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Early exposure to general anesthesia (GA) causes developmental neuroapoptosis in the mammalian brain and long-term cognitive impairment. Recent evidence suggests that GA also causes functional and morphological impairment of the immature neuronal mitochondria. Injured mitochondria could be a significant source of reactive oxygen species (ROS), which, if not scavenged in timely fashion, may cause excessive lipid peroxidation and damage of cellular membranes. We examined whether early exposure to GA results in ROS upregulation and whether mitochondrial protection and ROS scavenging prevent GA-induced pathomorphological and behavioral impairments. We exposed 7-day-old rats to GA with or without either EUK-134, a synthetic ROS scavenger, or R(+) pramipexole (PPX), a synthetic aminobenzothiazol derivative that restores mitochondrial integrity. We found that GA causes extensive ROS upregulation and lipid peroxidation, as well as mitochondrial injury and neuronal loss in the subiculum. As compared to rats given only GA, those also given PPX or EUK-134 had significantly downregulated lipid peroxidation, preserved mitochondrial integrity, and significantly less neuronal loss. The subiculum is highly intertwined with the hippocampal CA1 region, anterior thalamic nuclei, and both entorhinal and cingulate cortices; hence, it is important in cognitive development. We found that PPX or EUK-134 co-treatment completely prevented GA-induced cognitive impairment. Because mitochondria are vulnerable to GA-induced developmental neurotoxicity, they could be an important therapeutic target for adjuvant therapy aimed at improving the safety of commonly used GAs.

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Beta amyloid (Ab) peptides accumulate in Alzheimer's disease and are neurotoxic possibly through the production of oxygen free radicals. Using brain microdialysis we characterized the ability of Ab to increase oxygen radical production in vivo. The 1±40 Ab fragment increased 2,3-dehydroxybenzoic acid ef¯ux more than the 1±28 fragment, in a manner dependent on nitric oxide synthase and NMDA receptor channels. We then examined the effects of Ab peptides on mitochondrial function in vitro. Induction of the mitochondrial permeability transition in isolated rat liver mitochondria by Ab(25±35) and Ab(35±25) exhibited dose dependency and required calcium and phosphate. Cyclosporin A prevented the transition as did ruthenium red, chlorpromazine, or N-ethylmaleimide. ADP and magnesium delayed the onset of mitochondrial permeability transition. Electron microscopy con®rmed the presence of Ab aggregates and swollen mitochondria and preservation of mitochondrial structure by inhibitors of mitochondrial permeability transition. Cytochrome c oxidase (COX) activity was selectively inhibited by Ab(25±35) but not by Ab(35±25). Neurotoxic Ab peptide can increase oxidative stress in vivo through mechanisms involving NMDA receptors and nitric oxide sythase. Increased intracellular Ab levels can further exacerbate the genetically driven complex IV defect in sporadic Alzheimer's disease and may precipitate mitochondrial permeability transition opening. In combination, our results provide potential mechanisms to support the feed-forward hypothesis of Ab neurotoxicity.

Many models of Parkinson's disease (PD) have succeeded in replicating dopaminergic neuron loss or a-synuclein aggregation but not the formation of classical Lewy bodies, the pathological hallmark of PD. Our cybrid model of sporadic PD was created by introducing the mitochondrial genes from PD patients into neuroblastoma cells that lack mitochondrial DNA. Previous studies using cybrids have shown that information encoded by mitochondrial DNA in patients contributes to many pathogenic features of sporadic PD. In this paper, we report the generation of fibrillar and vesicular inclusions in a longterm cybrid cell culture model that replicates the essential antigenic and structural features of Lewy bodies in PD brain without the need for exogenous protein expression or inhibition of mitochondrial or proteasomal function. The inclusions generated by PD cybrid cells stained with eosin, thioflavin S, and antibodies to a-synuclein, ubiquitin, parkin, synphilin-1, neurofilament, b-tubulin, the proteasome, nitrotyrosine, and cytochrome c. Future studies of these cybrids will enable us to better understand how Lewy bodies form and what role they play in the pathogenesis of PD.