Possible synergistic effect of direct angiotensin II type 2 receptor stimulation by compound 21 with memantine on prevention of cognitive decline in type 2 diabetic mice.

Type 2 diabetes mellitus (T2DM) is known to be associated with increased risk of cognitive impairment including Alzheimer disease. Recent studies have suggested an interaction between angiotensin II and N-methyl-d-aspartic acid (NMDA) glutamate receptors. We previously reported that stimulation of the angiotensin II type 2 (AT2) receptor exerts brain protective effects. A newly developed AT2 receptor agonist, compound 21 (C21), has enabled examination of the direct effect of AT2 receptor stimulation in vivo. Accordingly, we examined the possible synergistic effect of C21 and memantine on cognitive impairment in T2DM mice, KKAy. KKAy were divided into four groups; (1) control, (2) treatment with C21 (10 μg/kg/day), (3) treatment with memantine (20mg/kg/day), and (4) treatment with both for 4 weeks, and subjected to Morris water maze tasks. Treatment with C21 or memantine alone at these doses tended to shorten escape latency compared to that in the control group. C21 treatment increased cerebral blood flow (CBF), but memantine did not influence CBF. Treatment with C21 or C21 plus memantine increased hippocampal field-excitatory postsynaptic potential (f-EPSP). Moreover, treatment with memantine or C21 increased acetylcholine level, which was lower in KKAy than in wild-type mice, and C21 plus memantine treatment enhanced memantine or C21-induced acetylcholine secretion. This study provides an insight into new approaches to understand the interaction of angiotensin II and neurotransmitters. We can anticipate a new therapeutic approach against cognitive decline using C21 and memantine.