Chapter 8 – Pharmacologic (Receptor-Based) Mechanisms of Perioperative Neurocognitive Disorder

Chapter 8 Pharmacologic (Receptor-Based) Mechanisms of Perioperative Neurocognitive Disorder

Lauren G. Powlovich , MD and Zhiyi Zuo , MD, PhD

Introduction

Perioperative neurocognitive disorder (PND, formerly POCD) is an important and well-recognized complication after surgery, especially in the elderly population, as it affects 24%–40% of patients aged 60 years or older at hospital discharge and about 10% of these patients at 3 months after noncardiac surgeries [1–3]. The incidence is higher in patients after cardiac surgery [3]. In addition to affecting patients’ daily living, PND is associated with increased mortality and early withdrawal from the job market [2,4]. Thus, PND has become a significant clinical issue.

It was reasonable to think that PND, a cognitive disorder, is a result of disturbances of normal learning and memory processes. These processes clearly involve a host of neurotransmitters and their receptors. Some of the most important neurotransmitters are glutamate and acetylcholine [5–8]. In this article, we will first very briefly review the role of the neurotransmitter receptors in learning and memory. We will focus our review on the literature showing the involvement of these receptors in PND.

Role of Glutamatergic, GABAergic, and Cholinergic Transmission in Learning and Memory

Glutamate Receptors

Glutamate is the primary excitatory neurotransmitter in the brain. Its receptors are critical components for the formation of neuronal pathways underlying the learning and memory process. Glutamate has both ionotropic (ion channel coupled) and metabotropic (second messenger coupled) receptors. The ionotropic channel receptors, which account for fast transmission and are most responsible for learning and memory, are the N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and kainate receptors [5]. They are so named after agonists that bind with high affinity to them. These receptors are tetra- or pentameric ion channels.

NMDA receptors are composed of three major subunits, the NR1, NR2A-D, and NR3A-B [9]. Binding studies have shown that NMDA receptors are distributed heterogeneously throughout the brain with high levels noted in the forebrain, hippocampus, thalamus, and cortex with the hippocampus containing the highest density of receptors [5]. When glutamate binds, the NMDA receptor opens an ionotropic channel permeable to Ca²⁺ ions as well as Na⁺ and K⁺ ions [5].

Numerous studies have proven the role of NMDA receptors in learning and memory (reviewed in [5]). Such studies have shown that in aged mammals and those with diseases of memory, such as Alzheimer’s disease, there are decreased numbers of NMDA receptors as shown by decreased glutamate and NMDA binding [10]. There has been an abundance of studies performed on rats that show that NMDA receptor antagonists hinder the ability of rats to learn how to navigate maze tests and also that NMDA receptor agonists attenuate impairment of learning or memory caused by various stimuli [5]. Thus, the involvement of NMDA receptors in learning and memory is reasonably well established.

AMPA receptors consist of four subunits: GluR1-4. These subunits can be translocated from intracellular compartments to the plasma membrane after training stimulation, which is considered as a fundamental biochemical process of learning and memory [11]. Various studies using antagonists and agonists have shown that inhibition of AMPA receptors impairs learning and memory [5]. There is very little evidence for the involvement of kainate receptors in learning and memory. The metabotropic receptors include three groups. They regulate intracellular pathways related to learning and memory [5].

GABA Receptors

GABA is the major inhibitory neurotransmitter in the brain. Two types of GABA receptors are known. GABA_A receptors are ligand-gated ionotropic receptors. GABA_B receptors are G protein-coupled receptors. GABA_A receptors consist of five subunits arranged to form a central chloride channel. Once the receptor is activated, chloride anions flow through the receptor according to their electrochemical gradients. In mature neurons, this effect usually results in hyperpolarization of the resting membrane potential, which decreases the excitability of the cells [12]. It has been shown that activation of specific GABA_A receptors inhibits learning and memory [13]. However, a confounding factor is that the agents that activate GABA_A receptors affect the states of wakefulness and attention.

Cholinergic System

An important system involved in memory is the central cholinergic system [7,8,14]. Interest in the cholinergic system was greatly enhanced after evidence surfaced that cholinergic markers in the cerebral cortex are reduced in patients with Alzheimer’s disease and that the reduction in markers correlates with severity of disease [15]. After such information was revealed, immense study on the localization and function of cholinergic neurons and acetylcholine receptors (AChRs) in both animal and human ensued [7,8,14].

Acetylcholine is released into the synaptic cleft after depolarization-induced Ca²⁺ influx. Acetylcholine then binds to both pre- and postsynaptic muscarinic and nicotinic AChRs (abbreviated mAChRs and nAChRs, respectively). Acetylcholine hydrolysis by acetylcholinesterase and butyrylcholinesterase occurs within milliseconds of its release into the synaptic cleft. mAChRs belong to the metabotropic receptor family; whereas nAChRs are ligand-gated ion channels. Similar to GABA_A receptors, nAChRs have five subunits and allow the diffusion of Na⁺ and K⁺, which depolarizes the cell membrane [16]. The mAChRs link to intracellular signaling pathways via G-proteins. Both mAChRs and nAChRs have been shown to play an important role in cognitive functions, such as learning and memory [17].

