Anesthesia-mediated neuroinflammatory sequelae in post operative cognitive dysfunction: mechanisms and therapeutic implications

Introduction

Post-operative cognitive dysfunction (POCD) has been reported as early as 1887 but only recently has been shown to be a consequence of complex microglial interactions with the surrounding microenvironment (1, 2). While the guidelines remain unclear, emerging evidence suggests that the interplay of age, gender, administration of anesthesia, and microglial responses may culminate in a post-operative neuropsychiatric change in cognition (3). However, the unclear condition and nature of POCD may partly be due to the variability of POCD assessments that have been previously reported (4). Despite the assessment variabilities, the commonly reported conditions involve decline in cognitive functioning and, more recently, microglial involvement (5).

Microglia are the resident, antigen-presenting, macrophage-like cells of the brain that primarily mediate central nervous system (CNS) inflammation through complex interactions with neurons, endothelial cells, astrocytes, oligodendrocytes, and other resident cells of the CNS (6, 7). The interactions between glial cells and neurons influence how the brain perceives, experiences, and interacts with the world; thus, states of immune dysregulation may compromise this functioning leading to neuropsychiatric pathologies (7, 8). In normal homeostasis, microglia survey their microenvironments and interact with the cellular landscape of the brain, thereby affecting cognition, memory, and learning (7). Thus, aberrant changes to microglial functioning due to anesthesia and surgery may directly impact cognitive functioning, mental health, and emotional regulation through complex interactions within the brain parenchyma (Figure 1, Table 1).

Figure 1

Figure 1. Schematic of the general summary of anesthetic effects on inflammatory phenotypes with associated historical depictions of pro- and anti-inflammatory (ameboid and ramified) microglia morphologies (9). Studies from the figure are cited in Table 1. Created with Biorender.com.

Table 1

Table 1. General summary of the studies regarding anesthesia-mediated inflammatory phenotype changes.

Moreover, anesthetic mechanisms of action are complex and affect blood-brain-barrier (BBB) permeability, neuronal functioning, and glial responses. Previous studies have proposed neuroinflammation, oxidative stress, BBB integrity, and metabolism dysregulation as mechanisms of POCD. Here, we examine these studies through the intersection of age and anesthetics on the BBB, with the goal of shedding new insight into the pathogenesis of POCD. Moreover, we review the clinical, basic science, and translational studies of POCD, focusing on the neuro-immune axis and interplay with the complex pharmacology of cardiac- and non-cardiac surgery.

POCD incidence discrepancies

POCD has varying reports of prevalence following surgery (46, 47). The reported incidences of POCD following non-cardiac surgery vary between 41%–75% at seven days and 18%–45% after three months postoperatively (46–48). Conversely, POCD incidences following coronary-artery bypass surgery have been reported to be 53%, 36%, and 42% at discharge, six weeks, and five years, respectively (49). In 2005, Gao et al. reported that POCD was observed in more than 40% of patients several months following cardiac surgery. This was also observed in 25% in patients over 60 in non-cardiac surgery one week following surgery with a resolution to 10% after 3 months (46). The discrepancies in prevalence may be due to a lack of previously standardized diagnostic criteria (48).

New nomenclature has been reportedly introduced for POCD in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (47, 50). Recent efforts have been made to update the nomenclature from POCD to peri-operative neurocognitive disorders (PND) to encompass delirium and cognitive dysfunction under an umbrella description (47). To date, however, POCD does not appear in DSM-5 and only describes post-operative delirium with an incidence that ranges between 15% and 53% (50).

Clinical risk factors for POCD

Age is widely recognized as a significant risk factor for POCD. Studies have consistently shown that advanced age is associated with a higher incidence of POCD, which refers to a decline in cognitive function following surgery (51). The underlying mechanisms are not fully understood but may involve age-related changes in the brain, increased vulnerability to perioperative stressors, and the presence of pre-existing cognitive impairment (52, 53). Several studies have investigated the impact of age on POCD, highlighting its negative influence on postoperative cognitive outcomes. Moller et al. found that among POCD patients followed for three months, duration of anesthesia, education, multiple surgeries, postoperative infections, and respiratory complications were risk factors for early POCD, but only age was a risk factor for late POCD (54).

Preoperative cognitive impairment or decline could be a potential risk factor for POCD (55, 56). Patients with cognitive impairment before surgery are more vulnerable to experiencing cognitive decline following the procedure (57). Chen et al. conducted a meta-analysis and revealed that preoperative cognitive impairment in older non-cardiac surgical patients significantly increased the risk of delirium, 1-year mortality, discharge to assisted care, 30-day readmission, and postoperative complications (58). Similarly, Au et al. (59) found that in older cardiac surgical patients, preoperative cognitive impairment was associated with an 8-fold increased risk of delirium and an increased hospital and ICU length of stay (59).

The type of surgery is highly influential in the development of POCD (60). Different surgical interventions can impact the incidence and severity of cognitive decline following surgery. Factors such as the invasiveness of the surgery, duration of anesthesia, and exposure to certain anesthetic agents can influence the risk of POCD (4). Cardiac surgery has been given special attention when researching POCD given the higher prevalence of dysfunction following surgical procedures (61). Bhushan et al. (62) found that the incidence of POCD ranged from 9% to 54% in different studies and the highest incidence was observed after open aortic, transcatheter aortic valve implantation, and coronary artery bypass graft surgery (CABG) (62). Understanding the impact of specific surgeries' cognitive outcomes is crucial for optimizing patient care and implementing preventive strategies.

The duration and complexity of surgery may also affect the risk of POCD. Prolonged surgical procedures and complex surgeries are associated with an increased likelihood of cognitive decline in the postoperative period. Extended exposure to anesthesia, physiological stress, and surgical trauma can contribute to cognitive impairment. In an animal study designed to test learning abilities following prolonged disruption after general anesthesia, Culley et al. (63) found a persistent deficit in performance that was not explained by other factors (63). The authors' findings suggest a long-term impairment in learning and memory following an extended duration of anesthesia.

The route of anesthesia administration (intravenous vs. inhalation) may contribute differently to the severity of POCD. Negrini et al. (64) completed a thorough meta-analysis on the rates of POCD incidence following inhalation and total intravenous/injectable anesthesia (TIVA) (64). The researchers defined two objectives: identifying POCD incidence within the first 30 days after the procedure and assessing cognitive function from 30 days to 1 year. With 10 total studies, 1,660 participants were assigned to the TIVA group and 1,730 participants to the inhalation group (64). It was determined for the first objective that the incidence of POCD in the TIVA group was 11.4% compared to the inhalation group at 27.7% (64). Another meta-analysis carried out by Yongbo Di et al. on the outcomes of elderly patients undergoing cancer surgery found no significant difference between intravenous and inhalation anesthetics after one month, but also agreed with the finding that those using inhalation anesthetics have 1.49 times higher risk of having delayed neurocognitive recovery when compared with intravenous agents (65). From these two metanalysis, it seems that the difference between inhaled and intravenous anesthetics is primarily found in the first month after surgery.

Genetic risk factors

One genetic risk factor for POCD is individuals with APOE4 carrier status (66). The longitudinal study performed by Schenning et al. (66) revealed that genetic variations in APOE4 may contribute to POCD pathogenesis. However, conflicting reports are currently present. One study was unable to show a significant association between APOE4 and POCD—whether this is from low statistical power or the pathobiology is unclear (67).

