Improvement of cognitive impairment in female type 2 diabetes mellitus mice by spironolactone

Abstract

Patients with type 2 diabetes mellitus (T2DM) exhibit more severe cognitive decline in females compared with males; however, the preventive approach to this gender-specific cognitive decline is still an enigma. Spironolactone is a potassiumsparing diuretic that also acts as an androgen receptor antagonist. Here, we investigated whether spironolactone attenuates cognitive impairment observed in female T2DM mice. Adult wild-type (WT) mice and an obese T2DM model, KKAy mice, were employed in this study. Cognitive function was evaluated by the shuttle avoidance test and Morris water maze test. Administration of spironolactone (50 mg/kg per day in chow) had no significant effect on blood pressure, glucose tolerance or insulin resistance. In WT mice, no significant sex difference in cognitive function was observed; however, treatment with spironolactone improved spatial memory in the water maze, especially in female WT mice. Administration of spironolactone markedly improved the cognitive decline in female KKAy mice up to the level in male KKAy mice. Spironolactone treatment also improved cognitive function in ovariectomized-KKAy mice, but failed to improve it in those with administration of estradiol (200 μg/kg per day). In diabetic mice, spironolactone improved impaired cognitive function observed in female mice, suggesting that spironolactone may prevent cognitive impairment associated with diabetes in females clinically.

The effects of aldosterone on diet-induced fatty liver formation in male C57BL/6 mice

“…Similar results were observed in adrenalectomized obese mice and patients with primary aldosteronism after ADX [20][21][22][23]. The discrepancy between our study and other studies showing improved fasting glucose levels with MRB [10,11] could be explained, at least in part, by the degree of insulin resistance, which was much higher in our study (HOMA index 5 vs. 14, respectively). These results are in agreement with other previously published reports studying the effects of MRB on insulin resistance [4][5][6][7][8][9].…”

“…Some previous reports have shown that MRBs exerted no beneficial effects or even led to the aggravation of hyperglycemia and metabolic syndrome [5][6][7][8][9][10], but other studies have shown that spironolactone treatment ameliorated insulin resistance in obese mice or in diet-induced metabolic syndrome [11,12]. Some previous reports have shown that MRBs exerted no beneficial effects or even led to the aggravation of hyperglycemia and metabolic syndrome [5][6][7][8][9][10], but other studies have shown that spironolactone treatment ameliorated insulin resistance in obese mice or in diet-induced metabolic syndrome [11,12].…”

Gender differences in cognitive deficits in schizophrenia with and without diabetes

“…Gender differences in cognitive deficits in diabetes have also been investigated. Many studies support that female individuals with diabetes have more cognitive deficits than males [29][30][31], whereas another study found that male individuals with diabetes had worse cognitive deficits than females [32]. Another study has also found no gender differences in the cognitive deficits of diabetes [33].…”

“…Studies have also shown that female individuals with diabetes have poorer glycemic control and a higher HbA1c concentration than males [24]. Many studies support that female individuals have more cognitive impairments than males with diabetes only [29][30][31]. However, it is different for individuals with diabetes only.…”

Renin–angiotensin–aldosterone system has a pivotal role in cognitive impairment

“…59 We previously showed that a high plasma aldosterone level is a risk factor for CI, and that the administration of an MR blocker prevents further CI in patients with hypertension. 62 Sakata et al 63 demonstrated that MR blockage with spironolactone improved impaired cognitive function observed in diabetic female mice in a BP-independent manner.…”