Is There Justification to Treat Neurodegenerative Disorders by Repurposing Drugs? The Case of Alzheimer’s Disease, Lithium, and Autophagy

Damri, Odeya; Shemesh, Netta; Agam, Galila

doi:10.3390/ijms22010189

Cited by 30 publications

(34 citation statements)

References 154 publications

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“…In the context of AD, impaired autophagy is thought to be responsible in major part for the accumulation of Aβ and Tau aggregates [ 50 , 52 ]. Not surprising, drugs that activate autophagy have been found to be neuroprotective in cell culture and mouse models of AD [ 172 , 219 , 220 , 221 ]. GSK3 is a well-established inhibitor of autophagy and some studies have shown that inhibitors of GSK3 reduce AD pathology by stimulating autophagy [ 172 , 173 ].…”

Section: The Enzymesmentioning

confidence: 99%

When Good Kinases Go Rogue: GSK3, p38 MAPK and CDKs as Therapeutic Targets for Alzheimer’s and Huntington’s Disease

D’Mello¹

2021

IJMS

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Alzheimer’s disease (AD) is a mostly sporadic brain disorder characterized by cognitive decline resulting from selective neurodegeneration in the hippocampus and cerebral cortex whereas Huntington’s disease (HD) is a monogenic inherited disorder characterized by motor abnormalities and psychiatric disturbances resulting from selective neurodegeneration in the striatum. Although there have been numerous clinical trials for these diseases, they have been unsuccessful. Research conducted over the past three decades by a large number of laboratories has demonstrated that abnormal actions of common kinases play a key role in the pathogenesis of both AD and HD as well as several other neurodegenerative diseases. Prominent among these kinases are glycogen synthase kinase (GSK3), p38 mitogen-activated protein kinase (MAPK) and some of the cyclin-dependent kinases (CDKs). After a brief summary of the molecular and cell biology of AD and HD this review covers what is known about the role of these three groups of kinases in the brain and in the pathogenesis of the two neurodegenerative disorders. The potential of targeting GSK3, p38 MAPK and CDKS as effective therapeutics is also discussed as is a brief discussion on the utilization of recently developed drugs that simultaneously target two or all three of these groups of kinases. Multi-kinase inhibitors either by themselves or in combination with strategies currently being used such as immunotherapy or secretase inhibitors for AD and knockdown for HD could represent a more effective therapeutic approach for these fatal neurodegenerative diseases.

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Section: The Enzymesmentioning

confidence: 99%

When Good Kinases Go Rogue: GSK3, p38 MAPK and CDKs as Therapeutic Targets for Alzheimer’s and Huntington’s Disease

D’Mello¹

2021

IJMS

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“…Additionally, highly dynamic calcium fluctuations happen inside neurons, requiring their steady buffering capacity [ 16 ]. It has recently been suggested that aberrant neuronal function caused by mitochondrial dysfunction may be ameliorated either by ROS scavenging or by enhancing mitophagy [ 17 , 18 , 19 , 20 , 21 ]. Due to the postmitotic nature and metabolic dependence on mitochondria, insufficient or dysregulated mitophagy is detrimental to neurons.…”

Section: Introductionmentioning

confidence: 99%

Do Autophagy Enhancers/ROS Scavengers Alleviate Consequences of Mild Mitochondrial Dysfunction Induced in Neuronal-Derived Cells?

