RESUMEN
Stressors during the adolescent period can affect development of the brain and have long-lasting impacts on behavior. Specifically, adolescent stress impairs hippocampal neurogenesis and can increase risk for anxiety, depression, and a dysregulated stress response in adulthood. In order to model the functional effects of reduced hippocampal neurogenesis during adolescence, a transgenic neurogenesis ablation rat model was used to suppress neurogenesis during the adolescent period and test anxiodepressive behaviors and stress physiology during adulthood. Wildtype and transgenic (TK) rats were given valganciclovir during the first two weeks of adolescence (4-6 weeks old) to knock down neurogenesis in TK rats. Starting in young adulthood (13 weeks old), blood was sampled for corticosterone at several time points following acute restraint stress to measure negative feedback of the stress response, and rats were tested on a battery of anxiodepressive tests at baseline and following acute restraint stress. Although TK rats had large reductions in both cell proliferation during adolescence, as measured by bromodeoxyuridine (BrdU), and ongoing neurogenesis in adulthood (by doublecortin), resulting in decreased volume of the dentate gyrus, negative feedback of the stress response following acute restraint was similar across all rats. Despite similar stress responses, TK rats showed higher anxiety-like behavior at baseline. In addition, only TK rats had increased depressive-like behavior when tested after acute stress. Together, these results suggest that long-term neurogenesis ablation starting in adolescence produces hippocampal atrophy and increases behavioral caution and despair amid stressful environments.
RESUMEN
BACKGROUND: The low carbohydrate, high fat ketogenic diet can be an effective anticonvulsant treatment in some pediatric patients with pharmacoresistant epilepsy. Its mechanism(s) of action, however, remain uncertain. Direct sampling of cerebrospinal fluid before and during metabolic therapy may reveal key changes associated with differential clinical outcomes. We characterized the relationship between seizure responsiveness and changes in lipid and carbohydrate metabolites. METHODS: We performed metabolomic analysis of cerebrospinal fluid samples taken before and during ketogenic diet treatment in patients with optimal response (100% seizure remission) and patients with no response (no seizure improvement) to search for differential diet effects in hallmark metabolic compounds in these two groups. Optimal responders and non-responders were similar in age range and included males and females. Seizure types and the etiologies or syndromes of epilepsy varied but did not appear to differ systematically between responders and non-responders. RESULTS: Analysis showed a strong effect of ketogenic diet treatment on the cerebrospinal fluid metabolome. Longitudinal and between-subjects analyses revealed that many lipids and carbohydrates were changed significantly by ketogenic diet, with changes typically being of larger magnitude in responders. Notably, responders had more robust changes in glucose and the ketone bodies ß-hydroxybutyrate and acetoacetate than non-responders; conversely, non-responders had significant increases in fructose and sorbose, which did not occur in responders. CONCLUSIONS: The data suggest that a differential and stronger metabolic response to the ketogenic diet may predict a better anticonvulsant response, and such variability is likely due to inherent biological factors of individual patients. Strategies to boost the metabolic response may be beneficial.
RESUMEN
Epilepsy is a common neurologic disorder in humans and domesticated canines. In both species the etiology is diverse and complex, and even with medication a significant portion of the population does not experience sufficient seizure control and/or has unacceptable side effects. Humans often try alternatives such as dietary therapy or brain surgery, but in dogs, brain surgery is rarely an option and, despite potential benefits, there are no standard recommendations for a dietary approach. Herein we describe 2 retrospective case studies detailing the effects of homemade diets prepared for dogs with uncontrolled epileptic seizures and/or toxic side effects of medication. Basic recipes are provided for each formula-a high-fat "ketogenic" diet and a partial "whole food" diet. Carbohydrate content was reduced or controlled, and in one case this was proven to be essential for seizure control: ingesting carbohydrates would reverse the benefits of the diet and precipitate a seizure. Both dogs experienced fewer seizures and side effects when eating these modified diets compared to when they were administered antiepileptic drugs, including complete cessation of seizures for extended periods. Practical advantages and success of these homemade dietary interventions highlight the potential for diet-based metabolic therapy as a treatment option for seizures not only in humans but also in dogs.
