Influence of aging on chondroitin sulfate proteoglycan expression and neural stem/progenitor cells in rat brain and improving effects of a herbal medicine, yokukansan

There is evidence of structural and functional deterioration in the brain, including the prefrontal cortex (PFC) and hippocampus, during the normal aging process in animals and humans. Extracellular matrix-associated glycoproteins, such as chondroitin sulfate proteoglycans (CSPGs), are involved in not only maintaining the structures and functions of adult neurons, but also regulating the proliferation, migration, and neurite outgrowth of neural stem cells in the brain. On the other hand, a herbal medicine, yokukansan (YKS), is used in a variety of clinical situations for treating symptoms associated with age-related neurodegenerative disorders such as Alzheimer's disease, but its pharmacological properties have not been fully understood. The present study was designed to clarify the influence of aging and the improving effects of YKS on the expression of aggrecan, a major molecule of CSPGs, and on the proliferation and migration of neural stem/progenitor cells identified by bromodeoxyuridine (BrdU) incorporation in the PFC and hippocampus including the dentate gyrus. Aged rats (24 months old) showed a significant increase in aggrecan expression throughout the PFC and in the hippocampus particularly in the CA3 subfield, but not the dentate gyrus compared to young rats (5 months old), evaluated by the immunohistochemical method. YKS treatment decreased the age-related increase in aggrecan expression as well as normal expression in young rats. Aged rats also showed a decreased number of BrdU-labeled cells in the PFC and hippocampus, and these decreases were improved by YKS treatment, which also increased the numbers in young rats. These results suggest that aging influences the microenvironment for adult and immature neurons in the brain, which may affect the proliferation and migration of neural stem/progenitor cells, and YKS has pharmacological potency for these age-related events. These findings help to understand the physiology and pathology of the aged brain and provide an anti-aging strategy for the brain.