title: Chotosan (Diaoteng San)-induced improvement of cognitive deficits in senescence-accelerated mouse (SAMP8) involves the amelioration of angiogenic/neurotrophic factors and neuroplasticity systems in the brain.
abstract: BACKGROUND
  Chotosan (CTS, Diaoteng San), a Kampo medicine (ie Chinese medicine) formula, is reportedly effective in the treatment of patients with cerebral ischemic insults. This study aims to evaluate the therapeutic potential of CTS in cognitive deficits and investigates the effects and molecular mechanism(s) of CTS on learning and memory deficits and emotional abnormality in an animal aging model, namely 20-week-old senescence-accelerated prone mice (SAMP8), with and without a transient ischemic insult (T2VO).
  
  
  METHODS
  Age-matched senescence-resistant inbred strain mice (SAMR1) were used as control. SAMP8 received T2VO (T2VO-SAMP8) or sham operation (sham-SAMP8) at day 0. These SAMP8 groups were administered CTS (750 mg/kg, p.o.) or water daily for three weeks from day 3.
  
  
  RESULTS
  Compared with the control group, both sham-SAMP8 and T2VO-SAMP8 groups exhibited cognitive deficits in the object discrimination and water maze tests and emotional abnormality in the elevated plus maze test. T2VO significantly exacerbated spatial cognitive deficits of SAMP8 elucidated by the water maze test. CTS administration ameliorated the cognitive deficits and emotional abnormality of sham- and T2VO-SAMP8 groups. Western blotting and immunohistochemical studies revealed a marked decrease in the levels of phosphorylated forms of neuroplasticity-related proteins, N-methyl-D-aspartate receptor 1 (NMDAR1), Ca2+/calmodulin-dependent protein kinase II (CaMKII), cyclic AMP responsive element binding protein (CREB) and brain-derived neurotrophic factor (BDNF) in the frontal cortices of sham-SAMP8 and T2VO-SAMP8. Moreover, these animal groups showed significantly reduced levels of vasculogenesis/angiogenesis factors, vascular endothelial growth factor (VEGF), VEGF receptor type 2 (VEGFR2), platelet-derived growth factor-A (PDGF-A) and PDGF receptor α (PDGFRα). CTS treatment reversed the expression levels of these factors down-regulated in the brains of sham- and T2VO-SAMP8.
  
  
  CONCLUSIONS
  Recovery of impaired neuroplasticity system and VEGF/PDGF systems may play a role in the ameliorative effects of CTS on cognitive dysfunction caused by aging and ischemic insult.
authors.affiliation: Division of Medicinal Pharmacology, Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan. mkinzo@inm.u-toyama.ac.jp.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhao
authors.forename: Takako
authors.initials: T
authors.lastname: Yokozawa
authors.forename: Koichi
authors.initials: K
authors.lastname: Tsuneyama
authors.forename: Ken
authors.initials: K
authors.lastname: Tanaka
authors.forename: Takeshi
authors.initials: T
authors.lastname: Miyata
authors.forename: Notoshi
authors.initials: N
authors.lastname: Shibahara
authors.forename: Kinzo
authors.initials: K
authors.lastname: Matsumoto