Role of arbutin and acetoside against Parkinson’s disease

Abstract

Parkinson’s disease (PD) is an incurable progressive neurodegenerative condition, which is characterized by a selective loss of dopaminergic neurons in the substantia nigra and subsequent development of motor impairment along with a non-motoric syndrome. It has a multifactorial etiopathogenesis, including oxidative stress, mitochondrial failure, lasting neuroinflammation, and α-synuclein aggregation. Interestingly, acetoside and arbutin are naturally occurring phenolic glycosides that have gained increased attention in recent times due to their strong antioxidant, anti-inflammatory, and neuroprotective capabilities. These agents have been empirically demonstrated to reduce reactive oxygen species, energize endogenous antioxidant defenses such as superoxide dismutase, catalase (CAT), glutathione, maintain mitochondrial integrity, and salvage adenosine triphosphate (ATP) generation. Furthermore, they inhibit pro-inflammatory mediators such as tumor necrosis factor-alpha (TNF-α), prevent the activation of caspase-3 and lipid peroxidation, regulate AMP-activated protein kinase and p62 signaling pathways, and alleviate the loss of dopaminergic neurons, which results in improved motor performance. Computational docking reports have revealed positive results between arbutin, acetoside, and key targets of PD (e.g., acetylcholinesterase [AChE], TNF-α, caspase-3, CAT, dopamine-associated proteins, and α-synuclein). Arbutin showed binding energies of − 7.6 kcal/mol (AChE), −7.0 kcal/mol (caspase-3), −9.0 kcal/mol (CAT), −8.8 kcal/mol (TNF-α), and − 7.0 kcal/mol (dopaminergic targets). In contrast, acetoside showed stronger interactions with corresponding targets, exhibiting binding energies of − 8.7 kcal/mol, −8.9 kcal/mol, −9.7 kcal/mol, and − 8.9 kcal/mol. Collectively, these findings highlight phenolic glycosides as promising multitarget neuroprotective candidates for PD.

Introduction

Parkinson’s disease (PD) is an irreversible, progressive neurodegenerative disorder that now threatens over 10 million people around the world, and its prevalence is increasing alongside aging populations in the world today.[1] The pathophysiology of the disease is characterized by a selective degeneration of dopaminergic neurons located in the substantia nigra pars compacta, which generates motor influences, such as bradykinesia, rigidity, rest tremor, and postural instability, as well as a continuum of nonmotor impairments, including cognitive impairments, depression, and dysautonomia.[2,3] Neuromorphologically, PD is characterized by deposits of Lewy bodies, intracellular inclusions, the main constituents of which are misfolded α-synuclein protein that constitutes the pathological basis of the disease.[4] PD has a complex pathogenesis and involves oxidative stress, mitochondrial dysfunction, neuroinflammation, excitotoxicity, and impaired proteostasis.[5,6] Modern pharmacotherapies, including levodopa and dopamine agonists, are symptomatic and do not halt or reverse underlying neurodegeneration, often developing chronic complications, such as motor swings and dyskinesias.[7] These findings highlight the urgency to have multi-target neuroprotective interventions that have the capacity to control central pathogenic pathways. Phenolic glycosides, which form a subclass of dietary polyphenols, have grown to promising prospects due to their pleiotropic pharmacological characteristics. These molecules are characterized by a phenolic core attached to sugar moieties, which is a structural property that determines solubility, metabolic stability, and biological activity.[8,9] There are significant examples of phenolic glycosides that exhibit remarkable antioxidant, anti-inflammatory and mitochondrial-stabilizing properties, including acetoside (synonym verbascoside, found in Plantago and Verbascum species) and arbutin (found in Arctostaphylos uva-ursi), that are reported in extensive in vivo and in vitro research.[10,11]

