title: The abolishment of anesthesia-induced cognitive impairment by timely protection of mitochondria in the developing rat brain: the importance of free oxygen radicals and mitochondrial integrity.
abstract: 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.
authors.affiliation: Department of Anesthesiology, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: A
authors.initials: A
authors.lastname: Boscolo
authors.forename: J A
authors.initials: JA
authors.lastname: Starr
authors.forename: V
authors.initials: V
authors.lastname: Sanchez
authors.forename: N
authors.initials: N
authors.lastname: Lunardi
authors.forename: M R
authors.initials: MR
authors.lastname: DiGruccio
authors.forename: C
authors.initials: C
authors.lastname: Ori
authors.forename: A
authors.initials: A
authors.lastname: Erisir
authors.forename: P
authors.initials: P
authors.lastname: Trimmer
authors.forename: J
authors.initials: J
authors.lastname: Bennett
authors.forename: V
authors.initials: V
authors.lastname: Jevtovic-Todorovic
mesh_terms: D000367:Age Factors; D000704:Analysis of Variance; D000768:Anesthesia, General / Q000009:adverse effects*; D000818:Animals; D000831:Animals, Newborn; D000975:Antioxidants / Q000627:therapeutic use; D052160:Benzothiazoles / Q000008:administration & dosage; D001921:Brain / Q000187:drug effects* / Q000254:growth & development / Q000473:pathology / Q000648:ultrastructure; D003072:Cognition Disorders / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D015237:Dinoprost / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005106:Exploratory Behavior / Q000187:drug effects; D005260:Female; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008874:Midazolam / Q000009:adverse effects; D008928:Mitochondria / Q000187:drug effects* / Q000473:pathology / Q000648:ultrastructure; D009942:Organometallic Compounds / Q000627:therapeutic use; D010100:Oxygen / Q000008:administration & dosage; D000077487:Pramipexole; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D012459:Salicylates / Q000627:therapeutic use; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000975:Antioxidants; D052160:Benzothiazoles; C433928:EUK-134; D009942:Organometallic Compounds; D017382:Reactive Oxygen Species; D012459:Salicylates; C075750:8-epi-prostaglandin F2alpha; D000077487:Pramipexole; D015237:Dinoprost; D008874:Midazolam; D010100:Oxygen