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.

Heat induced temperature dysregulation and seizures in Dravet Syndrome/GEFS+ Gabrg2+/Q390X mice

“…The EEG electrode implant surgery and synchronized video-EEG monitoring have been described before 19;20 . Briefly, synchronized video-EEGs were recorded from mice one week after electrode implantation and recorded with a synchronized video-EEG monitoring system from Pinnacle Technology.…”

Happily (n)ever after: Aging in the context of oxidative stress, proteostasis loss and cellular senescence

“…More amyloid-β plaque deposits have been observed in mice with moderate intracellular vitamin C deficiency [309]. Thus it has been suggested that populations at increased risk for epilepsy and seizures, such as in AD should avoid vitamin C deficiency [310]. It is known that aged individuals consume poor amounts of vitamin C [294], furthermore it declines with age and individuals with lowest intake seem to have the highest stroke mortality rate [311].…”

Dieta niskosalicylanowa a możliwość występowania niedoborów składników pokarmowych

“…Niedobory nie wynikają ściśle z ograniczenia salicylanów w diecie, ale doboru produktów spożywczych, jednak w przypadku znacznego ograniczenia warzyw i owoców mogą pojawić się niedobory witaminy C w organizmie, co będzie sprzyjało wielu niekorzystnym procesom. Wystąpienie klinicznych objawów szkorbutu jest mało prawdopodobne, niemniej jednak w wyniku nasilonego stresu oksydacyjnego istnieje zwiększone ryzyko spadku odporności organizmu, napadów padaczkowych, epilepsji czy choroby Alzheimera [16]. Przy znacznym ograniczeniu warzyw i owoców dodatkowo może wystąpić stosunkowo niskie spożycie błonnika.…”