It is now known that cholinergic innervation of the cerebral cortex and diencephalon originates predominantly from six regions of the basal forebrain and brainstem with the hippocampus and amygdala containing the highest density of acetylcholinesterase-rich neurons [7].

One of the ways in which the cholinergic system has been tested to be important to learning and memory is by studying the effects of cholinergic agonists and antagonists on learning and memory processes. Consistently, blockade of the mAChRs using scopolamine or atropine inhibits acquisition of spatial memory in rodents [17]. In addition, it has been shown that blockade of nAChRs leads to spatial memory deficits. In contrast, activation of nAChRs by nicotine has been reported to improve cognition [17]. Cholinesterase inhibitors, such as donepezil and rivastigmine, are the most commonly prescribed medications for the treatment of neurodegenerative disorders and dementia. One potential mechanism for nAChRs to improve learning and memory is to increase intracellular calcium and calcium-dependent signaling pathways, leading to increased glutamate release and glutamatergic synaptic plasticity [8].

Role of Glutamate Receptors in PND

The most well studied glutamate receptor in the field of PND is the NMDA receptor and more specifically, the NMDA receptor subunit 2B (NR2B). When overexpressed in neurons, the NR2B improves synaptic plasticity and memory. Many studies have tried to identify methods to up-regulate the expression of NR2B in order to enhance memory. In addition, hippocampal NR2B deficit has been shown to impair spatial learning [5,6]. With regards to PND, the NR2B subunit has been examined in multiple studies outlined below. Of note, most studies mentioned in this review are animal-based due to the difficulty of analyzing such parameters on humans given the need for histopathological analysis of brain tissues.

The effects of hindpaw incision-induced pain perception on NR2B in mice have been studied [18]. The reasoning for such a study was that NR2B plays a role in both pain perception and cognition. Thus, determining how the NR2B subunit changes when pain is perceived and correlating these changes with cognitive function were of interest to the researchers. In addition, cyclin-dependent kinase 5 (CDK5) that is activated by tumor necrosis factor (TNF)-α has been shown to regulate NR2B levels and surgical incision has been shown to increase TNF-α levels. The hypothesis was that nociception following surgical incision in mice would increase brain CDK5 levels and thus decrease NR2B levels, leading to learning impairment. The results showed that surgical incision-induced nociception decreased synaptic NR2B levels (specifically within the medial prefrontal cortex) and increased CDK5 at 3 days after surgery. The researchers also found that surgical incision-induced nociception was associated with a learning impairment in mice at 3 and 7 days after surgery, but not 30 days postoperatively. In addition, when the surgical stimulus was reduced using analgesia, learning impairment was mitigated. This study sheds light on the importance of the NR2B subunit of the NMDA receptor in PND. It also recognizes the importance of surgical nociception and a cascade of events that may contribute to PND. Interestingly, aged rats after laparotomy had impaired learning and memory and increased NR2 [19]. This finding seems to be contradictory to the results of the study using the hindpaw model. However, the second study did not specify which NR2 subunit was measured [19]. These two studies used different surgical models and animal species.

The role of general anesthesia in the development of PND has also been investigated. Volatile anesthetics, such as isoflurane, are known to acutely depress NMDA receptor-mediated synaptic transmission [20] but the effect of volatile anesthetic on actual receptor density after removal of the anesthetic is not as well established. The effect of isoflurane anesthesia without surgery on cognitive function and levels of NMDA receptors in mice has been investigated [21]. It was found that the cognitive performance of mice 1 day after 2 hour isoflurane anesthesia was statistically significantly better than nonanesthetized controls. Isoflurane anesthesia up-regulated both the NR1 and NR2B subunits of the NMDA receptor in the hippocampus 1 day after isoflurane anesthesia and this up-regulation was reversed 7 days after isoflurane anesthesia. Furthermore, blocking the NR2B receptor with specific NR2B antagonists reversed the isoflurane effect on cognitive performance. These data suggest that isoflurane general anesthesia reversibly induces elevation of the NR2B subunit in the hippocampus, resulting in an improvement of learning. A similar phenomenon occurred after sevoflurane anesthesia [22]. However, when isoflurane exposure was for 4 hours, NR2B was decreased and cognition of these mice was impaired [23]. However, it has been reported that NR2B was increased and that this increase was associated with impaired learning and memory in aged rats after being exposed to isoflurane-nitrous oxide anesthesia for 4 hours [24]. Nevertheless, impaired learning and memory of rats after volatile anesthetic exposure for 2 hours have been reported [25,26]. These studies do not study the expression of NMDA receptors. Thus, whether NMDA receptors are involved in the volatile anesthetics-induced cognitive impairment is not completely clear.

