372-P: Activation of the Nrf2 Pathway Provides Protection against Hypoglycaemia-Induced Cognitive Impairment in a Rodent Model of Type 1 Diabetes

Abstract

Whether recurrent mild-moderate hypoglycaemia (RH) has pathological effects on the brain in the long-term remains unknown, but is of major concern to people with type 1 diabetes (T1D). We have previously demonstrated in a rodent model of T1D that RH is associated with impaired cognitive function resulting from a reduced ability to cope with enhanced oxidative stress and that this was associated with activation of the Nrf2 pathway. This study sought to investigate whether pre-treatment with sulforaphane (SFN), a potent Nrf2 inducer would ameliorate the impact of RH on cognitive function in the T1D rodent model. A chronic stable model of chronic insulin-treated T1D was achieved using streptozotocin (125mg/kg i.p) and insulin implants (Linbit®). Diabetic (male C57bl6 mice n=8-10/group) mice were randomly allocated to one of 3 groups: (i) T1D, (ii) T1D+RH, (iii) T1D+RH+SFN and subjected to repeated episodes of insulin-induced moderate hypoglycemia (3 episodes/week for 4 weeks; mean glucose 2.9±0.6 mmol/l). SFN (50mg/kg i.p.) or Vehicle (1% DMSO/PBS) was administered 24 hour prior to each hypoglycemic episode. Cognition was assessed by novel object recognition (NOR) and spontaneous alternation tasks. Data are mean±SEM. Pre-treatment with SFN had no impact upon body weight (p=ns) or fasting blood glucose (p=ns). SFN significantly improved cognitive performance in the 24 hour NOR task in T1D+RH animals when compared to vehicle (80% improvement; p<0.01). Furthermore, performance in the spontaneous alternation task was enhanced to Control levels in T1D+RH following treatment with SFN (25% improvement; p<0.01). The beneficial effects of SFN on cognition were not observed in Nrf2 null mice. Treatment with the SFN significantly improves RH-induced cognitive impairments in a rodent model of T1D. Therefore, activation of the Nrf2 antioxidant pathway offers a novel therapeutic target for the treatment of cognitive impairments associated with RH in T1D. Disclosure A.D. McNeilly: None. J. Gallagher: None. A.T. Dinkova-Kostova: None. R.J. McCrimmon: Advisory Panel; Self; Eli Lilly and Company, Novo Nordisk A/S, Sanofi-Aventis. Research Support; Self; The Leona M. and Harry B. Helmsley Charitable Trust. Funding Diabetes UK