Memantine reduces the production of amyloid-β peptides through modulation of amyloid precursor protein trafficking

Ito, Kaori; Tatebe, Takuya; Suzuki, Kenichi; Hirayama, Takashi; Hayakawa, Maki; Kubo, Hideo; Tomita, Taisuke; Makino, Mitsuhiro

doi:10.1016/j.ejphar.2017.02.001

Cited by 34 publications

(25 citation statements)

References 43 publications

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“…The key to understanding the greater effect of the combination on Aβ is that each drug acts differently. The ability of memantine to reduce Aβ levels in brains of AD animal models is well documented . Recently, it has been reported that memantine is able to inhibit the formation of Aβ (1–42) aggregates in a concentration‐dependent manner .…”

Section: Discussionmentioning

confidence: 99%

“…Recently, it has been reported that memantine is able to inhibit the formation of Aβ (1–42) aggregates in a concentration‐dependent manner . It is proposed that the effects of memantine on Aβ aggregation are mediated by an NMDA receptor‐independent mechanism but other data indicate that memantine may affect the convergence of APP and β‐site APP cleaving enzyme 1 through both NMDA‐dependent and NMDA‐independent pathways . Recent results indicate also that memantine affects the endocytosis of APP, which is required for its β‐secretase‐mediated cleavage; thus, causing decreased Aβ production Melatonin also displays anti‐amyloidogenic properties in AD (for review).…”

Section: Discussionmentioning

confidence: 99%

“…It is proposed that the effects of memantine on Aβ aggregation are mediated by an NMDA receptor‐independent mechanism but other data indicate that memantine may affect the convergence of APP and β‐site APP cleaving enzyme 1 through both NMDA‐dependent and NMDA‐independent pathways . Recent results indicate also that memantine affects the endocytosis of APP, which is required for its β‐secretase‐mediated cleavage; thus, causing decreased Aβ production Melatonin also displays anti‐amyloidogenic properties in AD (for review). Cell culture studies demonstrated that melatonin inhibits the formation of soluble APP, which in turn may prevent Aβ production .…”

Section: Discussionmentioning

confidence: 99%

“…The ability of memantine to reduce Ab levels in brains of AD animal models is well documented. [53,[56][57][58] Recently, it has been reported that memantine is able to inhibit the formation of Ab aggregates in a concentration-dependent manner. [59] It is proposed that the effects of memantine on Ab aggregation are mediated by an NMDA receptor-independent mechanism [59] but other data indicate that memantine may affect the convergence of APP and b-site APP cleaving enzyme 1 through both NMDA-dependent and NMDA-independent pathways.…”

Section: Discussionmentioning

confidence: 99%

“…[59] It is proposed that the effects of memantine on Ab aggregation are mediated by an NMDA receptor-independent mechanism [59] but other data indicate that memantine may affect the convergence of APP and b-site APP cleaving enzyme 1 through both NMDA-dependent and NMDA-independent pathways. [57] Recent results indicate also that memantine affects the endocytosis of APP, which is required for its b- Figure 3 The number of Iba-1-positive particles in the brain of untreated and treated 5xFAD animals. The number of Iba-1-positive particles in the brain of 5xFAD transgenic mice treated with melatonin 6 mg/kg, memantine 10 mg/kg or a combination of memantine 10 mg/kg + melatonin 6 mg/kg.…”

Section: Discussionmentioning

confidence: 99%

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Effects of the drug combination memantine and melatonin on impaired memory and brain neuronal deficits in an amyloid-predominant mouse model of Alzheimer's disease

Jürgenson

Zharkovskaja

Noortoots

et al. 2019

Journal of Pharmacy and Pharmacology

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Objectives Alzheimer's disease (AD) is a neurodegenerative disorder with no cure. Limited treatment options available today do not offer solutions to slow or stop any of the suspected causes. The current medications used for the symptomatic treatment of AD include memantine and acetylcholine esterase inhibitors. Some studies suggest that melatonin could also be used in AD patients due to its sleep‐improving properties. Methods In this study, we evaluated whether a combination of memantine with melatonin, administered for 32 days in drinking water, was more effective than either drug alone with respect to Aβ aggregates, neuroinflammation and cognition in the double transgenic APP/PS1 (5xFAD) mouse model of AD. Key findings In this study, chronic administration of memantine with melatonin improved episodic memory in the object recognition test and reduced the number of amyloid aggregates and reactive microgliosis in the brains of 5xFAD mice. Although administration of memantine or melatonin alone also reduced the number of amyloid aggregates and inflammation in brain, this study shows a clear benefit of the drug combination, which had a significantly stronger effect in this amyloid‐dominant mouse model of AD. Conclusion Our data suggest considerable potential for the use of memantine with melatonin in patients with AD.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 3 more Smart Citations

Effects of the drug combination memantine and melatonin on impaired memory and brain neuronal deficits in an amyloid-predominant mouse model of Alzheimer's disease

Jürgenson

Zharkovskaja

Noortoots

et al. 2019

Journal of Pharmacy and Pharmacology

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Memantine‐Loaded PEGylated Biodegradable Nanoparticles for the Treatment of Glaucoma

Sánchez-López

Egea

Davis³

et al. 2017

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Glaucoma is a multifactorial neurodegenerative disease associated with retinal ganglion cells (RGC) loss. Increasing reports of similarities in glaucoma and other neurodegenerative conditions have led to speculation that therapies for brain neurodegenerative disorders may also have potential as glaucoma therapies. Memantine is an N-methyl-d-aspartate (NMDA) antagonist approved for Alzheimer's disease treatment. Glutamate-induced excitotoxicity is implicated in glaucoma and NMDA receptor antagonism is advocated as a potential strategy for RGC preservation. This study describes the development of a topical formulation of memantine-loaded PLGA-PEG nanoparticles (MEM-NP) and investigates the efficacy of this formulation using a well-established glaucoma model. MEM-NPs <200 nm in diameter and incorporating 4 mg mL of memantine were prepared with 0.35 mg mL localized to the aqueous interior. In vitro assessment indicated sustained release from MEM-NPs and ex vivo ocular permeation studies demonstrated enhanced delivery. MEM-NPs were additionally found to be well tolerated in vitro (human retinoblastoma cells) and in vivo (Draize test). Finally, when applied topically in a rodent model of ocular hypertension for three weeks, MEM-NP eye drops were found to significantly (p < 0.0001) reduce RGC loss. These results suggest that topical MEM-NP is safe, well tolerated, and, most promisingly, neuroprotective in an experimental glaucoma model.

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Combination strategy employing BACE1 inhibitor and memantine to boost cognitive benefits in Alzheimer’s disease therapy

Tarif,

Huhe,

Ohno

2024

Psychopharmacology

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Memantine reduces the production of amyloid-β peptides through modulation of amyloid precursor protein trafficking

Cited by 34 publications

References 43 publications

Effects of the drug combination memantine and melatonin on impaired memory and brain neuronal deficits in an amyloid-predominant mouse model of Alzheimer's disease

Effects of the drug combination memantine and melatonin on impaired memory and brain neuronal deficits in an amyloid-predominant mouse model of Alzheimer's disease

Memantine‐Loaded PEGylated Biodegradable Nanoparticles for the Treatment of Glaucoma

Combination strategy employing BACE1 inhibitor and memantine to boost cognitive benefits in Alzheimer’s disease therapy

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