Harmine prevents 3-nitropropionic acid-induced neurotoxicity in rats via enhancing NRF2-mediated signaling: Involvement of p21 and AMPK

Habib, Mohamed Z.; Tadros, Mariane G.; Abd-Alkhalek, Hadwa A.; Mohamad, Magda I.; Eid, Dalia M.; Hassan, Fatma E.; Elhelaly, Hend; Faramawy, Yasser el; Aboul‐Fotouh, Sawsan

doi:10.1016/j.ejphar.2022.175046

Cited by 19 publications

(16 citation statements)

References 71 publications

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“…In line with the mentioned above, studies demonstrated an increase in oxidative molecules, such as TBARS, malonaldehyde, and nitric oxide, in the brain of 3-NPA-treated animals (Mehan et al, 2018; Abdelfattah et al, 2020; Habib et al, 2022; Kadir et al, 2022; Brondani et al, 2023). It is also observed an inhibition of antioxidant molecules (superoxide dismutase, catalase, and glutathione) in those animals (Mehan et al, 2018; Kadir et al, 2022; Brondani et al, 2023).…”

Section: Discussionsupporting

confidence: 55%

3-Nitropropionic acid induces histological and behavioral alterations in adult zebrafish: role of antioxidants on behavioral dysfunction

Wiprich,

Vasques,

Zaluski

et al. 2024

Preprint

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Huntingtons disease (HD) is a neurodegenerative disease marked by progressive motor and non-motor symptoms such as neuropsychiatric disruption and cognitive dysfunction. It has been reported that some pathogenic mechanisms resulting in neuronal cell death in this disease involve neurodegeneration and oxidative stress. 3-Nitropropionic acid (3-NPA), a natural toxin that promotes the irreversible suppression of mitochondrial complex II, has been used to understand the HD pathogenesis. This neurotoxin mimics the biochemical, central neurodegeneration, peripheral and behavioral phenotype alterations observed in HD. Here we investigated 3-NPA (60 mg/kg) effects on histological and oxidative stress parameters on brain and muscular tissues. We also evaluated the effects of three antioxidant compounds on 3-NPA-induced behavioral phenotypes in adult zebrafish. For the evaluation of the antioxidant effects, adult zebrafish were submitted to a single acute intraperitoneal injection of vitamin C, creatine, or melatonin following 3-NPA chronic administration (60 mg/kg). 3-NPA treatment caused neurodegeneration, but did not alter the muscular tissue. 3-NPA neither change thiobarbituric acid reactive substances (TBARS) nor nonprotein thiol levels. Vitamin C and creatine treatments recovered the hypolocomotion induced by 3-NPA. Also, vitamin C and melatonin treatments improved the memory dysfunction caused by 3-NPA. Altogether, our findings showed that the 3-NPA induces neurodegeneration in adult zebrafish, and the vitamin C, creatine, and melatonin are beneficial in managing HD-like behavioral phenotypes. Thus, these antioxidants could be thought as complementary pharmacotherapies for the treatment of late-stage HD symptoms.

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Section: Discussionsupporting

confidence: 55%

3-Nitropropionic acid induces histological and behavioral alterations in adult zebrafish: role of antioxidants on behavioral dysfunction

Wiprich,

Vasques,

Zaluski

et al. 2024

Preprint

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“…Harmine, a plant-derived β-carboline alkaloid with a wide spectrum of pharmacological actions, including antioxidant properties [ 149 ], was shown to decrease intracellular aggregation of mHTT and OS in a yeast model of HD [ 150 ]. Furthermore, harmine increased the levels of Nrf2 protein as well as AMPK and p21, and restored redox homeostasis by attenuating 3-NP-induced neurodegenerative changes, as shown by improving rats ’motor and cognitive performance [ 151 ]. In Table 1 , a summary of results from substances tested in vitro and/or in vivo is reported.…”

Section: Nrf2 and Hdmentioning

confidence: 99%

Nrf2 Pathway in Huntington’s Disease (HD): What Is Its Role?

Tucci

Lattanzi

Severini

et al. 2022

IJMS

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Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease that occurs worldwide. Despite some progress in understanding the onset of HD, drugs that block or delay symptoms are still not available. In recent years, many treatments have been proposed; among them, nuclear transcriptional factor-2 (Nrf2) enhancer compounds have been proposed as potential therapeutic agents to treat HD. Nrf2 triggers an endogenous antioxidant pathway activated in different neurodegenerative disorders. Probably, the stimulation of Nrf2 during either the early phase or before HD symptoms’ onset, could slow or prevent striatum degeneration. In this review, we present the scientific literature supporting the role of Nrf2 in HD and the potential prophylactic and therapeutic role of this compound.

