title: 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.
authors.affiliation: Department of Anesthesiology and Critical Care, University of Pennsylvania, 305 John Morgan Building, 3620 Hamilton Walk, Philadelphia, PA 19104, USA. Electronic address: weih@uphs.upenn.edu.
authors.forename: Huafeng
authors.initials: H
authors.lastname: Wei
authors.forename: Saadet
authors.initials: S
authors.lastname: Inan
mesh_terms: D018681:Anesthetics, General / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D006706:Homeostasis / Q000187:drug effects*; D006801:Humans; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D020258:Neurotoxicity Syndromes / Q000209:etiology*
chemical_list: D018681:Anesthetics, General; D018696:Neuroprotective Agents; D002118:Calcium
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