced by a brief (less than 1 s) tetanic stimulation of excitatory afferent fibres, was first reported in anaesthetized  and behaving animals  in 1973. LTP is assumed to underlie plastic changes associated with learning and memory and to be a cellular mechanism of learning and memory [3,4].
Stress is a condition that seriously perturbs the physiological/psychological homeostasis of an organism. The stress response is a complex biochemical cascade involving the release of diverse chemicals that can modulate hippocampal LTP and affect various aspects of cognitive processes such as learning and memory, brain structures and physiological processes by altering brain cell properties . The hippocampus is crucially involved in both memory and the neuroendocrine regulation of stress hormones. Extensive rodent and human research has shown that the hippocampus is not only crucially involved in memory formation, but is also highly sensitive to stress . Acute kidney injury has been shown to increase levels of the proinflammatory chemokines in the cerebral cortex and hippocampus that lead to functional changes in the brain . Cytokine-mediated inflammation within the central nervous system plays an important role in the development of cognitive dysfunction . Myocardial ischaemia–reperfusion injury is a key pathophysiological procedure during myocardial revascularization therapy as well as other cardiac surgeries. Neurocognitive decline in the early postoperative period after cardiac surgery, such as delirium and impairment of memory, concentration, language comprehension and social integration, is a common phenomenon with an incidence varying from 30 to 60% [9,10]. Although multiple factors have been considered to contribute to this complication, the mechanism is still not very clear. Like acute kidney injury, myocardial ischaemia–reperfusion injury may also induce inflammatory responses in the brain and change the neurological function. However, to our knowledge, there is no direct evidence that indicates a link between myocardial ischaemia–reperfusion injury and cognitive impairment.
Sevoflurane has long been known to provide powerful protection against myocardial ischaemia–reperfusion injury through a pathway that shares some components with those required for ischaemic preconditioning . Recently, sevoflurane preconditioning was reported to reduce neuron injury in rat cerebral slices after an in-vitro simulated ischaemia . Using an in-vivo model of global cerebral ischaemia in the rat, sevoflurane was also found to protect the neuronal function and morphology of the hippocampus against ischaemic injury . This evidence strongly suggests that sevoflurane may also provide beneficial effects on cognitive function impairment.
Therefore, LTP was used as a surrogate marker of cognitive function in the present study and we sought to test the hypothesis that myocardial ischaemia–reperfusion injury may induce remarkable impairment of hippocampal LTP after ischaemia and sevoflurane preconditioning would provide robust protective effects.
Adult male Wistar rats (body weight 300–350 g) were provided by the Experimental Animal Centre of the China Medical University. The experimental protocol was approved by the Ethics Review Committee for Animal Experimentation of the China Medical University and in accordance with the NIH Guide for the Care and Use of Laboratory Animals.
Surgical preparation was conducted according to the method described previously [14,15]. Animals were anaesthetized with pentobarbital sodium (40 mg kg−1, intraperitoneally, i.p.), and anaesthesia was maintained via supplemental doses of pentobarbital sodium (20 mg kg−1, i.p.), as needed. A tracheal intubation was performed and the animals were mechanically ventilated using a rodent ventilator (Harvard 638, USA). The right femoral artery was cannulated with a catheter to monitor mean arterial blood pressure (MAP) and heart rate (HR) and harvest blood samples. Core temperature was measured via a rectal temperature probe and was maintained at 36.5–37.5°C with a heating pad. After an equilibration period of 10 min, a thoracotomy was performed. Ligation of the left anterior descending coronary artery was performed using a 7-0 silk suture with a small piece of polyethylene tubing to secure the ligature without damaging the artery. Ischaemia was confirmed by visual inspection of blanching in the myocardium distal to the site of occlusion. After a period of coronary occlusion of 30 min, the 7-0 silk ligature was removed. Reperfusion was confirmed visually by the return of a red colour in the region that was previously pale. Then the thoracic cavity was closed. After a 120 min reperfusion, the femoral artery catheter was removed. The animals were sent back to the cage when they were fully awake.
