Treatment with the direct AT2 receptor agonist Compound 21 significantly enhanced cognitive function in mice and prevented cognitive decline in an Alzheimer's disease mouse model.
Direct stimulation of the AT2 receptor by Compound 21 enhances cognitive function and prevents cognitive decline in mouse models, likely via increased cerebral blood flow and neuronal enhancement.
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-β (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.
Fei et al. (Wed,) conducted a other in Cognitive decline / Alzheimer's disease. Compound 21 (C21) was evaluated on Cognitive function evaluated by the Morris water maze test. Treatment with the direct AT2 receptor agonist Compound 21 significantly enhanced cognitive function in mice and prevented cognitive decline in an Alzheimer's disease mouse model.