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: Timothy A Warner, Jing-Qiong Kang, John A Kennard, Fiona E Harrison
• Journal: Epilepsy research (Epilepsy Res) Vol. 110 Pg. 20-5 (Feb 2015) ISSN: 1872-6844 [Electronic] Netherlands
• PMID: 25616451 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2014 Elsevier B.V. All rights reserved.

Chemical References

• APP protein, human
• Amyloid beta-Protein Precursor
• PSEN1 protein, human
• Presenilin-1
• Slc23a2 protein, mouse
• Sodium-Coupled Vitamin C Transporters
• Malondialdehyde
• Ascorbic Acid
• Kainic Acid
• Pentylenetetrazole

Topics

• Alzheimer Disease (physiopathology)
• Amyloid beta-Protein Precursor (genetics, metabolism)
• Animals
• Ascorbic Acid (metabolism)
• Ascorbic Acid Deficiency (physiopathology)
• Brain (physiopathology)
• Disease Models, Animal
• Electrodes, Implanted
• Electroencephalography
• Female
• Humans
• Kainic Acid
• Male
• Malondialdehyde (metabolism)
• Mice, Knockout
• Mice, Transgenic
• Oxidative Stress (physiology)
• Pentylenetetrazole
• Presenilin-1 (genetics, metabolism)
• Seizures (physiopathology)
• Sodium-Coupled Vitamin C Transporters (deficiency, genetics)