Neuroprotective effect of synthetic chalcone derivatives as competitive dual inhibitors against μ-calpain and cathepsin B through the downregulation of tau phosphorylation and insoluble Aβ peptide formation

Jeon, Kyung Hwa; Lee, Eun-Young; Jun, Kyu Yeon; Eom, Ji Eun; Kwak, Soo Yeon; Na, Younghwa; Kwon, Young Joo

doi:10.1016/j.ejmech.2016.06.008

Cited by 27 publications

(12 citation statements)

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“…Other recent developments result from another study that showed that inhibiting calpain‐2 by its selective inhibitor C2‐I enhanced learning and memory in both normal and genetically memory impaired mice by prolonging ERK activation . Another report revealed the downregulatory effect of both τ hyperphosphorylation and Aβ peptide production of synthetic chalcone derivatives conferring them a neuroprotective effect via decreasing p‐MAPK and BACE1 protein levels. Two other calpain inhibitors NYC438 and NYC488, have also been developed and showed promising results and had proven efficacy, potency, and safety …”

Section: Calpain Inhibitors As Ad Therapymentioning

confidence: 99%

“…It is unfortunate to note that most of the currently used calpain inhibitors in AD therapeutics are limited due to their physical and/or chemical properties resulting in inefficient cellular penetration, selectivity, and kinetics. However, hope in this quest occurs from recent development of newly synthetic inhibitors, like A‐705053, A‐933548, A‐953227, NYC438, NYC488, and chalcone derivatives which have proven efficacy . Moreover, preliminary studies using these inhibitors in mouse and rat models of AD provided interesting results recovering cognitive functions when treatment was administered at an early age in these animals …”

Section: Future Directionsmentioning

confidence: 99%

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Involvement of calpain in the neuropathogenesis of Alzheimer’s disease

Mahaman

Huang

Afewerky

et al. 2018

Medicinal Research Reviews

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Alzheimer's disease (AD) is the most common (60% to 80%) age-related disease associated with dementia and is characterized by a deterioration of behavioral and cognitive capacities leading to death in few years after diagnosis, mainly due to complications from chronic illness. The characteristic hallmarks of the disease are extracellular senile plaques (SPs) and intracellular neurofibrillary tangles (NFTs) with neuropil threads, which are a direct result of amyloid precursor protein (APP) processing to Aβ, and τ hyperphosphorylation. However, many indirect underlying processes play a role in this event. One of these underlying mechanisms leading to these histological hallmarks is the uncontrolled hyperactivation of a family of cysteine proteases called calpains. Under normal physiological condition calpains participate in many processes of cells' life and their activation is tightly controlled. However, with an increase in age, increased oxidative stress and other excitotoxicity assaults, this regulatory system becomes impaired and result in increased activation of these proteases involving them in the pathogenesis of various diseases including neurodegeneration like AD. Reviewed here is a pool of data on the implication of calpains in the pathogenesis of AD, the underlying molecular mechanism, and the potential of targeting these enzymes for AD therapeutics.

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Section: Calpain Inhibitors As Ad Therapymentioning

confidence: 99%

Section: Future Directionsmentioning

confidence: 99%

Involvement of calpain in the neuropathogenesis of Alzheimer’s disease

Mahaman

Huang

Afewerky

et al. 2018

Medicinal Research Reviews

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“…Chalcones are one of the bioactive components present in M. urundeuva extracts and responsible for some of the biological activities of this plant. In addition, chalcone derivatives were shown to be neuroprotective, through the downregulation of tau protein phosphorylation and insoluble Aβ peptide formation, involved with the pathogenesis of Alzheimer's disease, a neurodegenerative disease as PD [56]. Furthermore, HDACs inhibitors have been shown to be neuroprotective, both in vitro (astrocyte assays) and in vivo models (rat traumatic brain injury and brain ischemia models) [57,58].…”

Section: Myracrodruon Urundeuva: Neuroprotective Potential On Pdmentioning

confidence: 99%

Neuroprotective and Anti-Inflammatory Properties from the Bioactive Constituents of Myracrodruon Urundeuva, a Brazilian Medicinal Species

