Abstract
BackgroundWe 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.MethodsEffects 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 Aβ(25–35)-induced neuritic atrophy by Kihi-to and the mechanism were investigated in cultured cortical neurons.ResultsAdministration of Kihi-to for consecutive 3 days resulted in marked improvements of Aβ(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 Aβ(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. Aβ(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 Aβ-induced axonal atrophy, expression levels of calpain and calpastatin were measured. Treatment with Kihi-to inhibited the Aβ(25–35)-evoked increase in the calpain level and decrease in the calpastatin level. In addition, Kihi-to inhibited Aβ(25–35)-induced calcium entry.ConclusionIn conclusion Kihi-to clearly improved the memory impairment and losses of neurites and synapses.
Highlights
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 [4]
Kihi-to ameliorates amyloid E (AE)(25–35)-induced impairments in spatial memory and object recognition The densities of neurites and synapses are decreased in the hippocampus and cerebral cortex of mice 7 days after i.c.v. administration of AE(25–35), and these deficits persist for at least 30 days
phosphorylated neurofilament-H (P-NF-H)-positive areas were quantified in the stratum oriens and stratum radiatum in CA1, the stratum oriens, stratum radiatum and stratum lucidum in CA3, the molecular layer and hilus in the dentate gyrus (DG), the parietal cortex, perirhinal cortex, frontal cortex, and the striatum. *p < 0.05 vs. Veh. n = 3
Summary
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. Neuritic atrophy, and loss of synapses underlie the pathogenesis of Alzheimer's [1,2,3]. Ginsenoside Rb1, a constituent of Ginseng Radix, and the aqueous extract of Astragali Radix attenuated spatial memory deficits and the loss of axons and synapses in the brain of AE(25–35)-injected mice. Cholinesterase inhibitors, such as donepezil hydrochloride, are clinically used for Alzheimer's disease, they do not prevent or reverse the underlying neurodegeneration [9] or attenuate impairments in memory and neuronal damage in AE(25– 35)-injected mice [6,10]
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