Immunomodulation by memantine in therapy of Alzheimer's disease is mediated through inhibition of Kv1.3 channels and T cell responsiveness

Lowinus, Theresa; Bose, Tanima; Busse, Stefan; Busse, Mandy; Reinhold, Dirk; Schraven, Burkhart; Bommhardt, Ursula

doi:10.18632/oncotarget.10777

Cited by 21 publications

(16 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We reported that in lymphocytes memantine blocks K v 1.3 channel activity and diminishes lymphocyte effector function [37, 38]. Furthermore, standard doses of memantine applied in Alzheimer therapy inhibit K v 1.3 channels on patients’ peripheral blood T cells and alter T cell reactivity in vivo [39]. Thus, we asked whether pharmacological inhibition of K v 1.3 channels by memantine could be an option to enhance cell death of acute leukemia cells induced by the chemotherapeutic drug cytarabine (AraC).…”

Section: Introductionmentioning

confidence: 99%

Memantine potentiates cytarabine-induced cell death of acute leukemia correlating with inhibition of Kv1.3 potassium channels, AKT and ERK1/2 signaling

et al. 2019

Self Cite

View full text Add to dashboard Cite

BackgroundTreatment of acute leukemia is challenging and long-lasting remissions are difficult to induce. Innovative therapy approaches aim to complement standard chemotherapy to improve drug efficacy and decrease toxicity. Promising new therapeutic targets in cancer therapy include voltage-gated Kv1.3 potassium channels, but their role in acute leukemia is unclear. We reported that Kv1.3 channels of lymphocytes are blocked by memantine, which is known as an antagonist of neuronal N-methyl-D-aspartate type glutamate receptors and clinically applied in therapy of advanced Alzheimer disease. Here we evaluated whether pharmacological targeting of Kv1.3 channels by memantine promotes cell death of acute leukemia cells induced by chemotherapeutic cytarabine.MethodsWe analyzed acute lymphoid (Jurkat, CEM) and myeloid (HL-60, Molm-13, OCI-AML-3) leukemia cell lines and patients’ acute leukemic blasts after treatment with either drug alone or the combination of cytarabine and memantine. Patch-clamp analysis was performed to evaluate inhibition of Kv1.3 channels and membrane depolarization by memantine. Cell death was determined with propidium iodide, Annexin V and SYTOX staining and cytochrome C release assay. Molecular effects of memantine co-treatment on activation of Caspases, AKT, ERK1/2, and JNK signaling were analysed by Western blot. Kv1.3 channel expression in Jurkat cells was downregulated by shRNA.ResultsOur study demonstrates that memantine inhibits Kv1.3 channels of acute leukemia cells and in combination with cytarabine potentiates cell death of acute lymphoid and myeloid leukemia cell lines as well as primary leukemic blasts from acute leukemia patients. At molecular level, memantine co-application fosters concurrent inhibition of AKT, S6 and ERK1/2 and reinforces nuclear down-regulation of MYC, a common target of AKT and ERK1/2 signaling. In addition, it augments mitochondrial dysfunction resulting in enhanced cytochrome C release and activation of Caspase-9 and Caspase-3 leading to amplified apoptosis.ConclusionsOur study underlines inhibition of Kv1.3 channels as a therapeutic strategy in acute leukemia and proposes co-treatment with memantine, a licensed and safe drug, as a potential approach to promote cytarabine-based cell death of various subtypes of acute leukemia.Electronic supplementary materialThe online version of this article (10.1186/s12964-018-0317-z) contains supplementary material, which is available to authorized users.

show abstract

Section: Introductionmentioning

confidence: 99%

Memantine potentiates cytarabine-induced cell death of acute leukemia correlating with inhibition of Kv1.3 potassium channels, AKT and ERK1/2 signaling

et al. 2019

Self Cite

View full text Add to dashboard Cite

show abstract

“…Furthermore, administration of memantine leads to a significant reduction of memory T cells (e.g., CD45RO+ CD4+) in the blood. This could be a double-edged sword as memantine can control unbalanced CD4+ T cells infiltration in AD, but may also increase the infection rate [ 75 ] Memantine can selectively inhibit Th1 but not Th2 or Treg [ 37 , 76 ] ( Figure 5 and Table 7 ). However, its effect on Th17 is still not known.…”