A prospective cohort study utilized genotype data on patients undergoing coronary artery bypass graft (CABG) surgery and showed that minor allelic variations in P-selection and C-reactive protein (CRP) influence POCD outcomes (68). Specifically, the 1059G/C (rs1800947) and 1087G/A (rs6131) minor alleles of CRP and the P-selection-encoding SELP gene, respectively, were associated with a reduction in cognitive dysfunction in 443 European Americans (68). These allelic variations were also associated with reduced perioperative serum CRP and platelet activation, thereby providing a physiological mechanism for the observed genotype variations (68). An additive effect was also demonstrated in patients carried at least one copy of 1059C and 1087A alleles; cognitive deficit incidence rates were 16.7% and 42.9% in patients for carriers of both loci compared to homozygous 1059G and 1087G major allele carriers, respectively (68). While the group examined 37 SNPs in 16 candidate genes including APOE, the major differences were only observed in the previously mentioned CRP and SELP alleles (68). Another study revealed that post-CABG patients who were homozygous for +1444TT had higher CRP levels compared to those who carried a +1444C allele (69).

In the setting of non-emergent cardiac surgery, a gene variant in PH-domain and leucine rich repeat protein phosphatase, PHLPP2 (rs78064607), was identified as having genome-wide significance in a genome-wide association study (GWAS) (70). PHLPP2 has been implicated in the response following ischemia/reperfusion injury and oxidative stress damage to the brain and kidney, respectively (70). In cellular settings PHLPP2 dephosphorylates and inactivates Akt, thereby inhibiting protective pathways following cerebral ischemia/reperfusion injury (70, 71).

Cholinergic gene variants in CHRM2 (rs8191992, rs6962027) and CHRM4 (rs2067482) have also been assessed in the context of post-operative delirium in a candidate-gene association study approach (72). However, no variants in this study reached significance with a GWAS approach (72).

Variations in BDNF have also been identified in Chinese Han populations (73). Xie et al. (73) revealed that an A > G polymorphism at rs6265 locus of BDNF may be protective for POCD development. Patients carrying GG and GA alleles had significantly lower POCD outcomes than those homozygous for the A allele at 7-days post-operatively (73). However no differences were seen 3-months following surgery (73).

Epigenetic involvement

Epigenetic modifications may enhance or protect from POCD-related changes. One group examined DNA methylation changes in the controversial APOE3 and APOE4 variants in a mouse model using isoflurane and surgery (74). The group found hypomethylated regions related to axonogenesis in both isoforms after surgery (74). Conversely, genetic segments relating to synaptic functioning, neurotransmitter trafficking, long term potentiation, and axon guidance in the E3 isoform were significantly hypermethylated following surgery (74). Specifically, Ephrin B2 and Eph A7 receptor gene segments were found to be hypermethylated (74). These cognitive changes and their associated epigenetic modifications were only observed in the E3 allele; this may be partially explained by the lower baseline cognitive performance by mice harboring the E4 allele (74).

Changes in N6-methyladenosine (m6a) methylation patterns have also been studied in the context of POCD mouse models using sevoflurane (75). The study revealed that m6A RNA methylation was significantly elevated in 56 genes and silenced in 1,244 genes in the POCD model compared to controls (75). There was overall a significant reduction in m6A methylation in the mouse hippocampus (75). These reductions could be explained by sevoflurane-mediated suppression of MAPK/ERK activity leading to inhibited methyltransferase activity by METLL3 (75).

Isoflurane rat models of POCD demonstrated abhorrent H3K9 and H4K12 acetylation resulting in dysregulated BDNF signaling (76). These modifications were reversed upon treatment with apigenin (77). Interestingly, sevoflurane models of POCD with exploratory laparotomy in mice resulted in increased histone deacetylase 2 (HDAC2) activity resulting in decreased BDNF and TrkB activity (78). A similar study revealed isoflurane in aged mice upregulated HDAC3 activity in the dorsal hippocampus leading to cognitive impairment (79). These impairments were ameliorated upon HDAC3 inhibition using RGFP966 (79). Overexpression of HDAC3 in young mice resulted in similar patterns of cognitive dysfunction (79). Isoflurane and surgery may lead to activation of HDAC, resulting in decreased acetylation of H3 and H4 histones while leading to a decrease in neuroligin 1 (78, 80, 81). Interestingly, environmental enrichment attenuated these cognitive and epigenetic changes when the environment was enriched two weeks before surgery (81).

miRNA targets

Analysis of preoperative miRNA may also be a promising candid biomarker for predicting POCD outcomes (82). Specifically, miRNA-155 was found to be a strong predictor of POCD progression in patients undergoing laparoscopic surgery for colon cancer (82). Recent studies have unveiled that miRNA is implicated in inflammatory processes and has even been described as a “master regulator of inflammation” (83). The expression of miRNA-155 has been implicated in cancer, asthma, cystic fibrosis, and cardiovascular disease (83, 84). One compound, MLN4924 (pevonedistat), has been demonstrated as a NEDD8-activating enzyme inhibitor that blocks NF-κB from upregulating the miRNA-155 promoter in the context of acute myelogenous leukemia (85).

Epigenetic targeting

As previously described, inhibition of HDAC2 and HDAC3 may ameliorate anesthesia-related cognitive changes following surgery (78, 79). Apigenin, a plant-derived flavonoid, was shown to recover histone acetylation in vivo that reduced isoflurane-induced suppression of BDNF and cognitive deficits while reducing inflammatory cytokines associated with neuroinflammation (76).

Neuroimmune functions

The CNS, composed of the parenchyma proper, ventricles, and meninges, has long been considered “immune privileged” (86). While the meninges, perivascular spaces, and choroid plexus are populated by dendritic cells (DC) and macrophages, the parenchyma is inhabited by microglia, a specialized immune cell that compromises nearly 10% of all glial cells (87). Microglia are vital to the parenchymal milieu for CNS homeostasis, development, and response to insult and trauma. These specialized, multifunctional cells engage in continuous surveillance of the microenvironment through their ramified processes (7, 88).

Morphologically these cells can be characterized as ramified, ameboid, or hypertrophic, depending on the stimuli (88–90). When ramified, microglia engage in surveillance through cell-cell contacts with the vasculature, astrocytes, and neuronal somas (90, 91). In the aging brain, however, dystrophic microglial morphologies have been observed while ameboid phenotypes have been reported to occur in the developing CNS (90, 92).

Historically, these cells have been described to become polarized to an “M1-like” or M2-like” state, which corresponds to a pro- and anti-inflammatory characteristic, respectively (93–95). According to Tang and Le (96), the M1 microglia are associated with sites of injury and inflammation, and are generally considered cytotoxic. Conversely, the M2 microglia are characterized by anti-inflammatory phenotypes and are associated with tissue-repair, phagocytosis, immunosuppression, regeneration, and neuroprotection. The M1 microglia produce pro-inflammatory mediators such as interleukin 1 beta (IL-1β), tumor necrosis factor α (TNF-α), IL-6, reactive oxygen species (ROS), nitric oxide (NO), and superoxide in response to injury through activation of iNOS and NF-κB pathways (95, 96). On the other hand, M2, alternatively-activated microglia are induced by interleukin-4, -10, and -13 (IL-4,-10,13) and transforming growth factor β (TGFβ), which result in phagocytosis, extracellular matrix (ECM) remodeling, and neuroprotection (96). However, current standards are moving towards describing microglia as having multiple states, such as M1 or M2, existing on a spectrum through proteomic, metabolic, transcriptomic, morphological, or epigenetic studies (9).

The functions of microglia-neuron crosstalk include engulfing apoptotic cells and dendritic spines, phagocytosing functional and non-functional synapses, forming axonal tracts, and clearing cellular debris (92, 97). Through these interactions, microglia regulate neuronal activity and synaptic plasticity and by extension, can influence cognition, learning, and memory depending on their physiological state (92). Additionally, microglial interactions with astrocytes contribute to homeostasis and neuroinflammation through complex signaling affecting the neurovascular unit (NVU), thereby affecting the BBB permeability and function (95).

Mechanistically, microglial responses to insult have been shown to be mediated through ATP signaling, neuronal NMDA receptor activation, and extracellular calcium signaling, as reviewed by Tay et al. (92). For example, microglial response to laser injury has been shown to be mediated by through microglial P2RY12 and ATP signaling in vivo (92, 98, 99). Another purinergic signaling mechanism was discovered to be through dendritic NDMA receptor activation, which resulted in the release of ATP, thereby causing an outgrowth of microglial processes (92, 100). Moreover, a decline in cerebral extracellular calcium concentrations has been shown to guide microglial processes towards neuronal dendrites (92, 101).

