The common inhaled anesthetic isoflurane increases aggregation of huntingtin and alters calcium homeostasis in a cell model of Huntington's disease.
Isoflurane is known to increase β-amyloid aggregation and neuronal damage. We hypothesized that isoflurane will have similar effects on the polyglutamine huntingtin protein and will cause alterations in intracellular calcium homeostasis. We tested this hypothesis in striatal cells from the expanded glutamine huntingtin knock-in mouse (STHdh(Q111/Q111)) and wild type (STHdh(Q7/Q7)) striatal neurons. The primary cultured neurons were exposed for 24h to equipotent concentrations of isoflurane, sevoflurane, and desflurane in the presence or absence of extracellular calcium and with or without xestospongin C, a potent endoplasmic reticulum inositol 1,4,5-trisphosphate (InsP(3)) receptor antagonist. Aggregation of huntingtin protein, cell viability, and calcium concentrations were measured. Isoflurane, sevoflurane, and desflurane all increased the aggregation of huntingtin in STHdh(Q111/Q111) cells, with isoflurane having the largest effect. Isoflurane induced greater calcium release from the ER and relatively more cell damage in the STHdh(Q111/Q111) huntingtin cells than in the wild type STHdh(Q7/Q7) striatal cells. However, sevoflurane and desflurane caused less calcium release from the ER and less cell damage. Xestospongin C inhibited the isoflurane-induced calcium release from the ER, aggregation of huntingtin, and cell damage in the STHdh(Q111/Q111) cells. In summary, the Q111 form of huntingtin increases the vulnerability of striatal neurons to isoflurane neurotoxicity through combined actions on the ER IP(3) receptors. Calcium release from the ER contributes to the anesthetic induced huntingtin aggregation in STHdh(Q111/Q111) striatal cells.
Department of Anesthesiology and Critical Care, University of Pennsylvania, 305 John Morgan Building, 3620 Hamilton Walk, Pennsylvania, PA 19104, USA.
Qiujun
Q
Wang
Ge
G
Liang
Hui
H
Yang
Shouping
S
Wang
Maryellen F
MF
Eckenhoff
Huafeng
H
Wei
D018685:Anesthetics, Inhalation / Q000633:toxicity*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000187:drug effects / Q000473:pathology; D000077335:Desflurane; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D055879:Gene Knock-In Techniques; D006706:Homeostasis; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000378:metabolism* / Q000473:pathology; D007530:Isoflurane / Q000031:analogs & derivatives / Q000633:toxicity*; D047028:Macrocyclic Compounds / Q000494:pharmacology; D008738:Methyl Ethers / Q000633:toxicity; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010080:Oxazoles / Q000494:pharmacology; D000077149:Sevoflurane
D018685:Anesthetics, Inhalation; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D047028:Macrocyclic Compounds; D008738:Methyl Ethers; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010080:Oxazoles; C511704:xestospongin C; D000077149:Sevoflurane; D000077335:Desflurane; D007530:Isoflurane; D002118:Calcium