Rats were placed in an induction chamber and exposed to 1.0 minimum alveolar concentration (MAC) of sevoflurane (2%) delivered via a variable bypass vaporizer for 1 h. Delivered and exhaled gas concentrations were confirmed with an anaesthetic drug monitor. After exposure, the rats were recovered for 30 min .
Sixty-six rats were randomly divided into one of the four groups: normal, no intervention was performed (n = 6); sham, rats received the surgical procedures without coronary artery occlusion (n = 18); control, animals subjected to a 30 min coronary occlusion (n = 21); sevo, sevoflurane-pretreated rats subjected to a 30 min coronary occlusion (n = 21). The experimental protocol is shown in Fig. 1. On the 1st and 3rd days after the operation, six rats from each of the three experimental groups were selected randomly for LTP evaluation and measurement of tumour necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and haem oxygenase-1 mRNA expression. The remaining rats in each of the three groups were enrolled for the measurement of LTP and expression of the cytokines on the 7th day after reperfusion.
Measurement of creatine kinase and lactate dehydrogenase
A blood sample was harvested from the femoral vein before ischaemia and 120 min after reperfusion. The plasma concentration of creatine kinase and lactate dehydrogenase (LDH) was determined by an automatic biochemistry analyser.
Long-term potentiation measurement
Rats were anaesthetized with pentobarbital sodium (40 mg kg−1, i.p.). A monopolar stimulation electrode was implanted stereotaxically into the Schaffer collateral fibres of the right CA3 region [coordinates: posterior, 3.8 mm; lateral (right), 3.8 mm from bregma, 3.5 mm ventral from dura] and a recording electrode filled with 3 mol l−1 KCl was implanted into the right CA1 region [coordinates: posterior, 3.3 mm; lateral (right), 1.5 mm from bregma]. Coordinates are based on the atlas of Paxinos and Watson . The depths of the stimulation and recording electrodes were optimized during implantation using established electrophysiological criteria. The intensity of single pulses was adjusted (intensity of 25 mV, duration of 0.2 ms) to elicit 80% of the maximal population-spike amplitude. At least 30 min after the population-spike became steady, the high frequency stimulus (HFS, same stimulus intensity as for population-spike testing with 200 Hz for 5 s) was added to induce LTP. Signals were transferred through a microelectrode amplifier (MEZ-7101; Nihon Kohden, Tokyo, Japan) to a dual-beam memory oscilloscope (VC-11; Nihon Kohden) and recorded by an X-Y electronic recorder (Nihon Kohden). The averaged population-spike at five time points (25, 20, 15, 10 and 5 min before HFS) was used as a baseline. A population-spike at five time points (5, 10, 15, 20 and 25 min) after HFS was recorded and the values were then averaged. The population-spike value after HFS was expressed as the percentage of baseline. LTP was defined when the population-spike value after HFS was at least 10% higher than the baseline; otherwise LTP inhibition was identified .
Total RNA was extracted from the hippocampus using TRIzol reagent (Invitrogen, Gaithersburg, Maryland, USA) according to the manufacturer's instructions and 1 μg RNA samples were used for cDNA synthesis. First-strand cDNA synthesis was primed with random hexamers and conducted according to the manufacturer's specifications (reverse transcription-PCR kit; Roche, Mannheim, Germany). The cDNA equivalent to 200 ng of total RNA was subjected to PCR using the manufacturer's protocol (PCR core kit; Roche). Assays for β-actin, haem oxygenase-1, TNF-α and IL-1β were designed using the published sequences for these genes. The sequences for primers are listed in Table 1. cDNA was generated from total RNA using Promega reagents (Promega, Madison, Wisconsin, USA). Two hundred micrograms of total RNA was reverse transcribed in a 10 μl reaction volume and the reverse transcription reaction was subsequently used for the PCR, performed as described previously . After amplification, a 5-μl aliquot of the polymerase chain reaction products was electrophoresed on 2% (wt/vol) agarose gels. Gels were run at 100 V for 1 h, and the bands were visualized with ethidium bromide and photographed under ultraviolet light using a Gel Doc 2000 System (BioRad Laboratories, Hercules, California, USA). Band densities were quantified by densitometric measurements of the PCR products by Scion Image Beta 4.02 Win (Scion Image, Frederick, Maryland, USA). The amount of mRNA was expressed as a ratio of the densitometric measurements derived from the gene-specific mRNA and β-actin (a housekeeping gene) mRNA.
