A new approach to the pharmacological regulation of memory: Sarsasapogenin improves memory by elevating the low muscarinic acetylcholine receptor density in brains of memory-deficit rat models

The purpose of this paper is to study the basic pharmacological action of sarsasapogenin, a sapogenin from the Chinese medicinal herb Rhizoma Anemarrhenae, (abbreviated as ZMS in this paper), on learning ability and memory of three animal models: aged rats and two neurodegeneration models produced either by single unilateral injection of beta-amyloid 1–40 (Aβ 1–40) plus ibotenic acid (Ibot A) or by bilateral injection of Ibot A alone into nucleus basalis magnocellularis. Y-maze test and step-through test revealed that learning ability and memory were impaired in the three models and were improved by oral administration of ZMS. ZMS did not inhibit acetylcholinesterase nor did it occupy the binding sites of muscarinic acetylcholine receptor (M receptor), hence it is neither an cholinesterase inhibitor nor an agonist or antagonist of M receptors. On the other hand, the densities of total M receptor and its M 1 subtype in the brain of the three models were significantly lower than control rats, and ZMS significantly raised the densities of total M receptors and its M 1 subtype. Linear regression revealed significant correlation between the learning ability/memory and the density of either total M receptor or its M 1 subtype. Autoradiographic study with 3H-pirenzipine showed that the M 1 subtype density was significantly lowered in cortex, hippocampus and striatum of aged rats, and ZMS could reverse these changes towards normal control level. Interestingly, the M 1 receptor density after ZMS administration only approached but did not exceed that of normal young control rats. Therefore, ZMS seems to represent a new approach to the pharmacological regulation of learning and memory and appears to be not simply palliative but may modify the progression of the disease.