In the pathology of PD, the loss of mitochondrial function is a crucial factor; phenolic glycoside comes into action by stabilizing the mitochondrial membrane potential (MMP), inhibiting cytochrome c release, and suppressing caspase stimulation.[12,13] These group activities secure neuronal survival and maintain cellular energy balance. In addition, these glycosids have an impact on proteostasis, preventing the aggregation of α-synuclein and promoting the autophagic removal of misfolded proteins.[14,15] Phenolic glycosides have been shown to possess neuroprotective properties in Parkinsonian models induced by neurotoxins, including 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxydopamine (6-OHDA). Indicatively, acetoside in MPTP-treated mice has produced improved motor activity, reduced dopaminergic neuronal loss, and reduced oxidative and inflammatory biomarkers.[16] Similarly, arbutin showed protective properties on mitochondrial dysfunction and neuroinflammation in rotenone-exposed animals, normalized antioxidant enzyme functions, and inhibited lipid peroxidation.[17,18]

Mechanistically, acetoside and arbutin directly scavenge reactive oxygen species (ROS) and enhance endogenous antioxidant defences, including superoxide dismutase (SOD), catalase (CAT), and glutathione-peroxidase (GSH-Px).[19,20] Their anti-inflammatory potential is mediated by inhibiting nuclear factor-kappa B (NF-κB) signaling and suppressing pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), (Interleukin-1 beta) IL-1β, and IL-6.[21,22] The binding energies obtained for arbutin with acetylcholinesterase (AChE), caspase-3, CAT, TNF-α, and dopamine targets were − 7.6 kcal/mol, −7.0 kcal/mol, −9.0 kcal/mol, −8.8 kcal/mol, and − 7.0 kcal/mol while acetoside exhibited binding energies of − 8.7 kcal/mol, −8.9 kcal/mol, −9.7 kcal/mol, and − 8.9 kcal/mol, respectively.[23,24] Although they have demonstrated therapeutic potential, phenolic glycosides have major limitations such as low bioavailability upon oral administration, short metabolic half-life, and poor blood–brain barrier (BBB) permeability.[25,26] Development of superior drug delivery systems – nanoencapsulations, liposomal carriers, and prodrug approaches – is being carefully considered to further target the central nervous system (CNS) and improve pharmacokinetic activity.[27,28] When combined, phenolic glycoside is a convincing type of dietary neuroprotectant with a multitarget effect in PD. The purpose of this review is to critically synthesize evidence on the neuroprotective properties of dietary phenolic glycosides in PD.

Classification of Phenolic Glycosides Based on their Anti-Parkinson Activity

The phenolic glycosides are a very varied group of plant-based products characterized by a core, which is a phenol ring covalently bonded with one or more saccharide units. Among them, arbutin and acteoside have drawn a lot of academic attention because of their putative neuroprotection properties in neurodegenerative diseases, especially in PD. Arbutin is a hydroquinone glycoside (found mainly in bearberry [Arctostaphylos uva-ursi], blueberry, and cranberry), whose structure is based on a hydroquinone nucleus attached to a glucose molecule via a β-glycosidic bond. This antioxidant is shown to have strong antioxidant activity in terms of scavenging ROS and has been reported to preserve mitochondrial performance and reduce apoptosis in neuronal cultures subjected to Parkinsonian poisons like rotenone. Notably, a recent study using Drosophila melanogaster PD models showed that α-arbutin improved locomotor activity and mitochondrial integrity and placed this possible treatment by activity on AMP-activated protein kinase (AMPK) signaling and autophagic signaling. Acteoside, sometimes called verbascoside, is a complex caffeol phenylethanoid glycoside in numerous medicinal plants (such as Rehmannia glutinosa, Cistanche deserticola, and Verbascum thapsus). It contains hydroxytyrosol and caffeic acid moieties that are conjugated with a disaccharide of rhamnose/glucose. This molecule is known to have a strong antioxidant and anti-inflammatory action. Actaeoside has also been found to inhibit microglial activity and attenuate the synthesis of pro-inflammatory cytokines (TNF-α and IL-6) in Parkinsonian models and protect dopaminergic neurons against degeneration. Its ability to regulate mitochondrial mechanisms and reduce oxidative stress makes it an interesting option for a neuroprotective intervention. In conclusion, as is illustrated in the diagram above, arbutin and acteoside represent two different subclasses of phenolic glycosides: hydroquinone and phenylethanoid, respectively. Nevertheless, they overlap on several neuroprotective functions, such as antioxidant activity, mitochondrial protection, and anti-inflammatory activity. All these compounds, dietary and pharmacological, have significant potential in the prevention of the advancement of PD.