Like neurons, microglia-astrocyte communication is influenced by the polarization state of microglia (95). Through cytokine, chemokine, and ATP signaling, microglia influence astrocytes to become neurotoxic or neuroprotective, depending on the stimuli (102).

Aging effects on the blood brain barrier

The BBB consists of continuous non-fenestrated endothelial cells (ECs) encompassed by pericytes, smooth muscle cells, astrocytes, microglia, oligodendrocytes, and neurons that are collectively called the neurovascular unit (103). As age progresses, there is natural deterioration of the BBB, allowing unwanted pathogenesis and an overall decrease in global cerebral blood flow (104). The BBB is a fundamental element of normal and healthy brain function and deterioration can be used as a biomarker for the normal aging process (105). Furthermore, the dysregulation of nutrients such as glucose consumption may cause metabolic-associated inflammation (106). As age progresses, a natural resistance to insulin develops and causes a general increase in blood glucose levels (107). Changes in plasma glucose levels are associated with altered BBB transport function, integrity, and oxidative stress in the CNS microcapillaries. An example is the increase in type 1 membrane-protein expression which transports amyloid-beta from the blood into the brain, establishing a link between glucose dysregulation and Alzheimer's disease. Hyperglycemia has been associated with progression to cerebral ischemia and enhancement of secondary brain injuries (108).

POCD, similar to the effects of aging, is also believed to be caused by mechanisms such as neuroinflammation and oxidative events, according to preclinical studies (109). Furthermore, the inflammatory hypothesis has been observed in clinical studies, with patients showing elevated levels of pro-inflammatory cytokines in both the CNS and periphery following surgeries such as primary total hip arthroplasty with spinal anesthesia (110, 111). Therefore, the correlation between the aging effects of the BBB's constituent cells and the impact of anesthesia on those cells can yield mechanistic understandings of the causes and effects of POCD. Cells notable for changes in aging are ECs, pericytes, astrocytes, and microglia that result in dysregulation and expression of extracellular components and tight junction proteins (104).

During aging, oxidative stress induces TNF-α production in EC, thereby causing degradation of the basement membrane and tight junctions (112, 113). Loss of capillary ECs has also been implicated during aging, resulting in elongation of the remaining ECs to maintain coverage (114). The upregulation of apoptotic pathways occurs in pericytes through the activity of caspases 3/7 (115) resulting in decreased cell viability (116). Focal pericyte loss induces capillary dilation and disrupts normal flow (117). Subsets of affected capillaries experience reduced perfusion due to flow steal and others are susceptible to stalls in flow and regression, leading to loss of capillary connectivity (118). Furthermore, senile pericytes produce NO which react with O₂ resulting in free radical damage (119). ROS increase results in calcium dysregulation in neurons, repressing calcium-binding proteins and causing further BBB degradation and neuronal loss (120). This oxidative stress triggers astrocytes to upregulate the expression of cytokines and chemokines such as matrix metalloproteinase 3 (MMP3) and p16INK4A (senescence associated secretory phenotype SASP) that induce neuroinflammation, increased permeability, and ultimately BBB disruption (121).

Once aging has impacted the integrity of the BBB, blood-derived proteins such as fibrinogen and plasminogen cross more readily. Pro-inflammatory fibrin aggregates in the brain, binding CD11b/CD18 and repolarizing microglia to a pro-inflammatory M1 phenotype, leading to further inflammation and neurodegeneration (122, 123). Primed microglia produce exaggerated and prolonged IL-6 activity, leading to a positive feedback loop in M1 activated microglia (124). This is a theme seen in aging microglia-hypersensitivity to inflammatory stimuli. This can further be attributed to the limited repopulating capacity of microglia and therefore increased number of aged microglia population and resulting overload of work due to the decreased number (125). Consequently, there are changes in several immune checkpoints resulting in increased immune vigilance along with dysregulated phagocytosis (126, 127). An increase in neurotoxic substances and reduced ability to phagocytose toxic debris and proteins results in apoptotic bodies, misfolded protein aggregates, and myelin—hallmarks of age-related neurogenerative diseases (128–130).

Anesthetic effects on the blood brain barrier

The effects of anesthetics such as isoflurane, sevoflurane, and desflurane have been previously studied (131–133). Globally, aging can cause dysregulation of glucose consumption and metabolism, leading to exacerbation of secondary brain injuries and Alzheimer's disease. Sevoflurane has been shown to induce iron overload and inhibit oxygen and glucose absorption rates by downregulating GLUT1 transporters in the cerebral endothelial cells (134). The combination of the natural insulin resistance seen in aging and the effects of anesthetics such as sevoflurane may lead to cumulative exacerbation of metabolism dysregulation. When looking at the effects of anesthesia on the BBB, it is important to account for the inflammatory effects of surgery itself. Surgery induces inflammatory processes both locally and systemically. The release of cytokines such as IL-1 and TNF-α from ECs and microglial activation following surgery can trigger cascades that increase BBB permeability (135). Earlier, it was discussed that intravenous drugs, such as propofol, may be relatively beneficial with regard to POCD incidence compared to inhaled anesthetics, especially in the first month of recovery. A mechanism through which this may be explained is propofol's phenol-based structure and anti-inflammatory effects (136). These anti-inflammatory effects may be explained in part due to suppression of prostaglandin E2 and leukotriene production, thereby attenuating the probability of POCD pathogenesis (137, 138).

The common initial mechanism believed to initiate damage of the BBB is limited ischemia due to sedation (139). Through scanning electron microscopy, it has been shown that sevoflurane and isoflurane can induce the death of brain ECs resulting in focal BBB breakdown (140). This was especially prevalent in the vicinity of BBB-associated tight junctional folds and appeared to be the first indication of cell death. The integrity of the BBB was studied through immunohistochemistry staining for immunoglobulin G, and recovery after 24 h was not observed. Of note, after 24 h, brain ECs in young and middle-aged animals appeared more comparable to controls than those of older animals, continuing the correlation between age and BBB integrity (140).

Employing dextran-tracer injection to reveal BBB formation and function, laparotomy under 1.4% isoflurane anesthesia was shown to induce BBB dysfunction as evidenced by increased permeability to 10-kDa dextran postoperatively in the brain tissues of 18-month-old mice compared to 9-month-old mice (141). The above findings were shown in conjunction with increased IL-6 signaling and attenuation with IL-6 knock-out, indicating an IL-6 dependent pathway. This highlights the significance of IL-6 increase in the brain with age and its effects on microglia (124). Regarding IL-6, microglia are the most potent secretory cells and targets for cytokines (130). This study demonstrated that anesthetics modulate microglial activation in a time and dose-dependent manner. Data show that MHC-II plays a role in microglial hypersensitivity and indicates that IL-6 significantly contributes to the microglia-induced exaggeration in neuroinflammation in aged mice following peripheral immune stimulation (142, 143). IL-6 is the main cytokine in producing classically activated M1 microglia, shown to induce inflammation and destruction of the BBB (124). In an established sevoflurane-induced neurotoxicity (SIN) animal model, prolonged anesthesia triggered the activation of NF-kB inflammatory pathway, neuroinflammation, inhibition of neuronal excitability, cognitive dysfunction, and anxiety-like behaviors (29). Specifically, RNA sequencing focused on the neuromorphopathological factors of SIN showed microglial migration, activation, and phagocytosis to be enhanced. Feng et al. found that C1qa and C3 were increased, and C1qa tagging of synapses was also elevated. These activated microglia are shown to be engulfing the hippocampus after prolonged anesthesia, destroying synapses in the area. A specific consequence was the reduction of dendritic spines and a downregulation of genes coding for glutamatergic, cholinergic, dopaminergic, and GABAergic synapses. Propofol as an intravenous anesthetic may be beneficial compared to inhalation anesthetics in offsetting these events as exposure has been shown to not be cytotoxic to macrophages and ELISA revealed significantly reduced levels of LPS-induced TNF-α, IL-1β, NO, and IL-6 biosynthesis by these same cells (144).