All values are reported as mean ± SD. Differences among the groups were analysed with a one-way analysis of variance (ANOVA) followed by the Student–Newman–Keuls posthoc test. Statistical significance was defined as a P value less than 0.05.
Mortality and exclusion
A total of 66 rats were enrolled in the present study. Seven rats were excluded because of marked hypotension (MAP below 30 mmHg) during coronary occlusion and reperfusion or death before the end of the observation period. Complete data were obtained in the remaining 59 rats. Final numbers in the groups were as follows: normal, n = 6; sham, n = 18; control, n = 17; sevo, n = 18.
MAP and HR were recorded in all groups throughout the experimental protocols. Table 2 indicates the haemodynamic values from all four groups. No significant differences of MAP and HR were observed among these groups at any observation time point (P > 0.05).
Creatine kinase and lactate dehydrogenase concentration
Figure 2 summarizes the data of the creatine kinase and LDH in all groups. No significant differences in concentrations of creatine kinase and LDH were observed among all groups before ischaemia. One hundred and twenty minutes after reperfusion, the concentrations of creatine kinase and LDH were markedly increased in the control group and the sevo group (P < 0.05, vs. sham group). However, compared with the control group, the concentrations of both creatine kinase and LDH were significantly lower in the sevo group (P < 0.05).
Measurement of long-term potentiation
The sham operation did not affect the LTP values (P > 0.05, compared with normal animals at the three observation time points, respectively). One and 3 days after myocardial ischaemia, LTP was markedly inhibited in the control group as evidenced by the significant decreases in population-spike values after HFS (P < 0.05, compared with the sham group at 1 and 3 days after myocardial ischaemia, respectively). LTP of the control group was restored to a normal level 7 days after myocardial ischaemia (P > 0.05, vs. sham group). Although LTP was also inhibited in the sevo group 1 and 3 days after myocardial ischaemia, population-spike values were significantly higher than those of the control group (P < 0.05, respectively; Fig. 3).
Expressions of haem oxygenase-1 mRNA, tumour necrosis factor-α mRNA and interleukin-1β mRNA
Figures 4–6 demonstrate the expressions of haem oxygenase-1 mRNA, TNF-α mRNA and IL-1β mRNA in the hippocampus and their densitometric analysis results. The sham operation did not increase haem oxygenase-1 mRNA, TNF-α mRNA and IL-1β mRNA expression at any time point when compared with the normal animals (P > 0.05, respectively). On days 1 and 3 after myocardial ischaemia, the levels of haem oxygenase-1 mRNA and IL-1β mRNA were significantly increased in the control and sevo groups (P < 0.05, compared with the sham group of the same time points, respectively), and the increased expressions were restored to normal levels on day 7 (P > 0.05, vs. sham group, respectively). However, the expressions of haem oxygenase-1 mRNA and IL-1β mRNA in the sevo group on days 1 and 3 after myocardial ischaemia were markedly lower than those of the control group (P < 0.05, respectively). For TNF-α mRNA, the expressions in the control group and the sevo group were significantly increased only on day 1 after myocardial ischaemia (P < 0.05, vs. sham group, respectively). TNF-α mRNA expression in the sevo group 1 day after ischaemia was still significantly lower than that of the control group (P < 0.05).
