Abstract
BackgroundChotosan (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).MethodsAge-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.ResultsCompared 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.ConclusionRecovery 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.
Highlights
Chotosan (CTS, Diaoteng San), a Kampo medicine formula, is reportedly effective in the treatment of patients with cerebral ischemic insults
The sham- and transient two vessel occlusion (T2VO)-senescence-accelerated prone mice 8 (SAMP8) treated with vehicle spent a significantly longer time exploring the open arms than the senescence-resistant inbred strain mice (SAMR1) controls (t = -5.468, df = 17, P < 0.001, t-test)
The administration of CTS (750 mg/kg per day, p.o.) to sham- and T2VO-SAMP8 reduced the proportion of time spent in open arms by these animal groups [Fdrug treatment (1,34) = 76.639, P
Summary
Chotosan (CTS, Diaoteng San), a Kampo medicine (ie Chinese medicine) formula, is reportedly effective in the treatment of patients with cerebral ischemic insults. CTS and tacrine (a cholinesterase inhibitor) exhibit a preventive effect on cognitive deficits in a mouse model of transient cerebral ischemia and a therapeutic effect on learning and memory impairments in a mouse model of chronic cerebral hypoperfusion [2,3]. These findings suggest that CTS may be used as an anti-dementia drug. Since the beneficial effects of CTS have been demonstrated in young animals from eight to 15 weeks old, it is still unclear whether CTS is applicable to treat cognitive dysfunction caused by ischemic insult in aged animals
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