title: Kihi-to, a herbal traditional medicine, improves Abeta(25-35)-induced memory impairment and losses of neurites and synapses.
abstract: BACKGROUND
  We previously hypothesized that achievement of recovery of brain function after the injury requires the reconstruction of neuronal networks, including neurite regeneration and synapse reformation. Kihi-to is composed of twelve crude drugs, some of which have already been shown to possess neurite extension properties in our previous studies. The effect of Kihi-to on memory deficit has not been examined. Thus, the goal of the present study is to determine the in vivo and in vitro effects of Kihi-to on memory, neurite growth and synapse reconstruction.
  
  
  METHODS
  Effects of Kihi-to, a traditional Japanese-Chinese traditional medicine, on memory deficits and losses of neurites and synapses were examined using Alzheimer's disease model mice. Improvements of Abeta(25-35)-induced neuritic atrophy by Kihi-to and the mechanism were investigated in cultured cortical neurons.
  
  
  RESULTS
  Administration of Kihi-to for consecutive 3 days resulted in marked improvements of Abeta(25-35)-induced impairments in memory acquisition, memory retention, and object recognition memory in mice. Immunohistochemical comparisons suggested that Kihi-to attenuated neuritic, synaptic and myelin losses in the cerebral cortex, hippocampus and striatum. Kihi-to also attenuated the calpain increase in the cerebral cortex and hippocampus. When Kihi-to was added to cells 4 days after Abeta(25-35) treatment, axonal and dendritic outgrowths in cultured cortical neurons were restored as demonstrated by extended lengths of phosphorylated neurofilament-H (P-NF-H) and microtubule-associated protein (MAP)2-positive neurites. Abeta(25-35)-induced cell death in cortical culture was also markedly inhibited by Kihi-to. Since NF-H, MAP2 and myelin basic protein (MBP) are substrates of calpain, and calpain is known to be involved in Abeta-induced axonal atrophy, expression levels of calpain and calpastatin were measured. Treatment with Kihi-to inhibited the Abeta(25-35)-evoked increase in the calpain level and decrease in the calpastatin level. In addition, Kihi-to inhibited Abeta(25-35)-induced calcium entry.
  
  
  CONCLUSIONS
  In conclusion Kihi-to clearly improved the memory impairment and losses of neurites and synapses.
authors.affiliation: Division of Biofunctional Evaluation, Research Center for Ethnomedicine, Institute of Natural Medicine, University of Toyama, Toyama 930-0194, Japan. chihiro@inm.u-toyama.ac.jp
authors.forename: Chihiro
authors.initials: C
authors.lastname: Tohda
authors.forename: Rie
authors.initials: R
authors.lastname: Naito
authors.forename: Eri
authors.initials: E
authors.lastname: Joyashiki
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000187:drug effects*; D000818:Animals; D001369:Axons / Q000187:drug effects*; D004195:Disease Models, Animal; D004365:Drugs, Chinese Herbal / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D016501:Neurites / Q000187:drug effects*; D010446:Peptide Fragments / Q000187:drug effects*; D013569:Synapses / Q000187:drug effects*
chemical_list: D016229:Amyloid beta-Peptides; D004365:Drugs, Chinese Herbal; D010446:Peptide Fragments; C074636:amyloid beta-protein (25-35); C073747:kamikihi-to