A study using two- and six-month-old mice showed that anesthesia and surgery could exacerbate and mirror the results of aging on pericytes (116). CD13- and lectin-positive brain capillary distribution was examined using immunostaining to visualize brain pericytes. The results were decreased hippocampal pericyte coverage and capillary length in old mice compared to younger mice. A Pearson correlation analysis showed degeneration of brain capillaries in the hippocampus of aged mice was closely related to insufficient numbers of pericytes.

The few studies on anesthetics and their effects on astrocytes have been contradictory. Astrocytes are crucial to the emergence from anesthesia through mitochondrial complex 1 function (145). Loss of function of the complex I gene, Ndufs3, confers a profound hypersensitivity to volatile anesthetics (145). Further studies utilizing transgenic in vitro and in vivo models can shed light on anesthetic hypersensitivity involving astrocytes.

Reactive oxygen species effects on the blood brain barrier

Free radicals can be a causative factor in weakening BBB integrity (104). Following surgery, reperfusion injury in tandem with anesthesia-mediated ROS release may further weaken the BBB (146). Furthermore, calcium dysregulation in aging neurons leads to elevated ROS levels (120). Inflammation in the CNS is a major driver of local production of oxidative species, primarily through activity of the microglial proinflammatory phenotype (147). The result is a cumulative BBB insult and leakiness that may promote POCD pathogenesis (148). Thus, damage to the BBB may be a common denominator when examining the effects of ROS in aging and the incidence of POCD due to anesthesia and reperfusion injury.

During sedation, acute hypoxia in ECs and the consequent reperfusion and re-oxygenation produce active metabolites and resulting chemotactic mobilization (139). There is recruitment of activated neutrophils which coagulate with the ECs. More neutrophils adhere to the endothelium of post-capillary venules, causing damage with the release of proteolytic enzymes such as elastase, collagenase, β-glucuronidase, N-acetyl-β-glycosamindase, free radicals, and leukotrienes (149–151). These enzymes have been shown to contribute to general injury of the central and peripheral nervous system postoperatively in addition to more specific pathologies associated with POCD such as Alzheimer's Disease (AD), multiple sclerosis, and dementia after HIV-1 infection (152, 153).

Anesthesia and aging regarding age-related disorders

POCD may have a role in aggravating age-related disorders such as dementia, anticholinergic crisis, and AD. About 8.5 million AD patients need surgery each year (154). In those greater than 80 years of age, general anesthesia was associated with a greater risk of developing AD (155). An inverse correlation has been shown between the age of AD onset and cumulative exposure to general and spinal anesthesia before the age of 50 (156). Research has shown significant links between POCD and delirium, central anticholinergic syndrome, dementia, and akinetic crisis (4). The central cholinergic system plays a role in regular cognitive functioning; inhibition of these muscarinic and nicotinic receptors has been shown to contribute to learning and memory deficits associated with delirium (157). General anesthetics may potentially modulate cognitive function, especially by inhibiting the function of nAChRs. Imaging studies have shown that age-related increases in BBB disruption occur especially in regions most vulnerable to age-related deterioration, indicating that BBB disruption is an underlying mechanism of normal age-related decline (105, 158). Significantly increased BBB permeability along with mild cognitive impairments is often considered the transition state to AD (159). Nation et al. demonstrated that older patients showing early cognitive dysfunction had increased BBB permeability compared to those with no cognitive impairment, even in the absence of any diagnosed neurological or psychiatric condition (160).

The most significant risk factor for vascular-based neurocognitive disorders is aging, with more than 50% of the US population over the age of 80 suffering from AD or vascular disease (VaD) (106). In vitro and in vivo studies have shown that pro-inflammatory cytokines TNF-α and IL-1β down regulate the expression of tight junction proteins occluding-1, claudin-5, ZO-1, and ZO-2 (161). In natural aging, human brain ECs produce complement regulatory proteins, which become elevated during CNS injury or increased permeability/damage of the BBB (162). Normally, the BBB prevents complement protein and components from entering the CNS, but as age progresses, permeability increases, and complement alters the function of microglia, oligodendrocytes, and neurons (163). Again, this permeability can also be seen in POCD. Byproducts of the complement system, C3a and C6a, increase recruitment of inflammatory cells into the brain and the induction of cytokine cascades (IL-1, TNF-α, IL-6, IL-8, IL-17) (135, 164). This has been shown to be associated with AD pathogenesis, as complement binding to amyloid-beta (Aβ) results in pathological amyloid plaques (165). Another blood protein mentioned earlier that is allowed to pass the BBB is fibrinogen (123). Fibrinogen has been shown to contribute to the formation of amyloid plaques along with the cytokines mentioned above.

It has been proposed that the pathological mechanisms underlying POCD mimic that of AD disease (116, 124, 139). The previously reviewed mechanisms behind aging and AD have shown that many of the mechanisms are not only similar, but cumulative. Aggregated Aβ is the main constituent of amyloid plaques found in the brain of AD patients. Different studies have shown the ability of anesthetics to promote the oligomerization of Aβ peptide, supporting a potential link between anesthesia and the acceleration of Aβ-related toxicity (155).

Additionally, isoflurane has been shown to cause mitochondrial dysfunction through opening the mitochondrial permeability transition pores (mPTP) (154). When the mPTP are more readily opened through isoflurane, Zhang et al. (154) observed memory and learning deficits corroborated with a reduction in ATP and mitochondrial membrane potential and an increase in apoptosis marker caspase–3 (154). These mitochondrial dysfunctions have further been associated with AD pathogenesis (154). Isoflurane has also been shown to decrease cognitive performance and responsiveness in wild type animals compared to control, and increase mortality, apoptosis, and Aβ aggregation (166).

Mechanistic effects of anesthesia on neuroinflammation

Regional and local anesthesia

Regional and local techniques are utilized to induce analgesia and hypoesthesia at a surgical site without affecting the level of consciousness in a patient. They differ mainly in the site of application, with regional anesthesia being applied at a distance from the surgical site and local anesthesia being directly at a nearby nerve (167). The main types of regional anesthesia include neuraxial anesthesia, which includes epidural and subarachnoid blocks, peripheral nerves blocks and intravenous regional anesthesia (168). Local anesthesia is generally administered topically or subcutaneously, however it may be given orally in certain procedures as well (169). Drugs commonly used in local and regional anesthesia include amino amides and amino esters, both which act on voltage-gated sodium channels to block nerve signal transmission. They differ most significantly in their metabolism such that amino amides are hydrolyzed in the liver and amino esters are metabolized by plasma cholinesterases (169).

Amino amides frequently used in practice such as lidocaine, bupivacaine and ropivacaine have been shown to exhibit direct suppressive effects on microglia and astrocyte related inflammation. In one in vitro study of microglia clone cells from rat cerebella, researchers induced damage through incubation with LPS and IFN-γ in the presence or absence of lidocaine (170). The researchers found attenuated levels of LDH in the samples treated with lidocaine, which was correlated with decreased microglial activation and injury (170). Su et al. also performed an in vitro study on rat microglia, however they instead highlighted the effect of lidocaine on the production of inflammatory cytokines in response extracellular ATP-mediated activation of p38 MAPK. Lidocaine was shown to attenuate the transcription and serum levels of TNF-α, IL-1β and IL-6 in the two hours post-administration (171). Studies of bupivacaine yielded similar results, with one animal trial performed by Zhang and Deng also showing a significant reduction of TNF-α, IL-1β and IL-6 production in 32 rats administered complete Freund's adjuvant, a known mediator of inflammation. Additionally, the researchers also found that bupivacaine treatment significantly decreased the expression of the spinal microglial marker OX42 and the astrocyte marker GFAP (172). Lastly, ropivacaine was also found to suppress the activation of microglia and astrocytes through measurements of CD11, a marker of microglial activation, and GFAP in mouse models (173).

