Intranasal Insulin Administration To Prevent Delayed Neurocognitive Recovery And Postoperative Neurocognitive Disorder Part 1

Abstract

Delayed neurocognitive recovery and postoperative neurocognitive disorders are major complications of surgery, hospitalization, and anesthesia that are receiving increasing attention. Their incidence is reported to be 10–80% after cardiac surgery and 10–26% after non-cardiac surgery. Some of the risk factors include advanced age, level of education, history of diabetes mellitus, malnutrition, perioperative hyperglycemia, depth of anesthesia, blood pressure fluctuation during surgery, chronic respiratory diseases, etc. Scientific evidence suggests a causal association between anesthesia and delayed neurocognitive recovery or postoperative neurocognitive disorders, and various pathophysiological mechanisms have been proposed: mitochondrial dysfunction, neuroinflammation, increase in tau protein phosphorylation, accumulation of amyloid-β protein, etc. Insulin receptors in the central nervous system have a non-metabolic role and act through a neuromodulator-like action, while interaction between anesthetics and central nervous system insulin receptors might contribute to anesthesia-induced delayed neurocognitive recovery or postoperative neurocognitive disorders. Acute or chronic intranasal insulin administration, which does not influence blood glucose concentration, appears to improve working memory, verbal fluency, attention, recognition of objects, etc., in animal models, cognitively healthy humans, and memory-impaired patients by restoring the insulin receptor signaling pathway, attenuating anesthesia-induced tau protein hyperphosphorylation, etc. This review aims to report preclinical and clinical evidence of the implication of intranasal insulin for preventing changes in the brain molecular pattern and/or neurobehavioral impairment, which influence anesthesia-induced delayed neurocognitive recovery or postoperative neurocognitive disorders.

Keywords

intranasal insulin; postoperative cognitive dysfunction; neuroprotection; Cistanche benefits.

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Introduction

The nomenclature of postoperative cognitive dysfunction (POCD) is not defined in the Diagnostic and Statistical Manual of Mental Disease (DSM-5), and this has been associated with limitations such as an inconsistent definition and consequently recognition by nonanesthesia specialists [1,2]. To facilitate broad recognition, new terminology aligned with that of DSM-5 was adopted. The clinical nomenclature was proposed to be changed from POCD to delayed neurocognitive recovery (DNR) for neurocognitive impairment identified from 7 to 30 days postoperatively and postoperative neurocognitive disorder (pNCD) from the 30th postoperative day to the 12th postoperative month [1].

DNR and pNCD are major complications of surgery, hospitalization, and anesthesia that are receiving increasing attention [3–5]. Their incidence depends on the type of surgery, cognitive performance tests, time of postoperative assessment, and specificity and sensibility of the cognitive tests [6]. It is reported to be approximately 11% after noncardiac surgery and 60% in cardiac surgery patients [4]. This cognitive decline is associated with poorer recovery, increased use of social financial assistance, and a higher mortality rate [6,7].

Several preoperative, intraoperative, and postoperative risk factors are associated with DNR/pNCD, which include advanced age, education level, history of diabetes mellitus (DM), malnutrition, perioperative hyperglycemia, depth of anesthesia, blood pressure fluctuation during surgery, chronic respiratory diseases, etc. [5,8]. Despite the very limited evidence of a causative relationship between anesthetics and cognitive impairment >6 months after anesthesia, there is a lot of scientific evidence that suggests a causal association between anesthesia and DNR/pNCD within 6 months postoperatively, and various pathophysiological mechanisms have been proposed: mitochondrial dysfunction, neuroinflammation, calcium dysregulation, increase in tau protein phosphorylation, accumulation of amyloid-β (Aβ) protein, etc. [8–12]. Pharmacological and non-pharmacological approaches have been proposed to reduce or prevent the incidence of DNR/pNCD [8].

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The central nervous system insulin receptors (CNS-IRs) have the highest concentration in the thalamus, caudate-putamen, hippocampus, amygdala, and parahippocampal gyrus; intermediate concentration in the cerebellum, cerebral cortex, and caudate nucleus; and the lowest concentration in the substantia nigra, red nucleus, white matter, and cerebral peduncles [13,14]. Downregulation of insulin transport through the blood–brain barrier (BBB) and dysregulation of the insulin receptor (IR) intracellular cascade that occur in patients with DM is associated with a higher risk of Alzheimer’s disease (AD) because of Aβ peptide accumulation and increased neuronal tau protein phosphorylation [15]. The characteristic distribution of CNS-IRs and the proven association between IR dysregulation and chronic cognitive impairment (as reported in patients with AD) suggest a non-metabolic role of insulin in cognitive performance, memory, and neuromodulation [16]. This role can indicate that CNS-IRs act as neuromodulator-like mediators, and this might partially explain how the interaction between anesthetics and CNS-IRs might contribute to anesthesia-induced DNR/pNCD [13,17]. Perioperative intranasal insulin administration, possibly with a direct action on IRs, is proven to restore more effective signaling, thus preventing the onset of DNR/pNCD [18,19]. This narrative review was accomplished through a literature search of PubMed, EMBASE, and SCOPUS online medical databases, including only articles in English. The following search terms were used: anesthesia, delayed neurocognitive recovery, postoperative neurocognitive disorder, intranasal insulin, Alzheimer’s disease, and Parkinson’s disease.

