Direct Stimulation of Angiotensin II Type 2 Receptor Enhances Spatial Memory

Abstract

We examined the possibility that direct stimulation of the angiotensin II type 2 (AT 2 ) receptor by a newly generated direct AT 2 receptor agonist, Compound 21 (C21), enhances cognitive function. Treatment with C21 intraperitoneal injection for 2 weeks significantly enhanced cognitive function evaluated by the Morris water maze test in C57BL6 mice, but this effect was not observed in AT 2 receptor-deficient mice. However, C21-induced cognitive enhancement in C57BL6 mice was attenuated by coadministration of icatibant, a bradykinin B 2 receptor antagonist. Administration of C21 dose dependently increased cerebral blood flow assessed by laser speckle flowmetry and hippocampal field-excitatory postsynaptic potential (f-EPSP) determined by electrophysiological techniques in C57BL6 mice. Furthermore, activation of the AT 2 receptor by C21 promoted neurite outgrowth of cultured hippocampal neurons prepared from fetal transgenic mice expressing green fluorescent protein. Finally, we investigated the pathologic relevance of C21 for spatial learning using an Alzheimer's disease mouse model with intracerebroventricular injection of amyloid-b (1 to 40). We observed that treatment with C21 prevented cognitive decline in this model. These results suggest that a direct AT 2 receptor agonist, C21, enhances cognitive function at least owing to an increase in CBF, enhancement of f-EPSP, and neurite outgrowth in hippocampal neurons.

The Effect of Including the C2 Insert of Nonmuscle Myosin II-C on Neuritogenesis

“…3 Previously, Seidman et al (35) have shown that DMSO/low serum induced the expression of the angiotensin type 2 receptor, AT2, in neuroblastoma cells, NG108-15. The brain AT system has been shown to be involved in learning and memory as well as growth and development (53)(54)(55)(56). We are now further investigating the importance of the C2 insert-containing isoforms of NM II-C in this physiological process.…”

Angiotensin II type 2 receptor signaling affects dopamine levels in the brain and prevents binge eating disorder

“…23 Spontaneous alternation behavior (Figure 2(a)) and spontaneous activity (Figure 2(b)) determined by the Y-maze test were not different between vehicle-and C21-treated groups in C57BL/6 mice, indicating that treatment with C21 did not influence the willingness to explore new environments. However, spontaneous alternation behavior and spontaneous activity in diabetic KKAy mice were significantly impaired in comparison with those in C57BL/6 mice, and were improved by the administration of C21.…”

Compound 21 Induces Vasorelaxation via an Endothelium- and Angiotensin II Type 2 Receptor-Independent Mechanism

“…Taken together, this combination of both relaxant and constrictor effects can help explaining the hypertensive and hypotensive effects of C21 in vivo, including even the absence of such effects. [15][16][17]20,36 It rules out the application of C21 as an antihypertensive agent. Clearly, studies observing organ-protective effects of chronic C21 application should now carefully determine to what degree these effects truly depend on AT 2 receptor activation, by using either selective AT 2 receptor antagonists or by simultaneously studying the effects in AT 2 receptor knockout models.…”