There have been mixed reports on the efficacy of lidocaine attenuating POCD incidence rates during cardiac surgery (174–176). However, a potential benefit of lidocaine has been published in the context of laparoscopic colorectal surgery (177). Moreover, regional anesthesia alone or in conjunction with general anesthesia has not been shown to significantly attenuate the incidence of POCD in meta-analyses. Interestingly, one clinical trial including 438 elderly patients found no significant difference in POCD incidence rates three months post-surgery following general or regional anesthesia (178). One meta-analysis of 16 studies found that regional anesthesia showed no difference in cognitive function as opposed to general anesthesia in 13 of the studies, while 3 of the studies produced results slightly favoring regional anesthesia (179). Similarly, another meta-analysis of 7 studies found that regional anesthesia had no significant impact on MMSE testing results at 24 h, three days or seven days post-surgery as opposed to general anesthesia in elderly patients undergoing hip fracture surgery (180). Lastly, a third meta-analysis of 13 studies by Viderman et al., found that regional anesthesia produced no significant difference in cognitive testing at one week and three months post-surgery as opposed to general anesthesia (181). The authors of these meta-analysis highlight several limitations in the literature, such that more research is required for a better understanding of the complex pathogenesis of POCD.

Inhalational anesthetics

Inhalational anesthetics such as isoflurane and sevoflurane have been associated with pro-inflammatory phenotypes in vitro and in vivo (27–35) (Table 1). However, one study revealed a low POCD incidence (1.22%) and no difference in patients who received sevoflurane or desflurane during low-risk surgery (182).

When isoflurane and sevoflurane were compared, it was found that isoflurane depletes calcium from the endoplasmic reticulum (ER) in cerebrocortical and hippocampal neurons while sevoflurane increased calcium concentrations in cortical neurons (183–185). Wei et al. (185) further showed that only isoflurane induced cytotoxicity mediated through a decrease in the Bcl-2/Bax ratio when compared to sevoflurane.

However, the balance of cytotoxicity and cytoprotection may vary in the literature, depending on the experimental conditions. Isoflurane was reported to confer neuroprotection in models of stroke (186). Specifically, isoflurane was shown to protect against oxygen/glucose-deprivation in neurons while increasing transcription of hypoxia inducible factor 1α (HIF1α), Erk1/2, and iNOS (35). Both isoflurane and halothane were even shown to reduce brain damage from focal ischemia in rodent models (187).

Despite the evidence for neuroprotection with isoflurane, sevoflurane, and halothane in ischemia, there is emerging data supporting the association between isoflurane and cognitive impairment in an age-dependent fashion (32). Isoflurane was shown to induce the assembly of a NOD-like receptor protein 3 (NLRP3), forming an inflammasome composed of NLRP3, a caspase recruitment domain (ACS), and caspase-1 (32). As reviewed, this inflammasome mediates the secretion of pro-inflammatory cytokines such as IL-1β and IL-18. Similarly, exposure to sevoflurane has been shown to result in hippocampal microglial activation with elevated IL-1β, IL-6, and TNF-α, mediated through HCN2 channel inhibition (188). Specifically, sevoflurane resulted in downregulation in PEX5R/Trip8b-HCN2 channels in microglia and neurons while causing neuroinflammation in the rodent cortex and hippocampus. A gene enrichment analysis of HCN2 revealed to be associated with “learning and memory, positive regulation of glutamate secretion, regulation of nervous system processes, synaptic processes and transmission, behavior, membrane potential, and negative regulation of sodium ion transport”. Moreover, sevoflurane has been shown to promote microglia M1 polarization through suppression of STAT-6 and inhibition of IL-4 induced M2 polarization (30). Sevoflurane has been shown to induce microglial M1 polarization through release and transfer of neuron exosomes containing lncRNA Gas5 to microglia, which upregulates Foxo3 and activates the inflammatory NF-κB pathway (28). Another mechanism implicated has been increased transcription factor activity of CEBPα which activates the pro-inflammatory HDAC1/STAT3 pathway (27) (Table 1).

Likewise, studies of isoflurane have been demonstrated to upregulate IL-6, TNF-α, IL-1β, along with microglial NF-kB activation (31, 33). The isoflurane-induced model of neuro-inflammation may also be partially explained through activation of TLR4/P38 and TLR4/NF-kB pathways (34) (Table 1).

Ketamine

Ketamine is an NMDA receptor antagonist used as an induction agent for dissociative anesthesia and has been shown to prevent bronchospasms, act as an ionotrope, and even treat major depressive disorder (189–192). The anti-inflammatory characteristics of the (R,S) racemate have been described as early as 1998 (193, 194).

In 1988, Roytblat et al. performed a clinical trial on preoperative 0.25 mg/kg ketamine administration in patients undergoing elective CABG/coronary bypass surgery. The group revealed that patients undergoing CAPG had significantly lower serum levels of pro-inflammatory IL-6 seven days post-surgery with insignificant findings after day seven. Many years later, Beilin et al. (195) studied the effects of ex vivo ketamine administration in the early postoperative period on peripheral blood mononuclear cells (PBMCs). The clinical trial groups either received 0.15 mg/kg of I.V. ketamine or isotonic saline prior to general anesthesia induction. The ketamine-group PBMCs exhibited significantly reduced concentrations of IL-6 4 h post-operatively when compared to the control. IL-2 concentrations appeared unchanged, while TFN-α was significantly elevated in the group 4 h post-operatively (195). However, ketamine-related effects on POCD outcomes have been conflicting from clinical trials performed during cardiac surgery (196, 197). In non-cardiac studies, pre-treatment of sub-anesthetic (0.15 mg/kg) esketamine before gastrointestinal surgery did not result in differences in POCD outcomes at 3-months compared to controls (198).

As reviewed by Zanos et al. (194), the anti-inflammatory characteristics of ketamine were unveiled to result in a reduction of serum NF-κB, C-reactive protein (CRP), iNOS, and IL-6. The anti-inflammatory characteristics of ketamine have also been studied within the context of microglia (42, 41). Specifically, ketamine administration has been shown to induce anti-inflammatory phenotypes in vitro and in vivo (41, 43–45). In one study, Verdonk et al. (199) revealed that ketamine administration to mice caused an upregulation of neuroprotective gene expression along with decreased microglial activation when exposed to pro-inflammatory LPS, as seen through a decrease in the microglial cell body area (199) (Table 1). Interestingly, these morphological changes were only seen in pre-frontal, not hippocampal regions. The mechanism of the anti-inflammatory effects on microglia was revealed to be through a downregulation of heme oxygenase-1 (HO-1) gene expression along with a complex interplay with quinolinic acid, tryptophan, and kynurenine metabolism.

Recent research on ketamine in the prevention of POCD has revealed an overall benefit of ketamine utilization on attenuation of negative effects of anesthesia. One randomized, placebo controlled, double-blind clinical trial sought to study the utilization of ketamine in preventing POCD and delirium in 182 adult patients (200). The researchers found that neither ketamine, haloperidol, or a combination of the two provided superior results over the placebo group in preventing POCD and delirium via measurements of serum cortisol, neuron specific enolase and S100beta (200). Another randomized controlled trial studied the neuroprotective effects of ketamine and dexmedetomidine in reducing POCD in 90 patients aged 65–85 years old undergoing cataract extraction surgeries. In comparison to the placebo group, ketamine and dexmedetomidine groups experienced a significant reduction in POCD development (p < 0.0001) via neuropsychological testing at 1 week and 3 months post-surgery (201).

