Neuroprotective and Neurorestorative Effects of Holothuria scabra Extract in the MPTP/MPP+-Induced Mouse and Cellular Models of Parkinson’s Disease

Abstract

Extracts from Holothuria scabra (HS) have been shown to possess anti-inflammation, anti-oxidant and anti-cancer activities. More recently, it was shown to have neuroprotective potential in Caenorhabditis elegans PD model. Here, we assessed whether HS has neuroprotective and neurorestorative effects on dopaminergic neurons in both mouse and cellular models of PD. We found that both pre-treatment and post-treatment with HS improved motor deficits in PD mouse model induced with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) as determined by grid walk test. This was likely mediated by HS protective and restorative effects on maintaining the numbers of dopaminergic neurons and fibers in both substantia nigra pars compacta (SNpc) and striatum. In a cellular model of PD, HS significantly attenuated 1-methyl-4-phenylpyridinium (MPP+)-induced apoptosis of DAergic-like neurons differentiated from SH-SY5Y cells by enhancing the expression of Bcl-2, suppressing the expression of cleaved Caspase 3 and preventing depolarization of mitochondrial membrane. In addition, HS could stimulate the expression of tyrosine hydroxylase (TH) and suppressed the formation of α-synuclein protein. Taken together, our in vivo and in vitro findings suggested that HS is an attractive candidate for the neuroprotection rather than neurorestoration in PD.

Potential of marine compounds in the treatment of neurodegenerative diseases: a review

“…Regarding PD, Holothuria scabra, through its bioactive compounds, has shown promise, as well as Xylaria sp., since both seem to attenuate the degeneration of dopaminergic neurons (Li et al, 2013;Lu et al, 2010;Chalorak et al, 2018;Chalorak et al, 2021). Furthermore, Holothuria scabra was able to reduce alpha synuclein deposition, while Xylaria sp., with its metabolite Xyl-B, reduced the formation of Mhtt protein aggregates, suggesting a possible neuroprotective effect for HD (Noonong et al, 2020;Zeng et al, 2016). The other marine compounds present in this study show promising potential in the context of ND, however further studies are needed for a better understanding of the repercussion of these compounds in the course of ND.…”

“…In another study, Chalorak et al (2021) showed reduced a-synuclein accumulation in dopaminergic neurons after treatment with diterpene glycosides extracted from Holothuria Scabra (Figure 3A and 3B) (Chalorak et al, 2021). Noonong et al (2020) also evaluated the neuroprotective effect of Holothuria scabras metabolites (MHS-Friedelina, 3-hydroxybenzaldehyde, and 4-hydroxybenzaldehyde) in mice that were induced in PD by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, and showed neurorestorative effects in motor deficiencies, in addition to a significant increase in the cell viability of dopaminergic neurons, promoting the synthesis of tyrosine hydroxylase (TH) and suppressing the formation of α-synuclein protein (Noonong et al, 2020). Finally, the study by Tangrodchanapong et al (2021) demonstrated the effect of the cyclic ether 2-butoxytetrahydrofuran (2-BTHF), which presented a neuroprotective action by learning and memory deficits in a murine model of dementia (Che et al, 2017).…”

“…Diterpene glycosides extracted from the species Holothuria scabra showed a reduction of a-synuclein in muscle cells in the Caenorhabditis elegans model, promoting improved motility due to the degradation of a-synuclein induced by autophagic signaling (Chalorak et al, 2021). The MHS metabolite reduces mitochondrial depolarization and promotes the inhibition of pro-apoptotic substances (BCE-1 and caspase 3), in addition to upregulating BCL-2, preserving neurons, and promoting behavioral and motor improvement in murine models (Noonong et al, 2020). Another therapeutic potential in PD was observed in Xyl-B and its derivatives, which is a probable mechanism of action to restore glutathione levels in PC12 cells and attenuate the loss of mitochondrial potential through the reduction of ROS overproduction (Lu et al, 2010).…”

2-Butoxytetrahydrofuran, Isolated from Holothuria scabra, Attenuates Aggregative and Oxidative Properties of α-Synuclein and Alleviates Its Toxicity in a Transgenic Caenorhabditis elegans Model of Parkinson’s Disease

“…24 Furthermore, H. scabra extract was found to decrease α-synuclein formation induced by MPP + -induced SH-SY5Y cell apoptosis through alterations in cellular metabolism, resulting in the enhancement of tyrosine hydroxylase (TH)-stained DAergic neurons. 25 As a result, it is possible that 2-BTHF derived from H. scabra could alleviate α-synuclein-mediated toxicity, leading to an improvement in the GFP-tagged area of CEP DAergic neurons in the UA44 strain.…”

“…32 The deficiency in dopamine signaling, resulting from the absence of TH, is characterized by impaired dopaminedependent behaviors. 33 Importantly, the H. scabra extract was demonstrated to boost TH, 25 the rate-limiting enzyme in catecholamine biosynthesis. This enzyme catalyzes the hydroxylation of tyrosine to L-DOPA within the dopamine signaling pathway.…”