title: Low brain ascorbic acid increases susceptibility to seizures in mouse models of decreased brain ascorbic acid transport and Alzheimer's disease.
abstract: Seizures are a known co-occurring symptom of Alzheimer's disease, and they can accelerate cognitive and neuropathological dysfunction. Sub-optimal vitamin C (ascorbic acid) deficiency, that is low levels that do not lead the sufferer to present with clinical signs of scurvy (e.g. lethargy, hemorrhage, hyperkeratosis), are easily obtainable with insufficient dietary intake, and may contribute to the oxidative stress environment of both Alzheimer's disease and epilepsy. The purpose of this study was to test whether mice that have diminished brain ascorbic acid in addition to carrying human Alzheimer's disease mutations in the amyloid precursor protein (APP) and presenilin 1 (PSEN1) genes, had altered electrical activity in the brain (electroencephalography; EEG), and were more susceptible to pharmacologically induced seizures. Brain ascorbic acid was decreased in APP/PSEN1 mice by crossing them with sodium vitamin C transporter 2 (SVCT2) heterozygous knockout mice. These mice have an approximately 30% decrease in brain ascorbic acid due to lower levels of SVCT2 that supplies the brain with ASC. SVCT2+/-APP/PSEN1 mice had decreased ascorbic acid and increased oxidative stress in brain, increased mortality, faster seizure onset latency following treatment with kainic acid (10 mg/kg i.p.), and more ictal events following pentylenetetrazol (50 mg/kg i.p.) treatment. Furthermore, we report the entirely novel phenomenon that ascorbic acid deficiency alone increased the severity of kainic acid- and pentylenetetrazol-induced seizures. These data suggest that avoiding ascorbic acid deficiency may be particularly important in populations at increased risk for epilepsy and seizures, such as Alzheimer's disease.
authors.affiliation: Department of Neurology, Vanderbilt University Medical Center, Nashville, TN 37232, USA. Electronic address: timothy.warner@vanderbilt.edu.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Warner
authors.affiliation: Department of Neurology, Vanderbilt University Medical Center, Nashville, TN 37232, USA. Electronic address: jingqiong.kang@vanderbilt.edu.
authors.forename: Jing-Qiong
authors.initials: JQ
authors.lastname: Kang
authors.affiliation: Division of Diabetes, Endocrinology & Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA. Electronic address: john.kennard@vanderbilt.edu.
authors.forename: John A
authors.initials: JA
authors.lastname: Kennard
authors.affiliation: Division of Diabetes, Endocrinology & Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA. Electronic address: fiona.harrison@vanderbilt.edu.
authors.forename: Fiona E
authors.initials: FE
authors.lastname: Harrison
mesh_terms: D000544:Alzheimer Disease / Q000503:physiopathology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001205:Ascorbic Acid / Q000378:metabolism; D001206:Ascorbic Acid Deficiency / Q000503:physiopathology*; D001921:Brain / Q000503:physiopathology*; D004195:Disease Models, Animal; D004567:Electrodes, Implanted; D004569:Electroencephalography; D005260:Female; D006801:Humans; D007608:Kainic Acid; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018384:Oxidative Stress / Q000502:physiology; D010433:Pentylenetetrazole; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism; D012640:Seizures / Q000503:physiopathology*; D060347:Sodium-Coupled Vitamin C Transporters / Q000172:deficiency / Q000235:genetics
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; C508853:PSEN1 protein, human; D053764:Presenilin-1; C555165:Slc23a2 protein, mouse; D060347:Sodium-Coupled Vitamin C Transporters; D008315:Malondialdehyde; D001205:Ascorbic Acid; D007608:Kainic Acid; D010433:Pentylenetetrazole
keywords: Alzheimer's disease; Electroencephalography; Kainic acid; Mouse model; Pentylenetetrazol; Vitamin C