Neurodevelopmental consequences of sub-clinical carbon monoxide exposure in newborn mice.

Carbon monoxide (CO) exposure at high concentrations results in overt neurotoxicity. Exposure to low CO concentrations occurs commonly yet is usually sub-clinical. Infants are uniquely vulnerable to a variety of toxins, however, the effects of postnatal sub-clinical CO exposure on the developing brain are unknown. Apoptosis occurs normally within the brain during development and is critical for synaptogenesis. Here we demonstrate that brief, postnatal sub-clinical CO exposure inhibits developmental neuroapoptosis resulting in impaired learning, memory, and social behavior. Three hour exposure to 5 ppm or 100 ppm CO impaired cytochrome c release, caspase-3 activation, and apoptosis in neocortex and hippocampus of 10 day old CD-1 mice. CO increased NeuN protein, neuronal numbers, and resulted in megalencephaly. CO-exposed mice demonstrated impaired memory and learning and reduced socialization following exposure. Thus, CO-mediated inhibition of neuroapoptosis might represent an important etiology of acquired neurocognitive impairment and behavioral disorders in children.

Anesthesia in presymptomatic Alzheimer's disease: a study using the triple-transgenic mouse model.

BACKGROUND: Experimental evidence suggests that anesthetics accelerate symptomatic neurodegenerative disorders such as Alzheimer's disease (AD). Because AD pathology precedes symptoms, we asked ourselves whether anesthetic exposure in the presymptomatic interval accelerated neuropathology and appearance of symptoms. METHODS: Triple-transgenic AD mice were exposed to general aesthetics, either halothane or isoflurane, at 2, 4, and 6 months of age, they then underwent water maze cognitive testing 2 months later, and subsequently their brains were analyzed using enzyme-linked immunosorbent assay, immunoblots, and immunohistochemistry for amyloid and tau pathology and biomarkers. RESULTS: Learning and memory improved after halothane exposure in the 2-month-old group relative to controls, but no changes were noted in the isoflurane group. When gender was examined in all age groups, females exposed to halothane performed better as compared with those exposed to isoflurane or controls. Therefore, improvement in the 2-month exposure group is most likely because of a gender effect. Level of phospho-tau in the hippocampus was significantly increased 2 months after anesthesia, especially in the 6-month exposure group, but changes in amyloid, caspase, microglia, or synaptophysin levels were not detected. CONCLUSIONS: These results indicate that exposure to two different inhalation-type anesthetics during the presymptomatic phase of AD does not accelerate cognitive decline, after 2 months, and may cause a stress response, marked by hippocampal phosphorylated tau, resulting in preconditioning against the ongoing neuropathology, primarily in female mice.

Inhaled anesthetic potency in aged Alzheimer mice.

BACKGROUND: The number of elderly patients with frank or incipient Alzheimer's disease (AD) requiring surgery is growing as the population ages. General anesthesia may exacerbate symptoms of and the pathology underlying AD, so minimizing anesthetic exposure may be important. This requires knowledge of whether the continuing AD pathogenesis alters anesthetic potency. METHODS: We determined the induction potency and emergence time for isoflurane, halothane, and sevoflurane using the minimum alveolar anesthetic concentration for loss of righting reflex as an end point in 12- to 14-mo-old triple transgenic Alzheimer (3xTgAD) mice and wild type C57BL6 controls. 3xTgAD mice model AD by harboring three distinct mutations: the APP(Swe), Tau, and PS1 human transgenes, each of which has been associated with familial forms of human AD. RESULTS: The 3xTgAD mice exhibited mild resistance (from 8% to 30%) to volatile anesthetics but displayed indistinguishable emergence patterns from all three inhaled anesthetics. CONCLUSIONS: These results show that the genetic vulnerabilities and neuropathology associated with AD produce a small but significant decrease in sensitivity to the hypnotic actions of three inhaled anesthetics. Emergence times were not altered.

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

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.