Repair of amyloid beta(25-35)-induced memory impairment and synaptic loss by a Kampo formula, Zokumei-to.
Although Zokumei-to (ZMT), a Kampo formula, has been used for postapopletic sequelae such as paralysis and logopathy, only few studies of this drug have been carried out. We hypothesized that ZMT may affect neuronal plasticity and investigated whether or not this drug is capable of improving learning impairment and synaptic loss observed in patients with Alzheimer's disease (AD). Amyloid beta(25-35) [Abeta(25-35)] (4.7 nmol) was intracerebroventricularly injected into ddY mice (male, 6 weeks old). Fourteen days after the injection, mice were given ZMT extract (500 mg/kg/day) per os for 15 days. In a memory acquisition test, the Abeta(25-35)-injected mice required more time to master this task than did mice in the saline- or reverse peptide Abeta(35-25)-treated groups. ZMT-treated mice shortened escape latencies during trial days 3-5, but not significantly. Three days after the last drug treatment, a retention test was performed. Following ZMT, the number of crossings over a platform was significantly decreased in Abeta(25-35)-injected mice compared with those in the control groups. However, ZMT-treated mice showed complete recovery of this number. Although Abeta(25-35) injection decreased synaptophysin expression in the cerebral cortex and the hippocampus, ZMT treatment significantly increased the level of expression of synaptophysin up to the control level. Donepezil hydrochloride (DNP, 0.5 mg/kg/day, p.o.) clinically used for AD had no effect on memory retention and synaptophysin levels. Abeta(25-35)-induced neuronal loss was not observed in any region of the brain. The present results suggest that memory impairment and synaptic loss in AD patients may be improved by treatment with ZMT, even after such impairment has already progressed.
Tohda
Chihiro
C
Research Center for Ethnomedicines, Institute of Natural Medicine, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0194, Japan.
Tamura
Takayuki
T
Komatsu
Katsuko
K
D000544:Alzheimer Disease / Q000188:drug therapy / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D004365:Drugs, Chinese Herbal / Q000627:therapeutic use*; D007150:Immunohistochemistry; D007276:Injections, Intraventricular; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D020835:Medicine, Kampo; D008569:Memory Disorders / Q000139:chemically induced* / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009473:Neuronal Plasticity / Q000187:drug effects; D010446:Peptide Fragments / Q000633:toxicity*; D013569:Synapses / Q000187:drug effects / Q000473:pathology; D016708:Synaptophysin / Q000096:biosynthesis
D016229:Amyloid beta-Peptides; D004365:Drugs, Chinese Herbal; D010446:Peptide Fragments; D016708:Synaptophysin; C074636:amyloid beta-protein (25-35); C053241:Tsumura-Zokumeito