This review aims to report preclinical and clinical evidence of the implication of intranasal insulin for preventing changes in the brain molecular pattern and/or neurobehavioral impairment, which influence anesthesia-induced DNR/NCD.

Preclinical Evidence

Several preclinical studies have addressed the therapeutic role of intranasal insulin in preventing post-anesthesia changes in the brain molecular pattern and/or neurobehavioral impairment in animal models (Table 1).

A study published in 2014 investigated the effects of intranasal insulin on anesthesia-induced hyperphosphorylation of tau protein in the brain tissue of 3xTg-AD mice, a commonly used transgenic model of AD [20]. Intranasal insulin or saline (as control) was administered daily in 3xTg-AD and wild-type mice for seven consecutive days. After seven days, anesthesia was induced with intraperitoneal propofol or intralipid (as a control). Brain tissue was then prepared for Western blot and immunohistochemical analyses. In mice anesthetized with propofol, there was a marked increase in the phosphorylation status of tau protein when compared to controls; moreover, daily intranasal insulin administration before anesthesia was found to be associated with significantly lower phosphorylation levels of tau protein when compared to saline. These findings represent the first evidence supporting that intranasal insulin might ameliorate anesthesia-induced DNR, pNCD, and AD-like brain histological changes.

In 2016 and 2017, the same group published two studies on the efficacy of intranasal insulin in preventing anesthesia-induced spatial learning and memory deficit in mice [21,22]. The first one aimed to report whether pretreatment with intranasal insulin could prevent anesthesia-induced deficits in spatial learning, memory, and hyperphosphorylation of tau protein [21]. Intranasal insulin or saline (as the control) was administered daily in wild-type mice for seven consecutive days. On the day after the last dose was administered, anesthesia was induced with intraperitoneal propofol or intralipid (as the control), followed by 2.5% sevoflurane inhalation for 1 h. Mice were sacrificed at different times (immediately 24 h or 5 days post-anesthesia), and brain tissue was prepared for Western blot and immunohistochemical analyses, while the Morris water maze test was used to evaluate the mice’s spatial learning and memory. Anesthesia-treated mice showed higher phosphorylation levels of tau protein and impairment in spatial learning and memory when compared to non-anesthetized controls. Moreover, anesthesia-induced hyperphosphorylation of tau protein in the brain samples and impairment in spatial learning and memory were both prevented in mice treated with intranasal insulin administered before anesthesia when compared to controls. The study published in 2017 aimed to test the effects of intranasal insulin administration and anesthetic exposure on neurobehavioral performance such as spatial learning and memory in mice of different ages and conditions [22]. Intranasal insulin was administered for three consecutive days and was followed by anesthesia induced with intraperitoneal propofol or intralipid (as a control) and maintained by inhalation of 2.5% sevoflurane for 1 or 3 h. Deficits in spatial learning and memory, as tested using the Morris water maze 2–6 days after anesthesia exposure, were identified in aged (17–18 months old) wild-type mice and adult (7–8 months old) 3xTg-AD mice but not in adult wild-type mice. Long-term neurobehavioral changes were also reported in 3xTg-AD mice after anesthesia exposure. Intranasal insulin administration before anesthesia prevented deficits in spatial learning and memory and long-term neurobehavioral changes in 3xTg-AD mice. These findings suggest that aging and the prior existence of AD-like brain pathology might be associated with higher vulnerability to anesthesia-induced DNR/pNCD onset and that intranasal administration of insulin can effectively prevent these disorders.

