Brain and behavior changes in 12-month-old Tg2576 and nontransgenic mice exposed to anesthetics

Abstract

Inhaled anesthetics have been shown to increase the aggregation of amyloid beta in vitro through the stabilization of intermediate toxic oligomers, which are thought to contribute to neurocognitive dysfunction in Alzheimer's disease. Inhaled anesthetics may escalate cognitive dysfunction through enhancement of these intermediate oligomer concentrations. We intermittently exposed 12-month-old Tg2576 transgenic mice and nontransgenic littermates to isoflurane and halothane for 5 days. Cognitive function was measured before and after anesthetic exposures using the Morris Water Maze; amyloid beta plaque burden and caspase-3 mediated apoptosis were quantified by immunohistochemistry. At 12 months of age, anesthetic exposure did not further enhance cognitive decline in the transgenic mice. Immunohistochemistry, however, revealed that the halothane-exposed Tg2576 mice had more amyloidopathy than the isoflurane treated mice or the nonexposed transgenic mice. Isoflurane exposure impaired cognitive function in the nontransgenic mice, implying an alternative pathway for neurodegeneration. These findings indicate that inhaled anesthetics influence cognition and amyloidogenesis, but that the mechanistic relationship remains unclear.

Anesthetic-Induced Neurodegeneration Mediated via Inositol 1,4,5-Trisphosphate Receptors

“…A pilot study in 7-day-old rats (n ϭ 20) confirmed a success rate of intracerebroventricular injection of 100% (data not shown). After xestospongin C administration, rats were exposed to 1% (n ϭ 8) or 1.5% (n ϭ 10) isoflurane for 6 h in a chamber as described previously (Li et al, 2007;Bianchi et al, 2008). Control rats at P7 in the vehicle-only group (n ϭ 10) received the same amount of normal saline but without the addition of xestospongin C. The isoflurane concentration in the chamber was monitored and maintained by using a vaporizer.…”

“…Rats exposed at day P7 were allowed to mature before Morris water maze (MWM). Testing of spatial learning and memory was performed in the MWM with protocols and paradigms as previously described (Li et al, 2007;Bianchi et al, 2008). In brief, experimental and control P35 rats were trained to locate an escape platform (1.5 cm in diameter) within a fiberglass pool (1.5 m in diameter) by distant visual cues located on the walls around the pool and a pole with flags on the escape platform.…”

“…Anesthetics have been implicated as contributing to these forms of neurodegeneration as well (Eckenhoff et al, 2004;Xie et al, 2007;Liang et al, 2008;Wei et al, 2008). For example, in cells and animals, anesthetics increase the levels of BACE, amyloid ␤ (Xie et al, 2007), plaques, and cognitive impairment (Bianchi et al, 2008). Although the underlying mechanisms for these effects are still uncertain, recent reports seem to support a role for Ca 2ϩ dysregulation and activation of InsP 3 Rs in neurodegenerative conditions such as Alzheimer's and Huntington diseases Wei et al, 2008;Bezprozvanny, 2009).…”

“…For example, cognitive decline has been documented in both middle-aged and older patients several months after anesthesia and surgery, and cognitive decline at 1 week after surgery is correlated with the duration of anesthesia (Moller et al, 1998). Likewise, isoflurane alone causes learning and memory deficits in older rodents several weeks after exposure (Culley et al, 2004;Bianchi et al, 2008). At the other extreme of age, isoflurane has been associated with a massive increase in neonatal apoptosis and subsequent learning impairments in the rodent (Jevtovic-Todorovic et al, 2003;Ma et al, 2007;Wang et al, 2009).…”

Developmental Disability in the Young and Postoperative Cognitive Dysfunction in the Elderly After Anesthesia and Surgery: Do Data Justify Changing Clinical Practice?

“…114,133 In addition to the Aβ-anesthesia connection, Xie's group has utilized human neuroglioma cell cultures to add DOI:10.1002/MSJ anesthesia-induced apoptosis as a factor contributing to AD. 114,134 -136 Do the rodent and cell-culture findings apply to humans?…”