Memory Improvement by Yokukansankachimpihange and Atractylenolide III in the Olfactory Bulbectomized Mice

Alzheimer’s Disease (AD) shows cognitive dysfunction as core symptoms and Behavioral and Psychological Symptoms of Dementia (BPSD). Since acetylcholine nerve system derived from septum is collapsed in the AD patients, we have used Olfactory Bulbectomized (OBX) mice whose cholinergic system is largely impaired in the septum. Recently, Yokukansankachimpihange (YKH), a traditional Japanese Kampo medicine has used for BPSD in addition to improve cognitive dysfunction in AD patients. However the essential components for cognition and BPSD improvement and their mechanism are largely unknown. In present study, we found that Atractylenolide III (Aen-III), one of the components of YKH, improved cognitive deficits and depression in the OBX mice. OBX mice were orally administered with Aen-III (1.0 and 3.0 mg/kg) and YKH extracts daily for 18 days. Like YKH extracts, the Aen-III treatments ameliorated cognitive deficits and depression-like behavior observed in OBX mice. Importantly, Aen-III administration significantly restored the decreases in Ca2+/calmodulin-dependent protein kinase II (CaMKII) autophosphorylation and phosphorylation of Ca2+/calmodulin-dependent protein kinase IV (CaMKIV) and cyclic AMP response element binding protein (CREB). The restoration of CaMKII and CaMKIV signaling is closely related to the increased BDNF levels. Furthermore, ATP reduction in OBX mice was rescued by Aen-III (3.0 mg/kg) and YKH (1000 mg/kg) treatment. In summary, Aen-III as a component of YKH ameliorates cognitive dysfunctions and depression via restoring CaMKII and CaMKIV signaling.