The research does show some mixed results, however. One single-center randomized placebo-control trial studied the effect of the intraoperative infusion of S-ketamine in 120 patients aged 45–65 undergoing thoracoscopic surgery (202). The patients were split into three groups: patients receiving general anesthesia (C), patients receiving general anesthesia and ultrasound-guided paravertebral block (TP) and the patients receiving general anesthesia, ultrasound-guided paravertebral block, and perioperative s-ketamine. In comparison to the C and TS groups, researchers found that the TP group scored higher (p < 0.05) on a Mini-Mental State Examination (MMSE) at 1-day post-operation and that there was no significant difference in the three groups at 3 months post-operation. This led researchers to conclude that intraoperative ketamine did not significantly benefit neurocognitive function postoperatively (202). Lastly, one meta-analysis on intraoperative ketamine administration to prevent POCD reviewed six randomized controlled trials studying its beneficial effects (203). Only three trials showed any significant reduction of risk from ketamine administration, leading researchers to conclude that the quality of evidence for ketamine as an agent to prevent POCD (203).

Propofol

Propofol, a commonly used GABA_A agonist, increases Cl⁻ conduction, hyperpolarizes neurons, decreases cerebral metabolic rate, and has been shown to inhibit in vitro and in vivo microglial M1 polarization (36, 204). In 2023, Guan et al. discovered that propofol is neuroprotective and prevents hippocampal inflammation and microglial metabolic reprogramming through HIF-1α regulation and ROS/PI3K/Akt/mTOR/HIF-1α signaling septic mouse models. Moreover, Huang et al. (26, 205) found that prophylactic propofol before LPS administration reduced microglial M1 polarization. However, TNF-α remained elevated in the hippocampus during the experiments. As reviewed, the anti-inflammatory effects of propofol in microglia may be mediated through GSK-3β inactivation, NADPH oxidase, and NMDA receptor inhibition, and TLR4 downregulation (36–40). Moreover, propofol has been shown to inhibit microglia reprogramming and reduce LPS-induced expression of iNOS, NO, TNF-α, IL-1β, and COX-2 in microglia (36) (Table 1).

There are varying reports on the effects of propofol on POCD outcomes during cardiac and non-cardiac surgery, as described in Table 2 (197, 206–210). Evidence suggests that propofol administration might induce a lower incidence of POCD in comparison to other anesthetics and may offer some neuroprotective benefits during non-cardiac surgery (208, 209). Conversely, propofol used in combination with etomidate has been shown to lower POCD incidence while other studies have shown no difference in outcomes when propofol is compared to sevoflurane (210, 213, 217). During cardiac surgery, however, propofol was shown to be associated with a higher incidence rate of cognitive dysfunction when compared to desflurane and sevoflurane (206, 207).

Table 2

Table 2. Clinical POCD studies on the effects of various anesthetics during cardiac- and non-cardiac surgery.

One randomized controlled preliminary trial researched the effects of propofol, dexmedetomidine, and midazolam on POCD in elderly patients. The study of 164 patients aged 65 years or older undergoing hip or knee arthroplasty split the subjects into three groups given one of the three anesthetic agents with combined spinal-epidural anesthesia. Subjects were asked to complete neuropsychological tests before, 5 days after, and 1 year after surgery. The results showed that propofol had an advantage as compared to the other groups in terms of POCD incidence (209). Another double-blind, randomized control trial researched the incidence of POCD in patients given propofol, isoflurane or sevoflurane. This study of 150 patients aged 60 and older undergoing laparoscopic cholecystectomy found that the incidence of POCD was lower in the propofol group (208). One meta-analysis unveiled propofol as an optimal treatment option for lowering POCD incidence rates in non-cardiac surgery when compared to inhalational anesthetics (219). POCD in non-cardiac surgical patients given inhalational and propofol anesthetics. They reviewed 15 randomized control trials with 1,854 patients while examining MMSE scores, TNF-α levels, and IL-6 levels in patients post-surgery. The researchers found that propofol was superior to inhalational anesthesia at attenuating POCD (219). Lastly, one research group employed a meta-analysis to review 34 clinical trials in 4,314 patients to study the POCD incidence rates with a variety of anesthetic agents in a geriatric, noncardiac surgery cohort (220). Specifically, propofol, dexmedetomidine, sufentanil, and placebo POCD incidence rates were found to be 16.8%, 12.9%, 6.3%, and 27.7%, respectively (220). These rates appear starkly different when compared to sevoflurane (24.0%), desflurane (28.3%), and fentanyl (23.9%) (220). The researchers concluded that propofol, along with dexmedetomidine and sufentanil, attenuated incidence of POCD (220).

Opioids

Opioid administration may provide selective neuroprotection with anti-inflammatory effects on microglia (15, 221, 222) (Table 1). However, studies on the direct effects on glia have been inconsistent (223).

In 2000, Zhang & Xia revealed that opioid agonism at the δ-receptor, but not μ- and κ-opioid receptors, resulted in neuroprotection against models of neuronal excitotoxicity. Rat neocortical neurons were cultured, exposed to glutamate or co-administrations with glutamate and opioid agonists, and were assayed for markers of cellular injury using lactate dehydrogenase. Interestingly, the glutamate-mediated excitotoxicity appeared age-dependent, as eight-to-ten-day old neurons displayed markers of cell injury whereas the four-day neurons did not. Iwata et al. (222) corroborated these findings but found that δ-receptor agonism promoted survival in hippocampal CA3 and dentate gyrus (DG) neurons but not CA1 neurons.

In 2022, Mali & Novotny reviewed the efficacy of μ-, δ-, and κ-opioid receptor agonists on microglial polarization. The review indicated that opioid agonism may result in an M2 polarization in microglia in vitro, evidenced through inhibition of NO production in microglia exposed to pro-inflammatory lipopolysaccharide (LPS). The authors highlighted the work of Merighi et al. (13) focused on the mechanism of opioid-mediated M1 polarization (13). The study revealed that the phenotype change is mediated through TLR4/NF-κB inhibition and TREM2 activation. Addition of the opioid agonists also contributed to morphological changes such as lengthening of microglial processes, indicative of a “resting” phenotype (15). Within the study of hyperalgesia, it was revealed that morphine activated μ-receptors in spinal cord-derived microglia which resulted in BDNF/P2X4 disinhibition (223, 224). Moreover, cell culture models of dose-dependent morphine exposure (0.1 nM–1 µM) resulted in anti-inflammatory phenotypes such as a decrease in microglia chemotaxis (14) (Table 1).

However, it should be noted that studies of chronic opioid administration resulted in the opposite effects (225–227). M1 microglia exposed to opioid agonists after LPS treatment were shown to enhance the release of pro-inflammatory NO, IL-6, TNF-α, and IL-1β via activation of the Akt pathway (13). Specifically, the morphine was mediating the phosphorylation and translocation of PKC_ε isoforms which regulated Akt and ERK1/2 phosphorylation. However, the experimental groups did not include an “opioid-only” administered group and only included no drugs, LPS, and LPS co-administered with morphine. The studies demonstrating both neuroprotection and inflammation in microglia may be dose dependent, but nonetheless shed light on models of opioid administration to already-inflamed microglia.

Basic science investigations into the effects of fentanyl revealed pro-inflammatory physiological consequences in vitro and in vivo (10–12). Pro-inflammatory IL-1β, TNF-α, and IL-6 were found to be upregulated in spinal cord of rats following surgery and 60 μg/kg fentanyl administration (10). Higher doses of fentanyl (0.1 mg/kg) along with 10 mg/kg morphine administration were found to cause pro-inflammatory phenotype changes resulting in NLRP3 inflammasome formation in dorsal raphe nucleus glia and neurons in rats (11). Cell culture models in U937 cells revealed that morphine, but not fentanyl, inhibited TNF-α release following LPS incubation (12) (Table 1).

