PD is a neurodegenerative disease of the central nervous system characterized by a progressive loss of dopaminergic neurons that underlie the characteristic motor symptoms. This disease still doesn’t have an affective cure and therefore exists an increasing interest in the development of more selective and effective therapeutic agents in order to prevent or slow down the neurodegeneration progression [
15,
18,
25,
26,
39]. Although the causes PD pathogenesis remains incomplete, considerable evidences from human and animal studies have suggested that mechanisms such as oxidative stress, mitochondrial and lysosomal dysfunctions, neuroinflammatory processes, and the formation of pathologic inclusions contributes to neuronal death in PD [
4,
5]. In line with this, the present study was designed to evaluate the protective effects of seaweeds on SH-SY5Y cells exposed to the toxicity of 6-OHDA.
The neurotoxicity induced by 6-OHDA on SH-SY5Y cells has been previously reported by different authors, consequently, this model has been widely used to mimic experimental models of PD [
5,
6,
11,
40]. According to previous studies, once inside the neurons, 6-OHDA accumulates and undergoes a non-enzymatic auto-oxidation, promoting the reactive oxygen species formation (e.g. superoxide radical, hydrogen peroxide, quinones and hydroxyl radicals) and inhibit the mitochondrial complexes I and IV, causing adenosine triphosphate (ATP) depletion. All these supports the hypothesis that oxidative stress and mitochondrial dysfunction may be responsible for the cell death [
5,
41,
42]. Moreover, these two events are described as being entirely related, since the occurrence of mitochondrial dysfunction can lead to ATP depletion, inducing irreversible effects on the cellular processes, leading to the formation of free radicals. Consequently, the loss of mitochondrial transmembrane potential can result in the rupture of the outer mitochondrial membrane and in the release of pro-apoptotic proteins from the nucleus leading to cell death through activation of the intrinsic apoptosis pathway [
43‐
45]. Our results are entirely according with these facts, since the observed reduction on SH-SY5Y cells viability was accompanied by an increase of H
2O
2 production, depolarization of mitochondrial membrane potential and an increase of Caspase-3 activity, suggesting that cell death induced by the 6-OHDA treatment was mediated by these mechanisms. Moreover, our results are supported by Esmaeili-Mahani and co-workers [
11] that observed a significant increase of intracellular ROS, activated Caspase 3, Bax/Bcl-2 ratio, cytochrome c as well as DNA fragmentation in 6-OHDA-treated cells. For other side, when SH-SY5Y cells were treatment with 6-OHDA in the presence of seaweeds extracts was possible to see a marked increase of cell’s viability. The data obtained suggests that the protective effects induced by seaweeds extracts result in a reduction of oxidative stress condition (H
2O
2 production pathway) and an anti-apoptotic effect (mitochondrial protection and decrease of Caspase-3 activity). Several experiments revealed that therapies including the intake of antioxidants display a protective effect on the degeneration of dopaminergic neurons suggesting that pharmacological targeting of the antioxidant machinery may have therapeutic value [
6,
16‐
19,
46]. According with this, the neuroprotective effects of seaweeds can be mediated by the antioxidants molecules present in their extracts, since these were selected by having a high antioxidant capacity. Among marine organisms, seaweeds are an interesting source of new compounds with antioxidant activity and neuroprotective potential. They are subjected to periods of immersion and emersion being exposed to rapid variations of light, UV rays and different oxygen (O
2) and carbon dioxide (CO
2) concentrations, factors that are related with oxidizing effects. This situation stimulates the production of antioxidant defenses, such as the production of phenolic compounds [
47,
48]. The protective effects exhibited by seaweeds belonging to the brown algae group (
S. muticum,
S. polyschides and
P. pavonica) can be associated with the presence of phlorotannins (molecules produced exclusively by brown algae). Phlorotannins, are phenolic compounds with a strong antioxidant capability [
49,
50] suggesting that these may be responsible by the observed reduction of H
2
O
2 levels. In fact, seaweeds have revealed to produce a high diversity of compounds with antioxidant activity.
Codium tomentosum, a green seaweed also revealed an oxidative-stress protective effect. Celikler and co-workers [
51] demonstrated that
C. tomentosum extracts have strong anti-oxidative activity which can explain the highest reduction of the H
2O
2 production observed in presence of this extract.
On the other hand, several studies reported that the neuroprotection effect of different compounds is normally mediated by the prevention of mitochondrial depolarization, the reduction of ROS levels and the inhibition of apoptotic process leading to an increase of cell’s viability [
11,
52,
53]. In our study was also possible to observe these effects, since the increase of cell’s viability by seaweeds extracts seems to be mediated by the reduction of H
2O
2 levels, the protection of mitochondrial membrane potential and the inhibition of Caspase-3 activity. According to our results, several other compounds of natural origin such as, astaxanthin (obtained from
Haematococcus pluvialis) and 11-dehydrosinulariolide (obtained from the coral
Sinularia flexibilis) have exhibited anti-apoptotic effects, notably by decreasing the Caspase-3 expression and cytochrome c in SH-SY5Y cells when treated 6-OHDA. Similarly, the neuropeptide orexin-A, exhibit anti-apoptotic effects by the same mechanisms [
6,
11,
31]. In line with our findings, Jhamandas and co-workers [
54] showed neuroprotective activity of a fucoidan sulfated polysaccharide, isolated from the brown seaweed
Fucus vesiculosus, through the ability to protect neuronal death in rats treated with Aβ1–42 the by inhibition of Caspase-3 in an Alzheimer’s disease model. Although not directly related to the disease addressed in this work, the effects induced by fucoidan demonstrate the potential of seaweeds as source of new neuroprotective molecules.