Viana¹,

Calou²

2019

Transl Neurosci Res Rev

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Affecting more than 7 million people worldwide [1], Parkinson's disease (PD) remains cureless, leading patients to death in approximately 16-years after the onset of symptoms [2]. In spite of the large number of possibilities in pharmacological and non-pharmacological treatments, these offer only symptomatic relieve to patients. Hence, the first effective therapeutic option available, Levodopa, remains the most effective one, despite not altering the natural history of the disease [3]. Although the refinement of the pharmacological treatment, achieved over the years, reflects a significant improvement in the quality of life of those affected by the pathology, research is focusing on efforts to the discovery of effective neuroprotective strategies against the PD's progression. PD is characterized by the loss of dopaminergic neurons and the presence of alpha-synuclein in the substantia nigra pars compacta (SNPc). Clinical and preclinical studies, as well, support a role of neuroinflammation in the PD pathophysiology, pointing to chronic neuroinflammation as one of the hallmarks of the diseasy [4,5]. Importantly, neuroinflammation is considered a target for neuroprotection actions [6], thus, neuroprotective agents, mainly those from natural sources, could be potential agents to be used for PD prevention and treatment.

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“…3. Other IC 50 values for inhibiting CatB and calpain were obtained from the following references: a Butler et al, 2011; b Jeon et al, 2016; c Huang et al, 1992; d Viswanathan et al, 2012; e Ramalho et al, 2015; f Je Ma et al, 2009; g Weiss et al, 2009 and Coers et al, 2004 J Biol Chem 279:36397-404 h Montagne et al, 2017; i Inubushi et al, 1994; j Trinchese et al, 2008. CATI-1, Cathepsin Inhibitor 1; n.d., not determined.…”

Section: Figurementioning

confidence: 99%

“…E64d, however, was also found to potently inhibit the calcium-activated protease calpain and such inhibition was found to protect against different neuropathologies (Inubushi et al, 1994; Tsubokawa et al, 2006; Trinchese et al, 2008; Jeon et al, 2016). Thus, the current study compared the distinct compounds PADK and E64d with regard to the extent of their CatB modulation vs. their calpain blocking capacity.…”

Section: Introductionmentioning

confidence: 99%

Potential Alzheimer’s Disease Therapeutics Among Weak Cysteine Protease Inhibitors Exhibit Mechanistic Differences Regarding Extent of Cathepsin B Up-Regulation and Ability to Block Calpain

Romine

Rentschler

Smith

et al. 2017

ESJ

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Cysteine protease inhibitors have long been part of drug discovery programs for Alzheimer’s disease (AD), traumatic brain injury (TBI), and other disorders. Select inhibitors reduce accumulating proteins and AD pathology in mouse models. One such compound, Z-Phe-Aladiazomethylketone (PADK), exhibits a very weak IC50 (9–11 μM) towards cathepsin B (CatB), but curiously PADK causes marked up-regulation of the Aβ-degrading CatB and improves spatial memory. Potential therapeutic and weak inhibitor E64d (14 μM IC50) also up-regulates CatB. PADK and E64d were compared regarding the blockage of calcium-induced cytoskeletal deterioration in brain samples, monitoring the 150-kDa spectrin breakdown product (SBDP) known to be produced by calpain. PADK had little to no effect on SBDP production at 10–100 μM. In contrast, E64d caused a dose-dependent decline in SBDP levels with an IC50 of 3–6 μM, closely matching its reported potency for inhibiting μ-calpain. Calpain also cleaves the cytoskeletal organizing protein gephyrin, producing 49-kDa (GnBDP49) and 18-kDa (GnBDP18) breakdown products. PADK had no apparent effect on calcium-induced gephyrin fragments whereas E64d blocked their production. E64d also protected the parent gephyrin in correspondence with reduced BDP levels. The findings of this study indicate that PADK’s positive and selective effects on CatB are consistent with human studies showing exercise elevates CatB and such elevation correlates with improved memory. On the other hand, E64d exhibits both marginal CatB enhancement and potent calpain inhibition. This dual effect may be beneficial for treating AD. Alternatively, the potent action on calpain-related pathology may explain E64d’s protection in AD and TBI models.

show abstract

Neuroprotective effect of synthetic chalcone derivatives as competitive dual inhibitors against μ-calpain and cathepsin B through the downregulation of tau phosphorylation and insoluble Aβ peptide formation

Cited by 27 publications

References 50 publications

Involvement of calpain in the neuropathogenesis of Alzheimer’s disease

Involvement of calpain in the neuropathogenesis of Alzheimer’s disease

Neuroprotective and Anti-Inflammatory Properties from the Bioactive Constituents of Myracrodruon Urundeuva, a Brazilian Medicinal Species

Potential Alzheimer’s Disease Therapeutics Among Weak Cysteine Protease Inhibitors Exhibit Mechanistic Differences Regarding Extent of Cathepsin B Up-Regulation and Ability to Block Calpain

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