Lercanidipine boosts the efficacy of mesenchymal stem cell therapy in 3-NP-induced Huntington's disease model rats via modulation of the calcium/calcineurin/NFATc4 and Wnt/β-catenin signalling pathways

Elbaz, Eman M.; Helmy, Hanan; El-Sahar, Ayman E.; Saad, Marina; Sayed, Rabab H.

doi:10.1016/j.neuint.2019.104548

Cited by 28 publications

(21 citation statements)

References 62 publications

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“…Our findings were correlated with the histopathological changes evidenced by the increased striatal injury score and GFAP immunoreactivity as well as extensive neuronal loss shown by Nissl staining indicating neurodegeneration and reactive changes after 3-NP exposure. The elevation of GFAP following astrogliosis has been observed as a long-standing pathological feature in 3-NP model of HD (Ramachandran and Thangarajan 2018; Elbaz et al 2019 ). However, treatment with rhEPO or IFN-β-1b reversed these histopathological changes evidencing their neuroprotective properties.…”

Section: Discussionmentioning

confidence: 99%

Recombinant human erythropoietin and interferon-β-1b protect against 3-nitropropionic acid-induced neurotoxicity in rats: possible role of JAK/STAT signaling pathway

2022

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Abstract3-Nitropropionic acid (3-NP) model serves as a beneficial tool to evaluate the effect of novel treatments for Huntington’s disease (HD). The aim of the present study was to demonstrate the neuroprotective effect of recombinant human erythropoietin (rhEPO) and interferon-beta-1b (IFN-β-1b) in 3-NP-induced neurotoxicity in rats. Rats were injected with 3-NP (10 mg/kg/day, i.p) for 2 weeks and were divided into five subgroups; the first served as the HD group, the second received rhEPO (5000 IU/kg/every other day, i.p.) for 2 weeks, the third received rhEPO starting from the 5th day of 3-NP injection, the fourth received IFN-β-1b (300,000 units, every day other day, s.c) for 2 weeks, and the last received IFN-β-1b starting from the 5th day of 3-NP injection. All treatments significantly improved motor and behavior performance of rats. Moreover, all treatments markedly restored mitochondrial function as well as brain-derived neurotrophic factor level, and reduced oxidative stress biomarkers, pro-inflammatory mediators, nuclear factor kappa B expression, caspase-3, and Bax/Bcl2 ratio in the striatum. In conclusion, the present study demonstrates the neuroprotective potential of rhEPO or IFN-β-1b on 3-NP-induced neurotoxicity in rats. Furthermore, our study suggests that activation of JAK2/STAT3 or JAK1/STAT3 may contribute to the neuroprotective activity of rhEPO or IFN-β-1b, respectively. We also found that early treatment with rhEPO did not confer any benefits compared with late rhEPO treatment, while early IFN-β-1b showed a marked significant benefit compared with late IFN-β-1b.

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Section: Discussionmentioning

confidence: 99%

Recombinant human erythropoietin and interferon-β-1b protect against 3-nitropropionic acid-induced neurotoxicity in rats: possible role of JAK/STAT signaling pathway

2022

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“…On the other hand, the inactivation of tau phosphatases is a more probable cause of aberrant tau phosphorylation, since downregulation of PP1, PP2A, and PP2B was detected in different HD mouse models [24,150]. Indeed, the calcium channel blocker, lercanidipine, proved to have neuroprotective effects in 3-nitropropionic acid-induced HD rats via modulation of the Ca 2+ /PP2B/NFATc4 pathway [155]. In a recent study, elevated levels of caspase-2 and truncated tau species were detected in the brain of HD patients, indicating that caspase-2-mediated tau cleavage may play a role in the pathogenesis of HD [25].…”

Section: Tau Impairment and Aberrant Cytoskeleton In Hdmentioning

confidence: 99%

How Do Post-Translational Modifications Influence the Pathomechanistic Landscape of Huntington’s Disease? A Comprehensive Review

