Isoflurane anesthesia precipitates tauopathy and upper airways dysfunction in pre-symptomatic Tau.P301L mice: possible implication for neurodegenerative diseases.
The postoperative cognitive decline resulting from volatile anesthesia is gaining acceptance as a major health problem. The common anesthetic isoflurane is suspected to precipitate neurodegeneration in Alzheimer's disease by unknown mechanisms. We previously validated that 8month old Tau.P301L mice suffer upper airways defects related to tauopathy within the Kolliker-Fuse nucleus that controls upper airways function. We now report that isoflurane anesthesia in young, pre-symptomatic Tau.P301L mice triggered precocious upper airways defects and tauopathy in several brainstem nuclei, including the nucleus ambiguus that contains upper airways motor neurons and the Kolliker-Fuse. The prescription drug memantine, identified as an NMDA receptor antagonist, prevented the post-anesthesia upper airways dysfunction and alleviated tauopathy in the nucleus ambiguus and Kolliker-Fuse. We further identified protocols of anesthesia in young Tau.P301L mice that mitigated adverse effects of isoflurane anesthesia. Thus, our experimental findings in a validated mouse model for tauopathy demonstrate the link between isoflurane anesthesia, earlier onset of tauopathy and earlier onset of functional deficits, highlight the implication of NMDA-receptors in the mechanisms mediating the adverse effects of isoflurane, and potentially identify safer protocols for anesthesia in patients with tauopathy.
MP3-respiration team, Unité Mixte de Recherche 6231, Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille, Faculté Saint Jérôme, service 362, 13397 Marseille, cedex 20, France.
Clément
C
Menuet
Peter
P
Borghgraef
Nicolas
N
Voituron
Christian
C
Gestreau
Lies
L
Gielis
Herman
H
Devijver
Mathias
M
Dutschmann
Fred
F
Van Leuven
Gérard
G
Hilaire
D000544:Alzheimer Disease / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D018685:Anesthetics, Inhalation / Q000633:toxicity*; D000818:Animals; D001933:Brain Stem / Q000187:drug effects / Q000473:pathology; D004195:Disease Models, Animal; D007530:Isoflurane / Q000633:toxicity*; D051379:Mice; D008818:Mice, Neurologic Mutants; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control; D012131:Respiratory Insufficiency / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control; D024801:Tauopathies / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control
D018685:Anesthetics, Inhalation; D007530:Isoflurane