Kamikihi-to (KKT) Rescues Axonal and Synaptic Degeneration Associated with Memory Impairment in a Mouse Model of Alzheimer's Disease, 5XFAD

Tohda, Chihiro; Nakada, Rie; Urano, Takuya; Okonogi, Akira; Kuboyama, Tomoharu

doi:10.3109/00207454.2011.602809

Cited by 40 publications

(47 citation statements)

References 35 publications

(35 reference statements)

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“…42) Memory deficits in 5XFAD mice were demonstrated after 4 months old by contextual fear conditioning 43) and Y-maze test. 41) We additionally confirmed impairment of spatial memory 44) and object recognition memory 45,46) in these mice.…”

Section: Diosgenin Its Activities and Signaling Pathwaysupporting

confidence: 69%

New Age Therapy for Alzheimer’s Disease by Neuronal Network Reconstruction

Tohda

2016

Biological & Pharmaceutical Bulletin

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Alzheimer's disease (AD) is a recognized incurable neurodegenerative disorder. Clinically prescribed medicines for AD are expected to bring about only slight symptomatic improvement or a delay of its progression. Another strategy, amyloid β (Aβ) lowing agents, has not been successful at memory improvement. We have hypothesized that an improvement in cognitive function requires the construction of neuronal networks, including neurite regeneration and synapse formation; therefore, we have been exploring candidates for radical anti-AD drugs that can restore Aβ-induced neurite atrophy and memory impairment. Our studies found several promising drug candidates that may improve memory dysfunction in AD model mice. The main activity of these drugs is the restoration of damaged axons. Focusing on candidates based on the recovery of neurite atrophy in vitro certainly leads to positive effects on memory improvement also in vivo. This suggests that neuronal network reconstruction may importantly relate to functional recovery in the brain. When identifying the signaling mechanisms of exogenous compounds like natural medicine-derived constituents, molecules directly activated by the compound are hard to be identified. However, the drug affinity responsive target stability (DARTS) analysis may pave the way to an approach to determine the initial molecule of the signaling pathway. Exploring new drug candidates and clarifying their signaling pathways directly relating to neuronal network reconstruction may provide promising therapeutic strategies with which to overcome AD.

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Section: Diosgenin Its Activities and Signaling Pathwaysupporting

confidence: 69%

New Age Therapy for Alzheimer’s Disease by Neuronal Network Reconstruction

Tohda

2016

Biological & Pharmaceutical Bulletin

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“…In this model, KKT improved deficits in object recognition memory, as indicated on behavior analysis. Furthermore, on histopathology KKT improved axonal and presynaptic degeneration inside amyloid plaques in the frontal cortex [20]. Moreover, long-term KKT improved learning performance in a mouse model of accelerated senescence, and increased both muscarinic receptor density and ChAT activity in aged rats [21,22].…”

Section: Discussionmentioning

confidence: 98%

Effect of donepezil and kamikihito combination therapy on cognitive function in Alzheimer's disease: Retrospective study

Ishida

2016

Traditional & Kampo Medicine

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Aim: Kamikihito (KKT) is a herbal drug used in traditional Japanese medicine (kampo medicine) to treat psychological symptoms such as insomnia, restlessness, and fear. The aim of this study was to investigate the effect of the combination of KKT extract and donepezil (DPZ) on the cognitive function of patients diagnosed with Alzheimer's disease (AD). Methods: The effect of this combination therapy (CBT) was analyzed retrospectively using Mini-Mental State Examination (MMSE). AD patients were treated with DPZ (5 mg/day). Those with psychological symptoms, such as insomnia, were also given the KKT extract (7.5 g/day), beginning 3 months after the initiation of DPZ. Results: Medical records of patients who visited the outpatient department for the first time between May 2010 and January 2013 were retrospectively evaluated, and six patients from each group selected as candidates for this study. Changes in total MMSE score for the DPZ and CBT groups were unremarkable until 6 months; at 12 months the scores were markedly, but non-significantly, different: cognitive function was maintained in the CBT group while it deteriorated in the DPZ group. On MMSE subscale analysis, delayed memory recall score in the CBT group was sustained in a statistically significant manner. Conclusion: CBT may prolong the effect of DPZ and, thus, CBT may be more beneficial than monotherapy using DPZ.

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“…KKT is a herbal drug known for its effectiveness in treating insomnia, loss of appetite, amnesia, and depression. We previously reported the effect of KKT in the 5XFAD mouse model of AD [7]. 5XFAD mice exhibit increased A β production, A β plaques, and gliosis at 2 months of age and synapse loss and memory impairment at 4 months of age [8].…”

Section: Introductionmentioning

confidence: 99%

New Treatment for Alzheimer’s Disease, Kamikihito, Reverses Amyloid‐β‐Induced Progression of Tau Phosphorylation and Axonal Atrophy

Watari

Shimada

Tohda

2014

Evidence-Based Complementary and Alternative Medicine

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Aims. We previously reported that kamikihito (KKT), a traditional Japanese medicine, improved memory impairment and reversed the degeneration of axons in the 5XFAD mouse model of Alzheimer's disease (AD). However, the mechanism underlying the effects of KKT remained unknown. The aim of the present study was to investigate the mechanism by which KKT reverses the progression of axonal degeneration. Methods. Primary cultured cortical neurons were treated with amyloid beta (Aβ) fragment comprising amino acid residues (25–35) (10 μM) in an in vitro AD model. KKT (10 μg/mL) was administered to the cells before or after Aβ treatment. The effects of KKT on Aβ-induced tau phosphorylation, axonal atrophy, and protein phosphatase 2A (PP2A) activity were investigated. We also performed an in vivo assay in which KKT (500 mg/kg/day) was administered to 5XFAD mice once a day for 15 days. Cerebral cortex homogenates were used to measure PP2A activity. Results. KKT improved Aβ-induced tau phosphorylation and axonal atrophy after they had already progressed. In addition, KKT increased PP2A activity in vitro and in vivo. Conclusions. KKT reversed the progression of Aβ-induced axonal degeneration. KKT reversed axonal degeneration at least in part through its role as an exogenous PP2A stimulator.

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Kamikihi-to (KKT) Rescues Axonal and Synaptic Degeneration Associated with Memory Impairment in a Mouse Model of Alzheimer's Disease, 5XFAD

Cited by 40 publications

References 35 publications

New Age Therapy for Alzheimer’s Disease by Neuronal Network Reconstruction

New Age Therapy for Alzheimer’s Disease by Neuronal Network Reconstruction

Effect of donepezil and kamikihito combination therapy on cognitive function in Alzheimer's disease: Retrospective study

New Treatment for Alzheimer’s Disease, Kamikihito, Reverses Amyloid‐β‐Induced Progression of Tau Phosphorylation and Axonal Atrophy

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