Activation of the Nrf2 pathway by sulforaphane improves hypoglycaemia-induced cognitive impairment in a rodent model of Type 1 diabetes

In diabetes, chronic hyperglycaemia leads to cognitive impairment, neurodegeneration and dementia. In a rodent model of streptozotocin (STZ)-induced Type 1 diabetes (STZ-T1D), we have previously demonstrated that recurrent hypoglycaemia (RH) further exacerbates this process though a mechanism involving in-creased oxidative and inflammatory stress that overwhelms compensatory activation of the nuclear factor erythroid 2–related factor 2 (Nrf2) antioxidant system was insufficient to prevent cognitive impairment. The current study investigated whether induction of the antioxidant response through pre-treatment with Sulforaphane (SFN), a potent Nrf2 inducer, would ameliorate these cognitive deficits. A mouse model of chronic insulin-treated T1D was achieved using STZ (125mg/kg i.p.) and insulin implants (Linbit®). Diabetic and Control (C57BL6/J) mice were randomly allocated to one of 8 groups: (i) Control, (ii) STZ-T1D, (iii) Control + RH, (iv) STZ-T1D+RH, (v) Control + RH + SFN, (vi) STZ-T1D+RH+SFN, (vii) STZ-T1D+SFN or (viii) Control + SFN and subjected to insulin-induced hypoglyca-emia (3 episodes per week for four weeks). SFN (50mg/kg i.p.) or vehicle (0.1% DMSO/PBS) was administered 24 hours before each hypoglycemic episode. Cognition was assessed by Novel Object Recognition (NOR) and Spontaneous Alter-nation (SA) tasks. SFN significantly improved cognitive performance in the 24-hour NOR and SA tasks in STZ-T1D+RH groups. These improvements were ab-sent in Control or Nrf2-null mice receiving SFN. These studies show for the first time that pharmacological activation of the Nrf2 antioxidant pathway may prove a novel therapeutic target for treating cognitive impairment associated with RH in T1D.