Damri

Natour

Agam

2021

IJMS

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Mitochondrial function is at the nexus of pathways regulating synaptic-plasticity and cellular resilience. The involvement of brain mitochondrial dysfunction along with increased reactive oxygen species (ROS) levels, accumulating mtDNA mutations, and attenuated autophagy is implicated in psychiatric and neurodegenerative diseases. We have previously modeled mild mitochondrial dysfunction assumed to occur in bipolar disorder (BPD) using exposure of human neuronal cells (SH-SY5Y) to rotenone (an inhibitor of mitochondrial-respiration complex-I) for 72 and 96 h, which exhibited up- and down-regulation of mitochondrial respiration, respectively. In this study, we aimed to find out whether autophagy enhancers (lithium, trehalose, rapamycin, and resveratrol) and/or ROS scavengers [resveratrol, N-acetylcysteine (NAC), and Mn-Tbap) can ameliorate neuronal mild mitochondrial dysfunction. Only lithium (added for the last 24/48 h of the exposure to rotenone for 72/96 h, respectively) counteracted the effect of rotenone on most of the mitochondrial respiration parameters (measured as oxygen consumption rate (OCR)). Rapamycin, resveratrol, NAC, and Mn-Tbap counteracted most of rotenone’s effects on OCR parameters after 72 h, possibly via different mechanisms, which are not necessarily related to their ROS scavenging and/or autophagy enhancement effects. The effect of lithium reversing rotenone’s effect on OCR parameters is compatible with lithium’s known positive effects on mitochondrial function and is possibly mediated via its effect on autophagy. By-and-large it may be summarized that some autophagy enhancers/ROS scavengers alleviate some rotenone-induced mild mitochondrial changes in SH-SY5Y cells.

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“…Another study was discontinued after 16-36 weeks of treatment due to the vulnerability of the elderly patients to lithium side effects (Macdonald et al, 2008). Studies of lithium treatment in animal models of AD produced important therapeutic data that has been well summarized elsewhere (Morris and Berk, 2016;Kerr et al, 2018;Damri et al, 2020). Taken together, the clinical results suggest that long-term lithium treatment is required for a beneficial effect, and that it may be particularly effective when started in the early stages of disease.…”

Section: Neurodegenerative Diseases Alzheimer's Disease and Other Tauopathiesmentioning

confidence: 99%

“…Taken together, the clinical results suggest that long-term lithium treatment is required for a beneficial effect, and that it may be particularly effective when started in the early stages of disease. Importantly, the use of microdose lithium may overcome the toxicity problems that have forced the discontinuation of certain previous trials (Morris and Berk, 2016;Damri et al, 2020).…”

Section: Neurodegenerative Diseases Alzheimer's Disease and Other Tauopathiesmentioning

confidence: 99%

Glycogen Synthase Kinase-3 Inhibitors: Preclinical and Clinical Focus on CNS-A Decade Onward

Ruiz

Eldar-Finkelman²

2022

Front. Mol. Neurosci.

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The protein kinase, GSK-3, participates in diverse biological processes and is now recognized a promising drug discovery target in treating multiple pathological conditions. Over the last decade, a range of newly developed GSK-3 inhibitors of diverse chemotypes and inhibition modes has been developed. Even more conspicuous is the dramatic increase in the indications that were tested from mood and behavior disorders, autism and cognitive disabilities, to neurodegeneration, brain injury and pain. Indeed, clinical and pre-clinical studies were largely expanded uncovering new mechanisms and novel insights into the contribution of GSK-3 to neurodegeneration and central nerve system (CNS)-related disorders. In this review we summarize new developments in the field and describe the use of GSK-3 inhibitors in the variety of CNS disorders. This remarkable volume of information being generated undoubtedly reflects the great interest, as well as the intense hope, in developing potent and safe GSK-3 inhibitors in clinical practice.

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Is There Justification to Treat Neurodegenerative Disorders by Repurposing Drugs? The Case of Alzheimer’s Disease, Lithium, and Autophagy

Cited by 30 publications

References 154 publications

When Good Kinases Go Rogue: GSK3, p38 MAPK and CDKs as Therapeutic Targets for Alzheimer’s and Huntington’s Disease

When Good Kinases Go Rogue: GSK3, p38 MAPK and CDKs as Therapeutic Targets for Alzheimer’s and Huntington’s Disease

Do Autophagy Enhancers/ROS Scavengers Alleviate Consequences of Mild Mitochondrial Dysfunction Induced in Neuronal-Derived Cells?

Glycogen Synthase Kinase-3 Inhibitors: Preclinical and Clinical Focus on CNS-A Decade Onward

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