Lontay

Kiss

Virág

et al. 2020

IJMS

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Huntington’s disease (HD) is an autosomal dominant inherited neurodegenerative disorder characterized by the loss of motor control and cognitive ability, which eventually leads to death. The mutant huntingtin protein (HTT) exhibits an expansion of a polyglutamine repeat. The mechanism of pathogenesis is still not fully characterized; however, evidence suggests that post-translational modifications (PTMs) of HTT and upstream and downstream proteins of neuronal signaling pathways are involved. The determination and characterization of PTMs are essential to understand the mechanisms at work in HD, to define possible therapeutic targets better, and to challenge the scientific community to develop new approaches and methods. The discovery and characterization of a panoply of PTMs in HTT aggregation and cellular events in HD will bring us closer to understanding how the expression of mutant polyglutamine-containing HTT affects cellular homeostasis that leads to the perturbation of cell functions, neurotoxicity, and finally, cell death. Hence, here we review the current knowledge on recently identified PTMs of HD-related proteins and their pathophysiological relevance in the formation of abnormal protein aggregates, proteolytic dysfunction, and alterations of mitochondrial and metabolic pathways, neuroinflammatory regulation, excitotoxicity, and abnormal regulation of gene expression.

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“…A less common strategy recently evaluated involved the use of pharmacological agents in combination with MSC to treat polyQ disorders. Elbaz et al ( 2019 ) showed that the combined administration of Lercanidipine (LER), an antihypertensive drug, and MSC boosted their therapeutic efficiency in a rat model for HD. LER is a vasoselective dihydropyridine calcium channel blocker that can modulate calcium levels and, therefore may be able to influence the calcineurin (CaN)/nuclear factor of activated T cells c4 (NFATc4) pathway, which is deregulated in neurodegenerative disorders (Sompol and Norris, 2018 ).…”

Section: Methods To Increase Msc’s Efficacy In Vivomentioning

confidence: 99%

Mesenchymal Stromal Cells’ Therapy for Polyglutamine Disorders: Where Do We Stand and Where Should We Go?

Barros

Marcelo

Silva

et al. 2020

Front. Cell. Neurosci.

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Polyglutamine (polyQ) diseases are a group of inherited neurodegenerative disorders caused by the expansion of the cytosine-adenine-guanine (CAG) repeat. This mutation encodes extended glutamine (Q) tract in the disease protein, resulting in the alteration of its conformation/physiological role and in the formation of toxic fragments/aggregates of the protein. This group of heterogeneous disorders shares common molecular mechanisms, which opens the possibility to develop a pan therapeutic approach. Vast efforts have been made to develop strategies to alleviate disease symptoms. Nonetheless, there is still no therapy that can cure or effectively delay disease progression of any of these disorders. Mesenchymal stromal cells (MSC) are promising tools for the treatment of polyQ disorders, promoting protection, tissue regeneration, and/or modulation of the immune system in animal models. Accordingly, data collected from clinical trials have so far demonstrated that transplantation of MSC is safe and delays the progression of some polyQ disorders for some time. However, to achieve sustained phenotypic amelioration in clinics, several treatments may be necessary. Therefore, efforts to develop new strategies to improve MSC’s therapeutic outcomes have been emerging. In this review article, we discuss the current treatments and strategies used to reduce polyQ symptoms and major pre-clinical and clinical achievements obtained with MSC transplantation as well as remaining flaws that need to be overcome. The requirement to cross the blood-brain-barrier (BBB), together with a short rate of cell engraftment in the lesioned area and low survival of MSC in a pathophysiological context upon transplantation may contribute to the transient therapeutic effects. We also review methods like pre-conditioning or genetic engineering of MSC that can be used to increase MSC survival in vivo , cellular-free approaches—i.e., MSC-conditioned medium (CM) or MSC-derived extracellular vesicles (EVs) as a way of possibly replacing the use of MSC and methods required to standardize the potential of MSC/MSC-derived products. These are fundamental questions that need to be addressed to obtain maximum MSC performance in polyQ diseases and therefore increase clinical benefits.

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Lercanidipine boosts the efficacy of mesenchymal stem cell therapy in 3-NP-induced Huntington's disease model rats via modulation of the calcium/calcineurin/NFATc4 and Wnt/β-catenin signalling pathways

Cited by 28 publications

References 62 publications

Recombinant human erythropoietin and interferon-β-1b protect against 3-nitropropionic acid-induced neurotoxicity in rats: possible role of JAK/STAT signaling pathway

Recombinant human erythropoietin and interferon-β-1b protect against 3-nitropropionic acid-induced neurotoxicity in rats: possible role of JAK/STAT signaling pathway

How Do Post-Translational Modifications Influence the Pathomechanistic Landscape of Huntington’s Disease? A Comprehensive Review

Mesenchymal Stromal Cells’ Therapy for Polyglutamine Disorders: Where Do We Stand and Where Should We Go?

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