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Based on this preliminary evidence, two randomized controlled preclinical trials published in 2019 and 2020 investigated the role of intranasal insulin administration in preventing neurobehavioral modifications during general anesthesia administration in neonatal mice [23,24]. In the study published in 2019, the authors aimed to address the long-term effects of general anesthesia with sevoflurane in a neonatal mice model and to study the role of intranasal insulin in preventing anesthesia-related brain damage and neurobehavioral modifications [23]. Seven-day-old neonatal mice were randomly assigned into four groups: non-anesthetized mice + saline (controls); non-anesthetized mice + insulin; anesthetized + saline; and anesthetized + insulin. Anesthesia was induced using 5% sevoflurane and maintained with 3% sevoflurane for 3 h for 3 consecutive days. In mice treated with intranasal insulin, 0.14 international units (IU) were delivered 30 min before each anesthesia procedure. Behavioral tests included an open-field test for assessing general spontaneous activity and anxiety, a novel object recognition test for assessing memory, the Morris water maze test for assessing hippocampal spatial learning, and a memory and fear conditioning test to assess learning and memory that involve the amygdala. According to the results provided by the authors, while general anesthesia was demonstrated to induce long-term behavioral abnormalities; promote changes in synaptic proteins, in particular, post-synaptic density protein 95 (PSD95); and promote neuronal apoptosis in neonatal mice brains, intranasal insulin administration was found to prevent these abnormalities. In the randomized controlled preclinical trial published in 2020, the authors investigated the relationship between anesthesia exposure, neurobehavioral modifications, and intranasal insulin administration in neonatal mice [24]. Neonatal mice (7 days old) were randomized into four groups: non-anesthetized mice + saline (controls); unanesthetized mice + insulin; anesthetized mice + saline; and anesthetized mice + insulin. Anesthesia was induced with 5% sevoflurane and maintained with 3% sevoflurane for 3 h for a total of 3 consecutive days. Before each anesthesia procedure, the neonatal mice received intranasal administration of insulin or saline. All mice were tested at different times, including at old age (18 months old), with the following behavioral tests: open field, novel object recognition, Morris water maze, and fear conditioning. Brain samples were prepared for Western blot analysis. The authors showed that compared to non-anesthetized controls, neonatal mice exposed to anesthesia were not affected by spontaneous activity or anxiety when evaluated in old age. However, neonatal mice exposed to anesthesia did develop long-term cognitive impairment, including learning and memory deficit associated with specific brain areas such as the amygdala, hippocampus, frontal cortex, and cingulate cortex. Molecular investigations of the brains of aged mice reported no detectable alterations in the levels of tau phosphorylation or synaptic proteins (including PSD95) when comparing anesthetized mice with controls. Therefore, intranasal insulin administered before anesthesia induction can prevent the development of anesthesia-related behavioral and cognitive impairment.

To investigate the molecular mechanisms involved in insulin-induced prevention of anesthesia-related cognitive impairment, several intra- and extracellular brain factors were measured in wild-type, aged mice exposed to anesthesia [25]. Mice were treated with intranasal insulin administration or saline (as a control) for 7 consecutive days. The day after the last administration, the mice received anesthesia (intraperitoneal injection of propofol for induction and sevoflurane inhalation for 1 h as maintenance) or intralipid as a control. A group of mice was sacrificed, a group was tested with the Morris water maze test for spatial learning and memory evaluation, and a group was tested with an inhibitor of eukaryotic elongation factor 2 kinase (eEF2K), a blocker of the mammalian target of rapamycin-eukaryotic elongation factor 2 (mTOR-eEF2) signaling pathway. In this study, anesthesia was proven to induce a reduction in brain synaptic proteins and brain-derived neurotrophic factor (BDNF), while prior administration of the eEF2K inhibitor or intranasal insulin administration promoted the mTOR-eEF2 signaling pathway and effectively prevented the anesthesia-induced reduction in brain synaptic proteins and BDNF and neurocognitive disorders (NCD).

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Intranasal insulin administration in aged mice was also proven to prevent anesthesia-induced abnormalities of glycogen synthase kinase 3 beta (GSK-3β) and phosphoinositide 3-kinase/pyruvate dehydrogenase kinase 1/protein kinase B (PI3K/PDK1/Akt) signaling pathways, expression of synaptic proteins, and neurobehavioral impairment [26]. GSK-3β is a protein kinase involved in tau hyperphosphorylation; PI3K/PDK1/AKT is involved in the insulin signaling pathway and plays a role in preventing GSK-3β-mediated tau hyperphosphorylation. Intranasal insulin or saline (as a control) was administered daily for 26 days. From day 7 and for 5 consecutive days, general anesthesia was induced and maintained for 2 h after intraperitoneal injection of propofol. From the 27th day, intranasal insulin administration or saline was continued for 15 days and neurobehavioral tests (such as object recognition test, and fear-conditioning test) were administered. Intranasal insulin administration was shown to prevent NCD induced by anesthesia in aged mice when compared to controls. Moreover, insulin upregulated the PI3K/PDK1/AKT signaling pathway, attenuated the hyperphosphorylation of tau induced by GSK-3β, and prevented the loss of specific synaptic proteins (such as PSD95) involved in the signal pathway of cognition, memory, and movement.

References

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Rafael Badenes 1, Ega Qeva 2, Giovanni Giordano 2 , Nekane Romero-García 1 and Federico Bilotta 2

1 Department of Anesthesiology and Surgical Trauma Intensive Care, Hospital Clinic Universitari Valencia, the University of Valencia, 46010 Valencia, Spain; nekaneromerog@gmail.com

2 Department of Anesthesiology, Critical Care and Pain Medicine, Sapienza University of Rome, 00161 Rome, Italy; giordano.gj@gmail.com (G.G.); bilotta@tiscali.it (F.B.)