Imipramine alleviates memory impairment and hippocampal apoptosis in STZ-induced sporadic Alzheimer’s rat model: Possible contribution of MAPKs and insulin signaling

Javadpour, Pegah; Askari, Sahar; Rashidi, Fatemeh; Dargahi, Leila; Ahmadiani, Abolhassan; Ghasemi, Rasoul

doi:10.1016/j.bbr.2021.113260

Cited by 9 publications

(5 citation statements)

References 54 publications

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“…Our results, taken together with in vivo data showing efficacy of imipramine in rodent models of AD [61,62], suggest that prospective clinical studies of imipramine and olanzapine for the prevention/reversal of AD are warranted and could be accomplished relatively quickly and inexpensively with low risk of adverse events.…”

Section: Discussionmentioning

confidence: 70%

“…By comparison, the recent ENGAGE (NCT02477800) and EMERGE (NCT02484547) trials of aducanumab for AD enrolled more than 1000 subjects per treatment group. Our results, taken together with in vivo data showing efficacy of imipramine in rodent models of AD [ 61 , 62 ], suggest that prospective clinical studies of imipramine and olanzapine for the prevention/reversal of AD are warranted and could be accomplished relatively quickly and inexpensively with low risk of adverse events.…”

Section: Discussionmentioning

confidence: 81%

“…We have yet to evaluate imipramine in rodent AD models. Although previous in vivo studies using AD rodent models [ 61 , 62 ] and the clinical evidence provided herein are promising, prospective randomized controlled trials will be necessary to determine the efficacy and dosing of imipramine and the other hit compounds as AD-modifying therapies (rather than their original indications) in a more controlled population.…”

Section: Discussionmentioning

confidence: 99%

“…Imipramine is a tricyclic antidepressant that blocks norepinephrine and serotonin reuptake. Given the frequent use of antidepressants by AD patients, imipramine has also been evaluated in in vitro and in vivo models of AD, where it has been found to reduce Aβ accumulation and cognitive deficits [61][62][63]. Olanzapine is an antipsychotic drug that has been evaluated for acute treatment of behavioral and psychological symptoms of AD [64].…”

Section: Discussionmentioning

confidence: 99%

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Imipramine and olanzapine block apoE4-catalyzed polymerization of Aβ and show evidence of improving Alzheimer’s disease cognition

et al. 2022

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Background The apolipoprotein E (APOE) ε4 allele confers the strongest risk for late-onset Alzheimer’s disease (AD) besides age itself, but the mechanisms underlying this risk are debated. One hypothesis supported by evidence from multiple labs is that apoE4 binds to the amyloid-β (Aβ) peptide and catalyzes its polymerization into neurotoxic oligomers and fibrils. Inhibiting this early step in the amyloid cascade may thereby reduce or prevent neurodegeneration and AD. Methods Using a design of experiments (DOE) approach, we developed a high-throughput assay to identify inhibitors of apoE4-catalyzed polymerization of Aβ into oligomers and fibrils. We used it to screen the NIH Clinical Collection of small molecule drugs tested previously in human clinical trials. We then evaluated the efficacy and cytotoxicity of the hit compounds in primary neuron models of apoE4-induced Aβ and phosphorylated tau aggregation. Finally, we performed retrospective analyses of the National Alzheimer’s Coordinating Center (NACC) clinical dataset, using Cox regression and Cox proportional hazards models to determine if the use of two FDA-approved hit compounds was associated with better cognitive scores (Mini-Mental State Exam), or improved AD clinical diagnosis, when compared with other medications of the same clinical indication. Results Our high-throughput screen identified eight blood-brain barrier (BBB)-permeable hit compounds that reduced apoE4-catalyzed Aβ oligomer and fibril formation in a dose-dependent manner. Five hit compounds were non-toxic toward cultured neurons and also reduced apoE4-promoted Aβ and tau neuropathology in a dose-dependent manner. Three of the five compounds were determined to be specific inhibitors of apoE4, whereas the other two compounds were Aβ or tau aggregation inhibitors. When prescribed to AD patients for their normal clinical indications, two of the apoE4 inhibitors, imipramine and olanzapine, but not other (non-hit) antipsychotic or antidepressant medications, were associated with improvements in cognition and clinical diagnosis, especially among APOE4 carriers. Conclusions The critical test of any proposed AD mechanism is whether it leads to effective treatments. Our high-throughput screen identified two promising FDA-approved drugs, imipramine and olanzapine, which have no structural, functional, or clinical similarities other than their shared ability to inhibit apoE4-catalyzed Aβ polymerization, thus identifying this mechanism as an essential contribution of apoE4 to AD.

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Section: Discussionmentioning

confidence: 70%

Section: Discussionmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Imipramine and olanzapine block apoE4-catalyzed polymerization of Aβ and show evidence of improving Alzheimer’s disease cognition

et al. 2022

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“…Neuroinflammation leads to cellular impairment in various degrees, mainly synaptic dysfunction (Chugh et al 2015 ), inhibition of neurogenesis (Connolly et al 2022 ), microglial priming (Mumaw et al 2016 ), apoptosis (Javadpour et al 2021 ; Xu et al 2007 ), abnormal phosphorylation (Soto-Faguás et al 2021 ), cleavage (Bi et al 2021 ), and aggregation (Lodeiro et al 2017 ) of key functional CNS proteins. All these alterations result in accelerated brain aging and cognitive impairment (Jardanhazi-Kurutz et al 2010 ).…”

Section: Inflammation and The Central Nervous Systemmentioning

confidence: 99%

Inflammation as common link to progressive neurological diseases

Dias-Carvalho,

Sá,

Carvalho

et al. 2023

Arch Toxicol

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Life expectancy has increased immensely over the past decades, bringing new challenges to the health systems as advanced age increases the predisposition for many diseases. One of those is the burden of neurologic disorders. While many hypotheses have been placed to explain aging mechanisms, it has been widely accepted that the increasing pro-inflammatory status with advanced age or “inflammaging” is a main determinant of biological aging. Furthermore, inflammaging is at the cornerstone of many age-related diseases and its involvement in neurologic disorders is an exciting hypothesis. Indeed, aging and neurologic disorders development in the elderly seem to share some basic pathways that fundamentally converge on inflammation. Peripheral inflammation significantly influences brain function and contributes to the development of neurological disorders, including Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis. Understanding the role of inflammation in the pathogenesis of progressive neurological diseases is of crucial importance for developing effective treatments and interventions that can slow down or prevent disease progression, therefore, decreasing its social and economic burden.

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Cinnamaldehyde Regulates Insulin and Caspase-3 Signaling Pathways in the Sporadic Alzheimer’s Disease Model: Involvement of Hippocampal Function via IRS-1, Akt, and GSK-3β Phosphorylation

et al. 2022

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Imipramine alleviates memory impairment and hippocampal apoptosis in STZ-induced sporadic Alzheimer’s rat model: Possible contribution of MAPKs and insulin signaling

Cited by 9 publications

References 54 publications

Imipramine and olanzapine block apoE4-catalyzed polymerization of Aβ and show evidence of improving Alzheimer’s disease cognition

Imipramine and olanzapine block apoE4-catalyzed polymerization of Aβ and show evidence of improving Alzheimer’s disease cognition

Inflammation as common link to progressive neurological diseases

Cinnamaldehyde Regulates Insulin and Caspase-3 Signaling Pathways in the Sporadic Alzheimer’s Disease Model: Involvement of Hippocampal Function via IRS-1, Akt, and GSK-3β Phosphorylation

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