Therapeutic Potential of Phenolic Glycosides for Parkinson’s Disease

Anti-oxidative stress potential of phenolic glycosides: In vivo and in vitro evidence supporting free radical scavenging and cellular protection

Empirical evidence strongly supports the involvement of oxidative stress in both the onset and progression of PD.[29,30,31] Several studies have demonstrated that oxidative damage in Parkinsonian models arises from reduced activity of essential antioxidant enzymes, including SOD, glutathione (GSH), GSH-Px, and CAT.[30,32] A decline in these key antioxidant systems is closely associated with heightened susceptibility of dopaminergic neurons to injury and subsequent worsening of disease pathology.[29,31] A report by Ding et al. showed the anti-Parkinson’s potential of arbutin against rotenone-induced neurotoxicity in SH-SY5Y cells. The author demonstrated that arbutin (1, 10, and 100 µM) treatment significantly uplifted the survival rates of cells. Moreover, it also reduced the level of cleaved Poly (ADP-ribose) polymerase levels. Arbutin also reduced the level of ROS, whereas it increased the activity of GSH, SOD, and CAT in cells. It also increased the level of MMP and adenosine triphosphate (ATP) in cells. Furthermore, it also reduced the phosphorylation of AMPK and p62 in SH-SY5Y cells. Authors also revealed that the anti-Parkinson’s potential of arbutin against PD-induced mitochondrial dysfunction in drosophila. The authors revealed that arbutin uplifted the climbing activity. Moreover, it also increased the ATP level in Drosophila.[29] In addition, increased oxidative stress within the mitochondrial matrix, together with reduced MMP, diminished ATP production, and compromised activity of the mitochondrial respiratory chain, has been shown to promote mitochondrial dysfunction in PD.[29,32] These mitochondrial defects make substantial contributions to dopaminergic neurodegeneration by impairing energy homeostasis and amplifying oxidative damage.[29,30] Another study by Dadgar et al. showed the anti-Parkinson’s potential of arbutin against the MPTP-induced Parkinson’s mice model. Authors revealed that arbutin (50 mg/kg; i.p) treatment elevated the level of FRAP, whereas it reduced the level of thiobarbituric acid reactive substances and protein carbonyl in mice. Moreover, it also uplifted the level of SOD, CAT, and GSH in the brain.[30] A study by Kumar et al. showed the potential of arbutin against L-glutamate-induced neurotoxicity and cognitive dysfunction in rats. Arbutin also uplifted the level of SOD, CAT, and GSH in the brain.[32] A report by Zhao et al. showed the potential of arbutin against the MPTP-induced Parkinson’s mice model. The authors revealed that arbutin (50 and 100 mg/kg) treatment significantly increased the SOD, CAT, and GSH in the brain.[31] A study by Li et al. showed the neuroprotective potential of acetoside against 6-OHDA-induced dopaminergic damage in the zebra fish model. The authors revealed that acetoside treatment (200 mg/kg) increased locomotor activity in zebrafish. Moreover, it significantly decreased the dopaminergic loss.[33] Biochemical analysis revealed that acetoside significantly increased the activity of SOD, CAT, and GSH-Px. Furthermore, it also uplifted the messenger ribonucleic acid expression of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1, NAD (P) H quinone oxidoreductase 1.[33] Collectively, available evidence points to arbutin and acetoside as promising modulators of oxidative stress, but deeper mechanistic insights are required to pinpoint their exact molecular targets in Parkinson’s pathology.