There is an increasing body of evidence which indicates that surgical trauma, resulting in the release of inflammatory mediators, is a prominent pathological process for the development of PND [27–29]. The exact mechanism of how and why this inflammation leads to PND is being investigated. Xie et al. [30] studied the effects of a component of a natural Chinese medicine called Senegenin on POCD and the NR2B receptors after hepatic ischemia reperfusion. Senegenin is a component of the root Polygala tenuifolia that is used to treat insomnia and dementia. Pharmacologic data have indicated that Senegenin displays antioxidative activity in the hippocampus. Hepatic ischemia reperfusion has been shown to be a very strong activator of the systemic inflammatory response system and one of the most vulnerable organs to injury from this response is the brain. It has been reported that this can profoundly affect the function of the brain, including memory and cognition. The study showed that hepatic ischemia reperfusion produced cognitive deficit and that Senegenin administration attenuated this cognitive impairment. In addition, NR2B was increased in the hippocampus in mice who received Senegenin [30].

The role of AMPA receptors in the PND was indicated by data from our laboratory [31]. Rats that had carotid artery exposure procedure had learning and memory deficits. Their hippocampus had reduced GluR1 trafficking to the plasma membrane. A similar reduction was induced by pro-inflammatory cytokines interleukin (IL) 1β and 6. The surgical procedure increased IL-1β and IL-6 in the brain. These results suggest the role of AMPA receptors in PND. Consistent with our study, a recent study showed that surgery increased the internalization of GluR2 [22 ].

Role of the Cholinergic System in PND

In addition to glutamate receptors, the cholinergic system has been examined to establish whether the effects on this system contribute to PND.

A central cholinergic deficit has been shown to be associated with age-related cognitive impairment. Along the same lines, an increase in serum anticholinergic activity (SAA) has been shown to be associated with cognitive impairment in many studies (reviewed in [17]). For this reason, a study was designed to determine if anticholinergic medications, which decrease acetylcholine, lead to a form of PND [32]. The hypothesis was that an increase in SAA in the perioperative period would be associated with PND in elderly patients. The study included 79 patients older than 65 years who were undergoing major elective surgery. The patients were assessed for cognitive function pre- and postoperatively using a well-defined neuropsychological test. The patient’s SAA was assessed preoperatively and 7 days after surgery when the neuropsychological test was performed. Interestingly, 46% of the patients developed PND. However, there was no significant difference in the SAA of these patients [32]. Consistent with this, another study with 117 patients for cardiac surgery did not find that increased preoperative SAA predicts PND at 3 months after the surgery [33]. These studies suggest that anticholinergic medications administered during the perioperative period should not play a significant role in PND development. This is relevant information for anesthesiologists as they often use anticholinergic medications, such as atropine and glycopyrrolate, intraoperatively. The lack of effects of these drugs may be due to their inability to permeate the blood-brain barrier.

Interestingly, the cholinergic system has been shown to play a unique role in the brain during surgery not only due to its direct effect on neurotransmission but also due to a system called the cholinergic anti-inflammatory pathway [34]. Sensory input elicited by infection or injury moves through the afferent vagus nerve to the brainstem, which then generates action potentials in efferent nerves to organs of the immune system. Release of acetylcholine from a subset of CD-4 positive T cells activated the α7 subunit-containing nicotinic acetylcholine receptor (α7nAChR) on macrophages to decrease the production of the potent pro-inflammatory cytokines TNF-α, IL-1β, IL-6, and IL-18. This mechanism is referred to as the inflammatory reflex. This pathway is very probably related to PND as neuroinflammation is a key pathological process for cognitive decline [34].

It has been shown that isoflurane-induced cognitive impairment is associated with a decreased acetylcholine level in the brain of aged rats [35]. A study by Kalb et al. [36] examined whether acetylcholinesterase inhibitors lead to a reduction in neuroinflammation. Rats received either an acetylcholinesterase inhibitor (physostigmine or neostigmine) or saline before and during abdominal surgery. Hippocampus, cortex, and spleen were harvested to analyze the inflammatory markers. In addition to studying surgery alone, they also examined how application of lipopolysaccharide (LPS) to the open abdominal cavity would alter the inflammatory response as LPS is a well-known activator of the innate immune system. The study showed that LPS plus surgery led to increased IL-1β in the cortex and hippocampus and that this increase was attenuated in rats that received an acetylcholinesterase inhibitor. Interestingly, surgery alone did not increase IL-1β expression in the brain tissues. In addition, IL-1β and TNF-α were increased in the spleen after surgery plus LPS and this expression was lowered by physostigmine and neostigmine. Surgery combined with LPS treatment resulted in more neuronal damage compared to the control group and treatment with acetylcholinesterase inhibitor led to significantly reduced neuronal damage. This study shows that pro-inflammatory cytokines are up-regulated during surgery when LPS was applied. Therefore, it may be that subclinical infection during surgery leads to neuroinflammation. Most importantly, IL-1β was up-regulated in the hippocampus and this particular finding of increased IL-1β has been associated with memory impairment [36]. This study suggests the potential role that an acetylcholinesterase inhibitor could play in PND by decreasing neuroinflammation. This information is especially relevant to anesthesiologists due to the fact that many patients receive acetylcholinesterase inhibitors in the perioperative period.

To support a role of the cholinergic system in PND, a group of authors showed that tibia fracture and fixation-induced neuroinflammation and cognitive impairment were attenuated by α7nAChR stimulation [37]. These results provide evidence to suggest a potential approach to reduce PND .

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