The most important findings from this study are summarized as follows. First, acute myocardial ischaemia–reperfusion injury induced impairment of hippocampal LTP in rats that was associated with increased expressions of haem oxygenase-1 mRNA, TNF-α mRNA and IL-1β mRNA in the hippocampus. Second, sevoflurane preconditioning attenuated the impairment of LTP induced by myocardial ischaemia–reperfusion injury and decreased the enhancement of expressions of haem oxygenase-1 mRNA, TNF-α mRNA and IL-1β mRNA in the hippocampus. In summary, these data demonstrate that sevoflurane preconditioning provides protection against neurological dysfunction after transient myocardial ischaemia.
In the current study, myocardial ischaemia–reperfusion injury was induced by occlusion of the coronary left anterior descending artery for 30 min and was confirmed by the elevation of the plasma concentration of creatine kinase and LDH after the transient ischaemia. This model has been well described in collective studies. A 30 min transient ischaemia was reported to induce an ischaemia area of about 50% of the whole left ventricle and the infarct size was about 50% of the ischaemic area . Consistent with the published data [20,21], sevoflurane pretreatment also reduced the myocardial ischaemia–reperfusion injury in the current study, as evidenced by the significant decrease in plasma concentration of creatine kinase and LDH after myocardial ischaemia.
The water maze test is commonly used to assess cognitive function in rats [22,23]. However, this test could not be used in the current study, as all the experimental rats underwent a thoracotomy and the physical power needed to be rehabilitated. LTP has been considered to be the primary physiological model of memory for the past three decades  and cognitive dysfunction can be easily detected by the suppression of LTP. The current investigation demonstrated that a transient inhibition of LTP occurred during the early stage (1–3 days) after coronary artery occlusion and the LTP recovered to the normal level at about 7 days later. This impairment of LTP resulted from myocardial ischaemia–reperfusion injury but not from the operative trauma, because the sham operation did not induce such a similar neurological dysfunction. The hippocampus is a medial temporal lobe structure that is necessary for the formation of stable declarative memory in humans and spatial memory in rodents. One well described neuroendocrine function of the hippocampus is to participate in terminating the stress response through glucocorticoid-mediated negative feedback that inhibits the hypothalamus–pituitary–adrenal axis . Extensive studies have supported the idea that stress and stress hormones impair hippocampus-dependent forms of memory in both humans and animals . Hippocampal slices prepared from adult rats that had experienced unpredictable and inescapable restraint-tail shock stress showed marked impairments of LTP in the CA1 pyramidal cell region . Subsequent studies showed that stress-induced LTP impairment lasts for at least 48 h in rats  and 24 h in mice , and that stress also reduces LTP in the dentate gyrus of the hippocampus . Patients with posttraumatic stress disorder have hippocampal atrophy and marked deficits in hippocampus-dependent recall tasks . Myocardial ischaemia–reperfusion injury can be considered as a stress that perturbs the physiological/psychological homeostasis of an organism, and therefore the impairment of LTP induced by myocardial ischaemia–reperfusion injury is not a surprise. Neurocognitive decline after cardiac surgery has received significant attention in recent years, following the demonstration in multiple studies that cognitive deficits occurring early after cardiac surgery are predictive of late cognitive decline . However, the contribution of the surgical procedure and exposure to cardiopulmonary bypass to the occurrence of these deficits is not entirely clear. In a prospective and randomized study, no differences were detected in postoperative cognitive function after on-pump compared with off-pump coronary artery bypass grafting . The contribution of cardiopulmonary bypass to cognitive deficits was also denied in a report by Lund et al. . Considering the facts that cognitive dysfunction is not such a frequent and important complication after noncardiac surgeries, the stress of the cardiac surgical procedure may simply be unmasking an underlying cerebrovascular disorder that puts patients at risk of late cognitive decline. On the basis of the current experimental results, we infer that myocardial ischaemia–reperfusion injury may be one of the most important factors contributing to the cognitive dysfunction observed after cardiac surgeries.
