Lasting effects of general anesthetics on the brain in the young and elderly: "mixed picture" of neurotoxicity, neuroprotection and cognitive impairment

Abstract

General anesthetics are commonly used in major surgery. To achieve the depth of anesthesia for surgery, patients are being subjected to a variety of general anesthetics, alone or in combination. It has been long held an illusory concept that the general anesthesia is entirely reversible and that the central nervous system is returned to its pristine state once the anesthetic agent is eliminated from the active site. However, studies indicate that perturbation of the normal functioning of these targets may result in long-lasting desirable or undesirable effects. This review focuses on the impact of general anesthetic exposure to the brain and summarizes the molecular and cellular mechanisms by which general anesthetics may induce long-lasting undesirable effects when exposed at the developing stage of the brain. The vulnerability of aging brain to general anesthetics, specifically in the context of cognitive disorders and Alzheimer's disease pathogeneses are also discussed. Moreover, we will review emerging evidence regarding the neuroprotective property of xenon and anesthetic adjuvant dexmedetomidine in the immature and mature brains. In conclusion, "mixed picture" effects of general anesthetics should be well acknowledged and should be implemented into daily clinical practice for better patient outcome.

Keywords: Brain; General anesthetics; Neuroprotection; Neurotoxicity.

Fig. 1

Neurotoxicity and volatile anesthetics. Volatile anesthetics were shown to activate mitochondrial apoptosis pathway, by increasing mitochondrial ROS production, lowering anti-apoptotic Bcl-2/pro-apoptotic Bax ratio and promoting cytochrome C from mitochondrion into cytosol to form apoptosome, which subsequently cleaves pro-caspase 3 to caspase 3. In addition, volatile anesthetic isoflurane was demonstrated to directly activate and open inositol 1,4,5-trisphosphate receptor (InsP3R) calcium channel located on the smooth endoplasmic reticulum. Excessive opening of InsP3R calcium channel by isoflurane leads to significant Ca2 + leakage from ER and cause mitochondrial Ca2 + overload, which could aggravate cytochrome C release and caspase cleavage pathway. Apaf-1 Apoptotic protease-activating factor 1, Bax Bcl-2-associated X protein, Bcl-2 B-cell lymphoma 2 protein, Ca²⁺ calcium ion, InsP3R inositol 1,4,5-triphosphate receptor, ROS reactive oxygen species

Fig. 2

Excitotoxicity and general anesthetics. Glutamate released from pre-synaptic nerve terminals bind to NMDA and AMPA receptors on the post-synaptic membrane to lead to calcium ion (Ca²⁺) influx and membrane depolarization. Excessive glutamatergic signaling and calcium accumulation would result in mitochondrial calcium overload, reactive oxygen species (ROS) production, cellular energy failure, apoptosis protein (cytochrome C) release/activation, and ultimately neuron death. Activation of GABA receptor leads to chloride ion (Cl⁻) influx to hyperpolarize membrane and thus inhibits depolarization. Volatile anesthetics (in particular isoflurane) have been shown to antagonize NMDA and AMPA, inhibit Ca²⁺ influx and protect neuron death from ischemia-induced excitotoxicity. Isoflurane also agonizes GABA receptor to hinder excitatory neurotransmission. AMPA a-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate, Ca²⁺ calcium ion, Cl⁻ chloride ion, GABA gamma-aminobutyric acid-A, Na⁺ sodium ion, NMDA N-Methyl-d-aspartic acid, ROS reactive oxygen species

Fig. 3

The hypoxia-inducible factor-1 (HIF-1) signaling pathway. Volatile anesthetics has been shown to activate or suppress HIF-1 system. HIF-1 is a heterodimer that consists of HIF-1α (120 kDa) and HIF-1β (91–94 kDa), HIF1β is expressed constitutively in all cells and remains stable regardless of oxygen tension. At normoxia conditions, HIF-1α combines with the tumor-suppressor Von Hippel–Lindau (VHL) protein through a hydroxylated proline residue and is then hydroxylated by prolyl-4-hydroxylases (PHD) in the cytoplasm, and this interaction causes HIF-1α to be ubiquitinated and to be targeted by proteasome-mediated protein degradation. Under hypoxic conditions, oxygen deficiency inhibits the activity of prolyl hydroxylases and leads to the accumulation of HIF-1α. Production of HIF-1α is controlled by PI-3K/AKT/mTOR pathway and partially influenced by MAPK pathway, phophorylation of AKT and mTOR leads to translation of HIF-1α. HIF-1α is translocated into the cell nuclear and together with HIF-1β bind to hypoxia-response elements (HREs). A broad range of protective pathways is activated, which regulate several aspects of cellular activities, such as angiogenesis, erythropoiesis, cell proliferation, cell survival and energy metabolism. AKT protein kinase B, HIF-1 hypoxia-inducible factor-1, MAPK mitogen-activated protein kinase, mTOR mammalian target of rapamycin, PI-3K phosphatidylinositide 3-kinases

Fig. 4

The hypothesized pathways of volatile anesthetics induced neuropathology associated with Alzheimer’s disease. Volatile anesthetic was demonstrated to promote toxic Ab production and aggregation, and such effect was shown to be downstream of VA-induced caspase-3 cleavage and activation. The cleaved caspase 3 could inactivate Golgi-associated, gamma adaptin ear-containing, ARF-binding protein 3 (GGA3), which degrades b-site APP-cleaving enzyme (BACE, or b-secretase). The overall effect is cellular stabilization of BACE/b-secretase and increased processing of amyloid progenitor protein (APP) by β-secretase and γ-secretase, leading to accumulation of neurotoxic Ab aggregates. Reciprocal regulation of this pathway may also exist, whereby inhibiting Ab oligomerization could reduce caspase 3 activation. Caspase 3 activation and Ab accumulation could also be upstream of tau phosphorylation, as Ab oligomerization inhibitor prevented tau hyper-phosphorylation. In addition, owing to their small molecular size, volatile anesthetics have been shown to directly interact with residues G29, A30 and I31 of Ab to promote Ab oligomerization. Ab amyloid-beta protein, AICD amyloid precursor protein intracellular domain, BACE b-site amyloid precursor protein cleaving enzyme, GGA3 Golgi-associated, gamma adaptin ear-containing, ARF-binding protein 3, p-tau phosphorylated-tau; sAPPb, soluble amyloid precursor protein b, VA volatile anesthetics