Dual effects of neuroprotection and neurotoxicity by general anesthetics: role of intracellular calcium homeostasis

Abstract

Although general anesthetics have long been considered neuroprotective, there are growing concerns about neurotoxicity. Preclinical studies clearly demonstrated that commonly used general anesthetics are both neuroprotective and neurotoxic, with unclear mechanisms. Recent studies suggest that differential activation of inositol 1,4,5-trisphosphate receptors, a calcium release channel located on the membrane of endoplasmic reticulum (ER), play important role on determining the fate of neuroprotection or neurotoxicity by general anesthetics. General anesthetics at low concentrations for short duration are sublethal stress factors which induce endogenous neuroprotective mechanisms and provide neuroprotection via adequate activation of InsP3R and moderate calcium release from ER. On the other hand, general anesthetics at high concentrations for prolonged duration are lethal stress factors which induce neuronal damage by over activation of InsP3R and excessive and abnormal Ca(2+) release from ER. This review emphasizes the dual effects of both neuroprotection and neurotoxicity via differential regulation of intracellular Ca(2+) homeostasis by commonly used general anesthetics and recommends strategy to maximize neuroprotective but minimize neurotoxic effects of general anesthetics.

Keywords: 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; 5-HD; 5-Hydroxydecanoate; Akt; Anesthesia; Anesthetics; Calcium; ER; ERK; Endoplasmic reticulum; Extracellular signal-regulated kinases; GABA; GSK3β; Gamma-aminobutyric acid; Glycogen synthase kinase 3β; InsP(3) receptors; InsP(3)R; LDH; LTP; Lactate dehydrogenase; MAPK; MTT; Mitochondrial permeability transition pores; Mitogen-activated protein kinase; N-methyl-D-aspartate; NMDA; Neurodegeneration; Neuroprotection; Neurotoxicity; OGD; Oxygen-glucose deprivation; Protein kinase B; RYRs; Ryanodine receptors; VDCC; Voltage dependent Ca(2+) channels; Xc; Xestospongin C; long term potentiation; mPTP.

Figure 1. Summary of hypothetical pathways involved in neuroprotective and neurotoxic effects of commonly used general anesthetics

The left side of figure represents neuroprotection and the right side represents neurotoxicity. Short term and low concentration of anesthetics (left side) for pre- or post-conditioning induces moderate Ca²⁺ release from endoplasmic reticulum (ER) through InsP₃Rs. Adequate Ca²⁺ transfer into mitochondria stimulates ATP production and other mitochondria functions to provide neuroprotection. Similarly, modest increase in cytosolic Ca²⁺ concentration activates pro-survival pathways such as phosphotydyl inositol 3 kinase (PI3K) and the mitogen-activated protein kinase (MAPK) signaling cascades [extracellular signal-regulated kinases (ERK), c-Jun N-terminal protein kinases (JNK) and p38 as well as protein kinase B (Akt)]. Activation of cell-survival signaling decreases apoptosis and cell death. By contrast, prolonged exposure to high anesthetic concentrations (right side), increases cytosolic [Ca²⁺] to toxic levels due excessive Ca²⁺ release from ER. This results in excessive transfer of Ca²⁺ from ER into mitochondria and increased mitochondrial permeability transition pore (mPTP) activity, resulting in mitochondrial swelling and rupture, and release of pro-apoptotic molecules. Abnormally elevated cytosolic Ca²⁺ concentrations can also activate calpain and then caspases and induce cell death by apoptosis, resulting in neurodegeneration.