The following question is about the mechanism by which myocardial ischaemia–reperfusion injury induces the impairment of hippocampal LTP. In the current study, haem oxygenase-1 mRNA, TNF-α mRNA and IL-1β mRNA expressions were found to be increased transiently in the hippocampus during the first few days after reperfusion, with a time course similar to the suppression of LTP. Increasing evidence suggests that the haem oxygenase-1 gene is redox-regulated and its expression appears to be closely related to conditions of oxidative and nitrosative stress . The transient increase in haem oxygenase-1 mRNA expression observed in this study indicated that the oxidative stress reaction occurred in the hippocampus after injury by myocardial ischaemia–reperfusion. The high expression of TNF-α mRNA and IL-1β mRNA also implied that myocardial ischaemia–reperfusion injury induced an inflammatory process in the hippocampus. The brain has been considered to be more vulnerable to oxidative stress and inflammatory response than other organs. Increasing evidence supports the roles of oxidative damage and cytokine-mediated inflammatory processes in neurologic dysfunction induced by neurodegenerative diseases. More recent studies of patients with amnestic mild cognitive impairment (MCI) show significantly increased levels of lipid peroxidation and protein, DNA, and RNA oxidation in vulnerable regions of the brain . There is abundant evidence that inflammatory mechanisms within the central nervous system contribute to neurological impairment via cytokine-mediated interactions between neurons and glial cells [33,34]. Therefore, the transient inhibition of LTP observed in the current study may be related closely to the oxidative stress and inflammatory processes in the hippocampus. Myocardial ischaemia–reperfusion injury may not induce direct ischaemia in the brain, as its haemodynamics remained stable throughout the experimental process. The impairment of LTP observed in this study may be termed a remote injury or injury at a distance, implicates an endocrine action, and may involve humoral or neural–endocrine signalling. However, it is still not known by what mechanism myocardial ischaemia–reperfusion injury induces oxidative stress and an inflammatory response in the hippocampus.
Another important finding is that sevoflurane preconditioning significantly alleviated the inhibition of hippocampal LTP induced by injury by myocardial ischaemia–reperfusion. Sevoflurane is the drug most commonly used to maintain the state of general anaesthesia. It has long been known to provide protection against ischaemia and reperfusion injury in different organs such as the myocardium and brain [7–9]. Sevoflurane attenuated the inflammatory response during endotoxaemia in vivo, thus contributing to its beneficial role in clinical organ protection . Sevoflurane was shown to have direct anti-inflammatory effects in in-vitro cultures of proximal tubule cells  as well as in in-vivo renal ischaemia . Sevoflurane also reduced the release of deleterious quantities of reactive oxygen species (ROS) associated with cardiac ischaemia–reperfusion . Moreover, sevoflurane was further shown to be a potent neuroprotective agent by inhibition of ROS generation during the reoxygenation process . Consistently, sevoflurane pretreatment significantly attenuated the increased expressions of haem oxygenase-1 mRNA, TNF-α mRNA and IL-1β mRNA in the hippocampus in the present study. These data suggested that sevoflurane preconditioning may provide neuroprotection through a direct mechanism of attenuation of the oxidative stress and the inflammatory response in the hippocampus. However, the current data could not exclude the possibility that sevoflurane preconditioning mediated no direct effects on the LTP. The improvement of neurological function could be due to the attenuation of myocardial injury induced by sevoflurane preconditioning. Sevoflurane preconditioning could be acting via multiple mechanisms to change the LTP response to myocardial ischaemia, which needs further research.
The present study has demonstrated that sevoflurane preconditioning induced a neuroprotection against impairment by LTP resulting from myocardial ischaemia and reperfusion. The neuroprotective effects were associated with the attenuation of oxidative stress and inflammatory response in the hippocampus. To the best of our knowledge, this is the first study showing sevoflurane pretreatment provides neuroprotection against hippocampal LTP.
The present work was supported by the Department of Anesthesiology, First Affiliated Hospital, China Medical University, China.
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