Clinical investigations into fentanyl have shed light on its use and associations with POCD. One randomized controlled trial researched the effect of high and low dose fentanyl anesthesia on POCD in the elderly (212). The study of 350 patients aged 55 and older undergoing coronary artery bypass graft surgery were randomized into either a low dose fentanyl group (10 µg/kg) or a high dose fentanyl group (50 µg/kg). Each group completed a group of 8 neuropsychological tests during the week before surgery, 1 week after surgery, 3 months after surgery and 12 months after. The researchers concluded that there was no evidence of an association between high-dose fentanyl and POCD at 3 or 12 months after surgery. However, low dose fentanyl was associated with increased incidence of POCD at 1 week after surgery. One meta-analysis investigated anesthetic drugs and their ability to prevent POCD in elderly patients (220). This study involved a total of 34 trials with over 4,314 patients undergoing noncardiac surgery. The researchers found that fentanyl significantly increased the incidence of POCD when compared to sufentanil, however it showed non-significant ability to reduce the incidence of POCD when compared with a placebo group (220).

Moreover, there appears to be a difference in opioid-related POCD outcomes; these observed incidences may be due, in part, to opioid dosing and dose scheduling in acute and chronic settings. The difference in observed outcomes may also be due to the difference in binding affinities for the various opioid receptors.

Paralytics

Succinylcholine, vecuronium, rocuronium, and cisatracurium are commonly used paralytics during surgery. However, neuromuscular paralytic agents normally do not cross the BBB—except in certain circumstances (228, 229). In 1977, Matteo et al. found d-tubocurarine in the CSF of patients undergoing craniotomy for arteriovenous malformations, pituitary tumors, and cerebral aneurysms post-IV administration of the neuromuscular blocker (229, 230). Similar findings were reported, where atracurium and its metabolite, laudanosine, were found in the CSF of patients undergoing intracranial surgery (229, 231). As reviewed, neuromuscular blockers may cross the BBB in a dose-dependent fashion in critically ill patients. Neurotoxic effects may ensue if the neuromuscular blockers cross the BBB; the resulting effects involve excitotoxicity through an increase in intracellular calcium (229, 232, 233).

Benzodiazepines

Benzodiazepines are GABA-ergic compounds used as sedative agents used that can also reduce myoclonic movements and anxiety while promoting amnesia (204, 234). Midazolam is preferred perioperatively with later use of diazepam and lorazepam (204). Chronic models of diazepam treatment in mice have been shown to target mitochondrial 18 kDa translocator protein (TSPO) in microglia which results in the clearance of synaptic material and dendritic spines and by extension, contributes to cognitive dysfunction (20). However, in more acute models, midazolam has been shown to have anti-inflammatory effects on microglia exposed to LPS (235) (Table 1).

Through interactions at TPSO receptors, midazolam treatment has been shown to reduce LPS-induced NO and TNF-α release from rat microglia (16). Midazolam has also been shown to reduce IL1-B-induced IL-6 release in rat C6 glioma cells through the suppression of STAT3 activation and inhibit IL-1β and IL-18 release in BV-2 mouse microglial cells through the inactivation of the NLRP3 inflammasome (17, 18) (Table 1). Human data regarding the association of midazolam with POCD provides mixed results. In one randomized control trial by Li et al., the researchers found that midazolam impaired subjects' ability to complete a battery of neuropsychological testing compared to a control group at one-week and one-year post-surgery (210). Another randomized control trial by Mansouri et al. found that midazolam improved subjects' scores on an MMSE as compared to a control group undergoing general anesthetic at one-week post-surgery (236). The limitation of this study is that researchers only examined the short-term effects of cognitive function, hence more data is required to know if the reduction in POCD is long-lasting. One meta-analysis reviewed 34 studies involving elderly patients undergoing noncardiac surgery with varying anesthetics and found that midazolam conferred no significant benefit over placebo groups in reducing the incidence of POCD (220).

Diazepam is another benzodiazepine that is also utilized for its sedative and hypnotic properties for the induction of anesthesia. Diazepam acts at TSPO receptors similarly to midazolam in that it reduces the release of proinflammatory cytokines, NO and CD40 cell expression when exposed to inflammatory stimuli such as LPS (19). The exact mechanism of diazepam's reduction of neuroinflammation is unknown, however Fernandez et al. cites an increased production of glucocorticoids from the adrenal cortex, increased synthesis of neurosteroids from microglia and direct actions on peripheral immune cells as possibilities to be explored. Interestingly, studies in mouse models found that acute diazepam administration had no impact on the number and morphology of microglia or the density and formation of dendritic spines. Shi et al. also found that chronic models of diazepam treatment actually impaired the clearance of synaptic material and the structural plasticity of dendritic spines, which may contribute to impairments in spatial memory and long-term potentiation (20, 237) (Table 1). From this data, it seems plausible that the use of diazepam in surgical procedures would not be sustained enough to elicit substantial negative effects on cognition. Regardless, there is a lack of clinical human data regarding the effect of diazepam on POCD. One study conducted by Rasmussen et al., found that neither diazepam nor its metabolites were responsible for any deficits in cognitive functioning at one-week post-surgery (238). This study may be limited, however, due to a small sample size (n = 35).

Ketorolac

Ketorolac, a non-steroidal anti-inflammatory drug (NSAID), elicits a response of analgesia through inhibiting both cyclooxygenases 1 & 2 (COX1/2) and by extension, inhibition of prostaglandin, prostacyclin, and thromboxane synthesis (239, 240). While studies are limited, Shen et al. (21) showed that ketorolac treatment can prevent sevoflurane-induced cognitive dysfunction in young mouse models of anesthesia-mediated cognitive dysfunction (21) (Table 1).

Dexmedetomidine

Dexmedetomidine is a selective α2A adrenergic receptor agonist utilized as an anesthetic adjuvant for the induction and maintenance of anesthesia (241). Its sedative-hypnotic effects are believed to be mediated by pre- and post-synaptic α2A receptor activity in the locus coeruleus (242).

Cell culture and animal models of dexmedetomidine administration revealed anti-inflammatory phenotype effects (22–25, 243). Experiments utilizing in vitro BV-2 microglia revealed that dexmedetomidine incubation resulted in an increase in M2 polarization mediated through an increase in Akt phosphorylation (22). Another identified mechanism of anti-inflammatory microglial polarization has been through an increase in Nrf2/HO-1 signaling resulting in inhibition of NLRP3 inflammasome activation (23). When treating mice exposed to sevoflurane, 25 μg/kg dexmedetomidine administration was found to attenuate CEBPB-mediated microglial inflammatory phenotypes (24). In a similar study, mice treated with 40 ml/kg dexmedetomidine (3.3 μg/ml) prior to LPS injection resulted in a decrease in microglial activation and in oxidative stress markers when compared to 10 ml/kg of propofol (3 mg/ml) (26). Combined in vivo spinal cord injury and in vitro models of dexmedetomidine exposure showed an increase in microglial anti-inflammatory phenotypes following treatment (25) (Table 1).

The current research suggests the dexmedetomidine may attenuate perioperative neuroinflammation and immunosuppression, thereby potentially reducing the incidence of POCD. In 2019, Wang et al. performed a meta-analysis of 67 studies, which demonstrated that dexmedetomidine is associated with a reduced secretion of epinephrine, norepinephrine, cortisol, and blood glucose via suppression of the hypothalamic-pituitary-adrenal axis. The study also highlighted a significant decrease in the concentration of pro-inflammatory cytokines such as IL-6, TNF-α, CRP, IL-b and Il-8, which may be attributed to direct modification of cytokine production from macrophages and monocytes (241). Lastly, dexmedetomidine attenuated immunosuppression following surgery through increased activity of natural killer cells and a higher ratio of CD4 to CD8 T cells and Th1 to Th2. During cardiac surgery, dexmedetomidine was associated with improved POCD outcomes when compared with midazolam-only groups (211). Similar outcomes were observed in the context of non-cardiac surgery (214). Dexmedetomidine has also been shown to be associated with lower POCD incidence rates compared with elderly patients treated with propofol during hip arthroplasty (218). Zeng et al. performed a similar meta-analysis of dexmedetomidine in 2023, which also included data on MMSE testing of post-operative patients to evaluate cognitive functioning (220). The researchers found that there was a significant reduction in POCD occurrence at 12 h, 24 h and 72 h post-surgery (244). Another meta-analysis focused solely on cognitive function, which was evaluated through MMSE testing of post-operative elderly patients, found that dexmedetomidine had a preventative effect on the incidence of POCD (245). While these studies are promising, the evaluation of dexmedetomidine on POCD and neuroinflammation is generally limited to the immediate post-surgical period; therefore more research needs to be done to elicit if these effects are more long-lasting.

