Atorvastatin reduces alloxan-induced impairment of aversive stimulus memory in mice

BACKGROUND: An association between dysregulated glucose levels in patients with diabetes mellitus and detrimental effects on the central nervous system, particularly in Alzheimer disease, has been recognized. Atorvastatin treatment has improved memory and cognition in some patients with diabetes mellitus and Alzheimer disease. OBJECTIVES: To determine possible neuroprotective effects of atorvastatin on memory and cognition by measuring changes in an adverse stimulus avoidance learning deficit induced by alloxan in a murine model of diabetes mellitus and impaired memory and cognition. METHODS: We administered 150 mg/kg and 100 mg/kg alloxan in saline (intraperitoneally, i.p.) at a 48 h interval to produce a model of diabetes mellitus in male BALB/c mice. An oral glucose tolerance test (OGTT) was used to assess blood glucose regulation. After demonstrating hyperglycemia in mice (n = 7 per group) we administered vehicle (saline, i.p.), atorvastatin (10 mg/kg, i.p.), or liraglutide (200 μg/kg, i.p.) for 28 d except for those in a negative control group, which were given saline instead of alloxan, and a group administered atorvastatin alone, which were given saline instead of alloxan followed by atorvastatin (10 mg/kg, i.p.) for 28 d. Locomotor activity was measured 24 h after the final drug treatments, and subsequently their learned behavioral response to an adverse electrical stimulus to their plantar paw surface in a dark compartment was measured using a passive avoidance apparatus (Ugo Basile) in a model of impaired memory and cognition associated with Alzheimer disease. To determine any deficit in their learned avoidance of the adverse stimulus, we measured the initial latency or time mice spent in an illuminated white compartment before entering the dark compartment in the learning trial, and on the day after learning to avoid the adverse stimulus, the retention period latency in the light compartment and time spent in the dark compartment. RESULTS: Atorvastatin alone produced no significant change in blood glucose levels (F(4,10) = 0.80, P = 0.55) within 2 h. Liraglutide decreased blood glucose levels after 0.5 h (F(4,10) = 11.7, P < 0.001). We found no significant change in locomotor activity in any group. In mice with alloxan-induced diabetes, atorvastatin significantly attenuated the decreased avoidance associated with the diabetes (F(4,30) = 38.0, P = 0.02) and liraglutide also significantly attenuated the decreased avoidance (F(4,30) = 38.0, P < 0.001). Atorvastatin alone had no significant effect on the adversive learned response compared with vehicle treatment (F(4,30) = 38.0, P > 0.05). Atorvastatin significantly decreased the time mice with alloxan-induced diabetes spent in the dark compartment compared with mice in the diabetes group without atorvastatin treatment (F(4,30) = 53.9, P = 0.046). Liraglutide also significantly reduced the time mice with alloxan-induced diabetes spent in the dark compartment compared with vehicle-treated mice with alloxan-induced diabetes (F(4,30) = 53.9, P < 0.001). Atorvastatin treatment alone had no significant effect on the time mice spent in dark compartment compared with the control group (F(4,30) = 53.9, P > 0.05). CONCLUSION: Atorvastatin significantly attenuated the adverse stimulus avoidance learning deficit in the alloxan-induced murine model of diabetes suggesting decreased impairment of memory and cognition.