Activation of the Nrf2 Pathway by Sulforaphane Improves Hypoglycaemia-Induced Cognitive Impairment in a Rodent Model...

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 previously demonstrated that recurrent hypoglycaemia (RH) further exacerbates this process through a mechanism involving increased oxidative and inflammatory stress that overwhelms the compensatory activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant system, which was insufficient to prevent cognitive impairment. The current study investigated whether the 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 (125 mg/kg i.p.) and insulin implants (Linbit^®). Diabetic and Control (C57BL6/J) mice were randomly allocated to one of the following seven groups: (i) Control, (ii) STZ-T1D, (iii) Control + RH, (iv) STZ-T1D + RH, (v) Control + RH + SFN, (vi) STZ-T1D + RH + SFN or (vii) STZ-T1D + SFN, and subjected to insulin-induced hypoglycaemia (three episodes per week for four weeks). SFN (50 mg/kg i.p.) or a vehicle (0.1% DMSO/PBS i.p.) were administered 24 h before each hypoglycaemic episode. Cognition was assessed with the Novel Object Recognition (NOR) and spontaneous alternation (SA) tasks. SFN significantly improved the cognitive performance in the 24-h NOR and SA tasks in the STZ-T1D + RH groups. These improvements were absent in the Control or Nrf2-null mice receiving SFN. These studies show, for the first time, that the pharmacological activation of the Nrf2 antioxidant pathway may provide a novel therapeutic target for treating cognitive impairment associated with RH in T1D.