Targeting the neuro-immune axis

Several groups have examined pharmacotherapies for POCD in basic science models. Peng et al. (246) utilized metformin as a potential treatment option for isoflurane-induced cognitive dysfunction in vivo (246). The research group utilized a sub-minimal alveolar concentration (MAC) of 1.3% isoflurane to induce cognitive dysfunction in murine models (246). Intraperitoneal injections of metformin resulted in inhibition of M1 polarization in both hippocampal microglia and A1-like astrocytes and subsequent alleviation of cognitive dysfunction (246).

Cibelli et al. probed treatment of experimental POCD using minocycline, an antibiotic with anti-inflammatory properties (247, 248). The group demonstrated that intraperitoneal minocycline injections (40 mg/kg) prevented surgery- and anesthesia-induced behavioral impairment, ameboid morphological changes in microglia, and upregulation of hippocampal IL-1β in mouse models (248).

Celecoxib, a COX-2 inhibitor, has been shown to decrease early incidence of POCD in a geriatric cohort (249). Compared to the control group, patients receiving celecoxib also had decreased plasma levels of COX-2, IL-1β, IL-6, TNF-α, and S100β (249). Wang et al. also demonstrated that inhibiting COX-2 using parecoxib resulted in diminished hippocampal IL-1β, IL-6, TNF-α, and PGE-2 in rodent models (250). A meta-analysis on parecoxib efficacy revealed that treatment with the COX2 inhibitor resulted in lower levels of IL-6 and S100β within 2 days of surgery (205). Kamer et al. (251) studied another COX2 inhibitor, meloxicam, in a mouse model of surgery-induced neuroinflammation. This group found that 60 mg/kg i.p. administration of meloxicam 24 h post-splenectomy using 2.5% and 3.0% isoflurane in rats resulted in decreased glial activation and improved object recognition compared to controls (251). While studying the effect of steroids and general anesthesia on POCD and S100β, Valentin et al. (215) revealed that a single low dose of dexamethasone before noncardiac/non-neurological surgery can attenuate POCD in elderly patients (215). A similar study showed similar results using magnesium sulfate in tandem with general anesthesia in patients undergoing elective laparoscopic cholecystectomy (216).

NDMA receptor antagonism

Overactivation of NDMARs can contribute to POCD through dendritic spine loss and apoptosis mediated through activated calpain, a calcium dependent protease, and dysregulated BDNF/TrkB signaling (252). Memantine and MDL-28170, an NDMAr antagonist and calcium-dependent protease inhibitor, respectively, have also been shown to decrease elements of postoperative cognitive dysfunction in murine models (252). Qiu et al. administered intraperitoneal injections of 20 mg/kg of memantine or MDL-28170 to mice prior to isoflurane exposure and post-exposure daily for 5 days (252). Treatment with memantine attenuated isoflurane and surgery-induced microglial and astrocyte inflammation in the hippocampus (252). IL-1β and IL-6 were also decreased in 1- and 8-days post-surgery analysis of hippocampal proinflammatory cytokines following memantine treatment (252). Dendritic spine loss in the CA1 region was also attenuated following the memantine and MDL-28170 administration (252). Surgery- and anesthesia-induced cognitive impairments and cell apoptosis were further attenuated by administration of either the NDMAR or calpain inhibitor (252).

Calcium channel antagonism

Wei et al. (185) utilized dantrolene, a ryanodine receptor antagonist, to suppress isoflurane-mediated cytotoxicity in vitro (185). In this experimental model, isoflurane was shown to deplete calcium from the muscle sarcoplasmic reticulum (185). Similarly, isoflurane was shown to induce calcium release from the endoplasmic reticulum (ER) in hippocampal and cerebrocortical neurons (184). However, cytotoxicity and apoptosis were significantly decreased when cortical neuronal cultures were pretreated with 30 µM dantrolene before 24 h exposure to 2.4% isoflurane (185).

Nimodipine, a second generation 1,4-dihydropyridine calcium channel blocker, has also been shown to have therapeutic effects in rodent models of POCD (253–255). Nimodipine administration partially restored abhorrent expression of IL-6, IL-8, caspase-3, and TNF-α when administered with sevoflurane (253).

α₂-Adrenergic receptor agonism

Dexmedetomidine has been shown to have neuroprotective effects in models of sevoflurane-induced cognitive decline through targeting CCAAT/enhancer binding protein beta (CEPBPB) and activating the c-Jun N-terminal kinase (JNK)/p-38 (24). Through JNK/p-38 activation, dexmedetomidine suppresses M1 microglial polarization and reverses neuronal injury in the setting of sevoflurane-exposure (24).

Dexmedetomidine has also demonstrated anti-inflammatory properties in microglial polarization and in patients with resections of gastric cancer (22, 23, 25, 256). In a randomized control study, dexmedetomidine lowered serum levels of IL-6, IL-8, IL-10, TNF-α, and C-reactive protein (CRP) in patients undergoing intestinal surgery (77). These intestinal surgery patients also had improved cognitive recovery and an improved stress response following intravenous dexmedetomidine administration (77). Interestingly, dexmedetomidine has also been shown to serve as a potential “glympathic enhancer” by increasing clearance of rodent intraparenchymal glymphatic tracers (257). This is of emerging importance because reduced sleep quality hinders CSF flow, which can lead to neurodegenerative changes through a reduction in clearing metabolic waste such as lactate and amyloid-β (257). It may be possible that dexmedetomidine may have a therapeutic role by enhancing CSF flow and glymphatic clearance following surgery and anesthesia—especially given the evidence of isoflurane impairing glymphatic flow (257, 258). The lack of GABAergic or cholinergic property are particularly beneficial since this may carry an increased risk of developing delirium (242, 257).

Conclusions and future directions

While the definition of POCD appears to vary, it may be defined as an iatrogenic post-operative neuro-inflammatory state affecting primarily older individuals. The diverse pharmacological arsenal available in the operating theater especially requires attention to agents with potential pro-inflammatory effects. The role of polypharmacy of anesthetic cocktails should also be investigated further. While polypharmacy experimental investigations may be complex, in vitro experiments may provide insight into the complex drug-drug interactions of cell-cell interactions, morphologies, and gene expression patterns. The synergistic effects on known inflammatory and anti-inflammatory pathways should be assessed with a focus on a drug's binding affinity if common drug targets are shared. In all, it appears there may be pro-inflammatory consequences from inhalational anesthetics while agents such as ketamine, opioids, propofol, ketorolac, and benzodiazepines may confer protection against inflammatory phenotypes within the CNS. Experiments regarding prophylaxis and post-operative pharmacotherapy should be explored further within the context of cardiac and non-cardiac surgery.

Author contributions

GS: Conceptualization, Investigation, Writing – original draft, Writing – review & editing. NS: Conceptualization, Investigation, Writing – original draft, Writing – review & editing. TC: Conceptualization, Investigation, Writing – original draft, Writing – review & editing. BA: Conceptualization, Investigation, Writing – original draft, Writing – review & editing. JG: Supervision, Writing – review & editing.

Funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article.

This study was funded by the Touro College of Osteopathic Medicine Harlem Campus Department of Research.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher's note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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