The common inhaled anesthetic isoflurane increases aggregation of huntingtin and alters calcium homeostasis in a cell model of Huntington's disease

Journal Article · Tue Feb 01 00:00:00 EST 2011 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2010.10.032· OSTI ID:21535226

Qiujun, Wang ^[1]; Ge, Liang ^[1]; Hui, Yang ^[1]; Shouping, Wang ^[1]; Eckenhoff, Maryellen F ^[1]

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1. Department of Anesthesiology and Critical Care, University of Pennsylvania, 305 John Morgan Building, 3620 Hamilton Walk, Pennsylvania, PA 19104 (United States)

Isoflurane is known to increase {beta}-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{sup Q111/Q111}) and wild type (STHdh{sup Q7/Q7}) striatal neurons. The primary cultured neurons were exposed for 24 h 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{sub 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{sup 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{sup Q111/Q111} huntingtin cells than in the wild type STHdh{sup 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{sup 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{sub 3} receptors. Calcium release from the ER contributes to the anesthetic induced huntingtin aggregation in STHdh{sup Q111/Q111} striatal cells.

• OSTI ID: 21535226
• Journal Information: Toxicology and Applied Pharmacology, Vol. 250, Issue 3; Other Information: DOI: 10.1016/j.taap.2010.10.032; PII: S0041-008X(10)00425-4; Copyright (c) 2010 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
AGGLOMERATION
ANESTHESIA
ANESTHETICS
CALCIUM
DAMAGE
ENDOPLASMIC RETICULUM
HOMEOSTASIS
HYPOTHESIS
NERVE CELLS
NERVOUS SYSTEM DISEASES
RECEPTORS
SURGERY
ALKALINE EARTH METALS
ANIMAL CELLS
CELL CONSTITUENTS
CENTRAL NERVOUS SYSTEM AGENTS
CENTRAL NERVOUS SYSTEM DEPRESSANTS
DISEASES
DRUGS
ELEMENTS
MEDICINE
MEMBRANE PROTEINS
METALS
ORGANIC COMPOUNDS
PROTEINS
SOMATIC CELLS