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“…DYRK1A is required for normal brain development and axonal transport and is expressed in adult NMJ [ 90 ], where DYRK1A inhibitors, such as HH might possibly have adverse effects, though data in this respect are lacking. However, since DYRK1A overexpression in Down’s Syndrome (DS) is strongly implicated in DS-associated oxidative stress, Alzheimer’s disease [ 91 ], and motor dysfunction [ 90 ], DYRK1A inhibitors may be beneficial in this condition, e.g., by upregulating the nuclear factor erythroid 2-like 2 (NRF2) [ 92 ]. However, DYRK1B is mainly expressed in skeletal muscle, where it plays a role in antioxidative defense [ 93 , 94 ] somewhat in contrast to the role of MAO-A.…”

Section: Discussionmentioning

confidence: 99%

Effects of Monoamino-Oxidase-A (MAO-A) Inhibition on Skeletal Muscle Inflammation and Wasting through Pancreatic Ductal Adenocarcinoma in Triple Transgenic Mice

et al. 2023

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Cancer cachexia describes a syndrome of muscle wasting and lipolysis that is still largely untreatable and negatively impacts prognosis, mobility, and healthcare costs. Since upregulation of skeletal muscle monoamine-oxidase-A (MAO-A), a source of reactive oxygen species, may contribute to cachexia, we investigated the effects of the MAO-inhibitor harmine-hydrochloride (HH, intraperitoneal, 8 weeks) on muscle wasting in a triple-transgenic mouse model of pancreatic ductal adenocarcinoma (PDAC) and wild type (WT) mice. Gastrocnemius and soleus muscle cryo-cross-sections were analyzed for fiber type-specific cross-sectional area (CSA), fraction and capillarization using ATPase- and lectin-stainings. Transcripts of pro-apoptotic, -atrophic, and -inflammatory signals were determined by RT-qPCR. Furthermore, we evaluated the integrity of neuromuscular junction (NMJ, pre-/post-synaptic co-staining) and mitochondrial ultrastructure (transmission electron microscopy). MAO-A expression in gastrocnemius muscle was increased with PDAC vs. WT (immunohistochemistry: p < 0.05; Western blot: by trend). PDAC expectedly reduced fiber CSA and upregulated IL-1β in both calf muscles, while MuRF1 expression increased in soleus muscle only. Although IL-1β decreased, HH caused an additional 38.65% (p < 0.001) decrease in gastrocnemius muscle (IIBX) fiber CSA. Moreover, soleus muscle CSA remained unchanged despite the downregulation of E3-ligases FBXO32 (p < 0.05) and MuRF1 (p < 0.01) through HH. Notably, HH significantly decreased the post-synaptic NMJ area (quadriceps muscle) and glutathione levels (gastrocnemius muscle), thereby increasing mitochondrial damage and centronucleation in soleus and gastrocnemius type IIBX fibers. Moreover, although pro-atrophic/-inflammatory signals are reversed, HH unfortunately fails to stop and rather promotes PDAC-related muscle wasting, possibly via denervation or mitochondrial damage. These differential adverse vs. therapeutic effects warrant studies regarding dose-dependent benefits and risks with consideration of other targets of HH, such as the dual-specificity tyrosine phosphorylation regulated kinases 1A and B (DYRK1A/B).

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Harmine prevents 3-nitropropionic acid-induced neurotoxicity in rats via enhancing NRF2-mediated signaling: Involvement of p21 and AMPK

Cited by 19 publications

References 71 publications

3-Nitropropionic acid induces histological and behavioral alterations in adult zebrafish: role of antioxidants on behavioral dysfunction

3-Nitropropionic acid induces histological and behavioral alterations in adult zebrafish: role of antioxidants on behavioral dysfunction

Nrf2 Pathway in Huntington’s Disease (HD): What Is Its Role?

Effects of Monoamino-Oxidase-A (MAO-A) Inhibition on Skeletal Muscle Inflammation and Wasting through Pancreatic Ductal Adenocarcinoma in Triple Transgenic Mice

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