Esculetin Provides Neuroprotection against Mutant Huntingtin-Induced Toxicity in Huntington’s Disease Models

Pruccoli, Letizia; Breda, Carlo; Teti, Gabriella; Falconi, Mirella; Giorgini, Flaviano; Tarozzi, Andrea

doi:10.3390/ph14101044

Cited by 4 publications

(2 citation statements)

References 31 publications

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“…Keap1 and Nrf2 protein levels were assessed in SH-SY5Y cells using western blotting, as previously described [ 27 ]. The cells were placed in 60 mm dishes at 2 × 10 6 cells per dish, incubated for 24 h, and then treated with carotenoids (2.5–5 µM) for 3 h at 37 °C in 5% CO 2 .…”

Section: Methodsmentioning

confidence: 99%

Antioxidant and Neuroprotective Effects of Fucoxanthin and Its Metabolite Fucoxanthinol: A Comparative In Vitro Study

Pruccoli,

Balducci,

Pagliarani

et al. 2024

CIMB

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Fucoxanthin is the most abundant carotenoid found in marine brown algae that exhibits several healthy properties. Dietary fucoxanthin is metabolized in the intestine, plasma, and other tissues to various metabolites, including fucoxanthinol. In this regard, the contribution of fucoxanthinol to the healthy properties of its precursor, fucoxanthin, against pathogenetic events associated with neurodegenerative diseases remains unexplored. Here, we evaluated and compared the antioxidant and neuroprotective effects of the carotenoids fucoxanthin and fucoxanthinol in in vitro models of Alzheimer’s (AD) and Parkinson’s (PD) disease. Neuronal SH-SY5Y cells were used to evaluate the antioxidant properties of the carotenoids against ABTS radical in the membrane and cytoplasm and oxidative stress elicited by tert-butyl hydroperoxide using the 2′,7′-dichlorodihydrofluorescein diacetate probe. We also assessed the ability of the carotenoids to increase the glutathione (GSH) and activate the Nrf2/Keap1/ARE pathway using the monochlorobimane probe and western blotting method, respectively. The neuroprotective effects of the carotenoids against the neurotoxicity generated by oligomers of Beta-Amyloid (1–42) peptide (OAβ) and 6-hydroxydopamine (6-OHDA), which are neurotoxins of AD and PD, respectively, were finally evaluated in the same neuronal cells using the thiazolyl blue tetrazolium bromide assay. Both carotenoids could reach the cytoplasm, which explains the mainly free radical scavenging activity at this level. Notably, fucoxanthinol had higher and lower antioxidant activity than fucoxanthin at extracellular and cellular levels. Although studied carotenoids exerted the ability to activate the Nrf2/Keap1/ARE pathway, leading to an increase of intracellular GSH, our results suggested that the antioxidant activity of the carotenoids could be mainly attributed to their radical scavenging activity in neuronal membrane and cytoplasm, where they accumulate. Fucoxanthinol also shared similar neuroprotective effects as fucoxanthin against the neurotoxicity generated by OAβ and 6-OHDA, suggesting a potential neuroprotective contribution to the action of fucoxanthin administered as a food supplement in in vivo experimental models. These results encourage further research to evaluate the bioavailability of fucoxanthinol and other metabolites of fucoxanthin at the brain level to elucidate the dietary neuroprotective potential of fucoxanthin.

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Section: Methodsmentioning

confidence: 99%

Antioxidant and Neuroprotective Effects of Fucoxanthin and Its Metabolite Fucoxanthinol: A Comparative In Vitro Study

Pruccoli,

Balducci,

Pagliarani

et al. 2024

CIMB

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“…In pathological conditions, the expanded poly(Q) protein has an increased propensity to self-assemble, forming oligomers and subsequently poly(Q) aggregates, leading to a toxic gain of function mutation [3]. In human patients and animal models of poly(Q) diseases, these aggregates disrupt axonal transport, transcription, translation, redox reactions, and protein homeostasis [8][9][10][11]. While gain of function results in the disease phenotype, mutations causing loss of function in the Htt protein induce neurodegeneration [12].…”

Section: Introductionmentioning

confidence: 99%

Protective role ofPtendownregulation in Huntington’s Disease models

Nisha,

Thapliyal,

Gohil

et al. 2024

Preprint

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Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder that stems from the expansion of CAG repeats within the coding region of the Huntingtin gene. Currently, there exists no effective therapeutic intervention that can prevent the progression of the disease. Our investigation aims to identify a novel genetic modifier with therapeutic potential. We employ transgenic flies containing Htt93Q and Htt138Q.mRFP constructs, which encode mutant pathogenic Huntingtin proteins featuring 93 and 138 polyglutamine (Q) repeats, respectively. The resultant mutant protein causes the loss of photoreceptor neurons in the eye and a progressive loss of neuronal tissues in the brain and motor neurons in Drosophila. Several findings have demonstrated the association of HD with growth factor signaling defects. Phosphatase and tensin homolog (Pten) have been implicated in the negative regulation of insulin signaling/receptor tyrosine signaling pathway which regulates the growth and survival of cells. In the present study, we downregulated Pten and found a significant improvement in morphological phenotypes in the eye, brain, and motor neurons. These findings were further correlated with the enhancement of the functional vision and climbing ability of the flies. We also noted the reduction in both poly(Q) aggregate levels and caspase activity which are involved in the apoptotic pathway. Moreover, we elucidated the protective role of Pten inhibition through the utilization of VO-OHpic (referred to as PTENi). In alignment with the genetic modulation of Pten, pharmaceutical inhibition of Pten improved the climbing ability of flies and reduced the poly(Q) aggregates and apoptosis levels. A similar reduction in poly(Q) aggregates was observed in the mouse neuronal inducible HD cell line model. Our study illustrates that Pten inhibition is a potential therapeutic approach for HD.

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