Section: Effect Of Ad Drugs On Cd4+ T Cells Proliferation and Diffmentioning

confidence: 99%

Drugs Modulating CD4+ T Cells Blood–Brain Barrier Interaction in Alzheimer’s Disease

Kubick

Flournoy²,

Enciu

et al. 2020

Pharmaceutics

View full text Add to dashboard Cite

The effect of Alzheimer’s disease (AD) medications on CD4+ T cells homing has not been thoroughly investigated. CD4+ T cells could both exacerbate and reduce AD symptoms based on their infiltrating subpopulations. Proinflammatory subpopulations such as Th1 and Th17 constitute a major source of proinflammatory cytokines that reduce endothelial integrity and stimulate astrocytes, resulting in the production of amyloid β. Anti-inflammatory subpopulations such as Th2 and Tregs reduce inflammation and regulate the function of Th1 and Th17. Recently, pathogenic Th17 has been shown to have a superior infiltrating capacity compared to other major CD4+ T cell subpopulations. Alzheimer’s drugs such as donepezil (Aricept), rivastigmine (Exelon), galantamine (Razadyne), and memantine (Namenda) are known to play an important part in regulating the mechanisms of the neurotransmitters. However, little is known about the effect of these drugs on CD4+ T cell subpopulations’ infiltration of the brain during AD. In this review, we focus on understanding the influence of AD drugs on CD4+ T cell subpopulation interactions with the BBB in AD. While current AD therapies improve endothelial integrity and reduce astrocytes activations, they vary according to their influence on various CD4+ T cell subpopulations. Donepezil reduces the numbers of Th1 but not Th2, Rivastigmine inhibits Th1 and Th17 but not Th2, and memantine reduces Th1 but not Treg. However, none of the current AD drugs is specifically designed to target the dysregulated balance in the Th17/Treg axis. Future drug design approaches should specifically consider inhibiting CD4+ Th17 to improve AD prognosis.

show abstract

“…CD45RO+ CD4+ ) in the blood. This could be a double edge sword as memantine can control unbalanced CD4+ T cells infiltration in AD, but may also increase the infection rate [38]. Regrettably, the information covering the difference in the impact of these drugs on CD4+ T cells subpopulations homing is scarce, however vital that could be.…”

Section: Main Text I)mentioning

confidence: 99%

Drugs Modulating CD4+ T Cells Blood-Brain Barrier Interaction in Alzheimer's Disease

Kubick¹,

Flournoy²,

Enciu³

et al. 2020

Preprint

View full text Add to dashboard Cite

The effect of Alzheimer's disease (AD) medications on CD4+ T cells homing has not been thoroughly investigated. Alzheimer's disturbs the life of at least five million persons in the USA. CD4+ T cells could both exacerbate and reduce AD symptoms. Regulating CD4+ T cells homing to the leaky blood-brain barrier (BBB) constitutes a new hope for enhancing AD prognosis. Alzheimer's drugs such as Donepezil (Aricept), Rivastigmine (Exelon), Galantamine (Razadyne) and memantine are known to play an important part in regulating the neurotransmitters mechanisms. However, little is known about the effect of these drugs on CD4+ T cells homing. In this review, we focus on current and new drugs that could modulate CD4+ T cells interactions with the BBB in AD.

show abstract

Immunomodulation by memantine in therapy of Alzheimer's disease is mediated through inhibition of Kv1.3 channels and T cell responsiveness

Cited by 21 publications

References 45 publications

Memantine potentiates cytarabine-induced cell death of acute leukemia correlating with inhibition of Kv1.3 potassium channels, AKT and ERK1/2 signaling

Memantine potentiates cytarabine-induced cell death of acute leukemia correlating with inhibition of Kv1.3 potassium channels, AKT and ERK1/2 signaling

Drugs Modulating CD4+ T Cells Blood–Brain Barrier Interaction in Alzheimer’s Disease

Drugs Modulating CD4+ T Cells Blood-Brain Barrier Interaction in Alzheimer's Disease

Contact Info

Product

Resources

About