PD is a multifactorial disorder deeply related to an increased burden of oxidative/nitrosative stress, especially during aging [
5]. PD is characterized by cellular degeneration in the striatum, where the increased level of peroxidized unsaturated fatty acids is paralleled by the progressive deficit of endogenous antioxidant systems [
1,
2]. The elevated levels of brain unsaturated fatty acids could be peroxidized by mitochondrial metabolism-derived ROS/RNS [
3], and lipid peroxidation is well known to be linked to neurodegeneration [
35,
36,
37]. On the other hand, preclinical studies have long suggested the importance of natural antioxidants as preventive agents of brain lipid peroxidation, particularly in pro-oxidant conditions [
10,
29]. Aging and neurodegenerative disorders are also characterized by a significant decrease in the levels of monoaminergic neurotransmitters, which in turn could explain, albeit partially, the progressive impairment in motor and cognitive functions [
10,
11,
12]. In the present study, a multidirectional approach was followed in order to characterize the water extracts of selected traditional medicinal plants commonly used as antioxidants. Consistently with their quali–quantitative phenolic profile (
Table 1), they have been long considered to be effective as protective agents in different PD experimental settings [
14,
15,
16]. Through the lethality test in the brine shrimp and the MTT viability assay in the HypoE22 cell line, we selected the extract concentration (5–85 µg/mL) for the pharmacological tests. This biocompatibility limit, especially if referred to the
G. glabra extract, is consistent with the findings of Azizsoltani and colleagues [
38]. In the HypoE22 cell line, we also investigated the protective effects of the extracts and the formula against 6-OH-DA-induced cytotoxicity. We observed that the extracts and the formula were able to protect the cell line against 6-OH-DA-induced LDH, a significant marker of cytotoxicity and tissue damage [
39]. The efficacy of the extracts was consistent with that reported in the literature [
40]. Consistently with its higher content in secondary metabolites, the formula was obviously more effective than the single ingredients in inhibiting LDH increase [
26,
41]. In analogy, we observed a different pattern of antioxidant effects exerted by the formula and the single extracts in isolated striatum specimens challenged with 6-OH-DA. Specifically, the formula displayed the highest efficacy in inhibiting the induction of LDH, 8-iso-PGF
2α, and nitrites by 6-OH-DA. The molecule 8-iso-PGF
2α, derived from ROS/RNS peroxidation of membrane arachidonic acid, has long been considered a stable marker of lipid peroxidation and tissue damage in vivo [
35], while herbal extracts rich in phenolic compounds with radical scavenger properties were revealed to be effective in blunting isoprostane production in ex vivo models of neurodegeneration [
29,
42,
43]. On the other hand, nitrites represent a stable marker of nitrosative stress, which is strictly related to lipid peroxidation [
44]. In PD, their levels reflect the upregulation of inducible nitric oxide synthase (iNOS), which is known to be inhibited by the catechin fraction of green tea and by resveratrol analogs [
6,
45]. Nevertheless, according to the cited literature, the effective iNOS inhibitory concentrations of these secondary metabolites appear to be higher compared to those measured in the single studied extracts, thus suggesting that the observed efficacy could involve other unidentified metabolites as well. In the isolated striatum, we also investigated the effects of the single extracts and the whole formula on DA turnover, expressed as DOPAC/DA ratio. The same ratio has long been considered an index of the activity of MAO-B, as well, whose upregulation is increased during aging and neurodegenerative diseases [
46]. We observed that all tested extracts and the formula inhibited, albeit in part, 6-OH-DA-induced DA turnover. Specifically, the formula, consistently with its richest phenolic content aforementioned, was able to totally blunt 6-OH-DA-induced DA turnover in the rat striatum, while the single extracts showed partial capability in preventing the increase in the DOPAC/DA ratio, with
G. glabra extract being the most promising. This is consistent with
G. glabra’s higher content in epicatechin and catechin, that were reported to act as MAO-B inhibitors [
47]. Conversely, the
V. faba extract was the least effective in limiting the DOPAC/DA ratio. This result, despite appearing paradoxical in consideration of the
l-dopa content in the
V. faba phytocomplex, could be explained by both its lowest content in catechin and epicatechin and the intrinsic pro-oxidant effect of
l-dopa itself. As a DA precursor,
l-dopa, once administered, is able to promote not only the synthesis of DA but also its auto-oxidation, thus further supporting the association of antioxidants with this drug for long-term therapy of PD [
5]. Additionally, despite there being clinical evidence indicating a significant increase in plasma DA concentrations following
V. faba derivative administration [
48], these studies did not include a functional dopaminergic evaluation in order to confirm the putative increased DA steady-state concentration in the striatum. Finally, considering the extensive
l-dopa metabolism in peripheral tissues [
5], the hypothetical increase of striatal DA following the sole administration of
V. faba, without the co-administration of selective amino acid decarboxylase inhibitors, is questionable. On the other hand, we cannot exclude that the improvement in motor functions described in case report studies [
14] could be the result of multiple antioxidant effects following
V. faba treatment, as evidenced by the reported inhibitory effects on 6-OH-DA-induced nitrite and 8-iso-PGF
2α levels.