Anti-inflammatory and neuroenhancing potential of phenolic glycosides: In vivo and in vitro evidence

Several reports highlighted the pivotal role of neuroinflammation in both the onset and progression of PD.[31,32,33,34] In a study by Yuan et al. (2016),[34] acetoside was shown to exert significant anti-inflammatory neuroprotection by reducing α-synuclein aggregation, downregulating caspase-3 expression, and preserving neuronal innervation in rotenone-induced Parkinsonian models. Supporting this evidence, Li et al. demonstrated that acetoside mitigates dopaminergic neuroinflammation by inhibiting lipid peroxidation and suppressing key oxidative-inflammatory markers in 6-OHDA-treated zebrafish, which consequently improved locomotor activity.[33] Yuan et al. demonstrated the neuroprotective potential of acetoside against rotenone-induced Parkinson’s rat model. The authors revealed that acetoside (30 mg/kg; p.o) treatment uplifted the movement, standing times, and time spent in the central area. Immunohistochemistry staining analysis showed that it also decreased the level of α-synuclein, whereas it increased the level of microtubule-associated protein 2 in the substantia nigra. Western blot analysis also revealed that it reduced the level of caspase-3 in the substantia part as shown in Figure 1.[34]

Figure 1.

Mechanistic illustration of phenolic glycosides’ neuroprotective action in Parkinson’s disease, showing suppression of nuclear factor-kappa B-mediated inflammation and reactive oxygen species-mediated oxidative stress

A study by Li et al. showed the neuroprotective potential of acetoside against 6-OHDA-induced dopaminergic damage in the zebra fish model. Authors revealed that acetoside treatment (200 mg/kg) increased locomotor activity in zebrafish. Moreover, it significantly decreased the dopaminergic loss. Acetoside also attenuated the level of malondialdehyde in zebrafish.[33] Arbutin has likewise been shown to reduce neuroinflammatory mediators, significantly lowering TNF-α levels, decreasing AChE activity, and increasing gamma-aminobutyric acid (GABA) levels in Parkinson’s models.[32] Increased inflammatory stress in the brain, characterized by elevated nitrite, lipid peroxidation, and pro-inflammatory biomarkers, is markedly reduced following arbutin treatment, further confirming its anti-inflammatory role in PD.[31] Authors revealed that arbutin (50 and 100 mg/kg) treatment significantly reduced the level of TNF-α in the brain. Arbutin also decreased the activity of AChE in rats. It also increased the level of GABA in the brain. Furthermore, it also decreased the level of lactate dehydrogenase in the brain.[32] Moreover, arbutin also reduced the level of lipid peroxidation, total nitrite levels, and inflammatory biomarkers in the brain.[31] Collectively, available evidence points to arbutin and acetoside as promising modulators of neuroinflammation, but deeper mechanistic insights are required to pinpoint their exact molecular targets in Parkinson’s pathology.

Role of Oxidative Stress and Inflammatory Stress in Parkinson’s Disease

Oxidative stress, the production of free radicals and ROS in both neuronal and glial populations, is a major pathogenic process in PD and other neurodegenerative diseases. The dopaminergic neurons of the substantia nigra, in particular, seem to be highly vulnerable to such redox disturbances, in part due to their extensive axonal arborization and to the sheer amount of synaptic connections requiring much energy to sustain them. Overexpression of dopamine turnover and accretion of its oxidative metabolites also contribute to oxidative load, and mitochondrial dysfunction is bound to increase this burden, becoming a vicious circle, self-sustaining in its escalation, increasing both mitochondrial and lysosomal insult.[14] At the same time, the CNS possesses a relatively poor defense system based on endogenous antioxidants, which restricts its ability to neutralize the harmful effects of the continued exposure to free radicals, especially as the development of the disease impairs the reserves of cellular antioxidants. This inadequacy allows unregulated oxidative damage, which adds to the degeneration process of PD. Exogenous antioxidant therapy has demonstrated potential toward neutralizing reactive species and thus reducing apoptotic cascades and salvaging the nigrostriatal dopaminergic pathway. These agents have been shown to provide significant neuroprotective benefit in PD situations due to their ability to protect against harmful radicals.[15] Neuroinflammation is also a key element of the pathogenesis of PD, which is characterized by increased microglial stimulation and an increase in pro-inflammatory cytokines and harmful mediators. In its insoluble fibrillar form, α-synuclein causes glial and immune cell activation, leading to the release of cytokines, chemokines, and neurotoxins that speed up the destruction of dopaminergic neurons. Furthermore, such pathogenic fibrils have direct pro-inflammatory effects, which further accelerate neurodegeneration and cell death.[16] Eventually, peripheral immune and inflammatory cells find their way into the brain parenchyma through a broken BBB, thereby enhancing neuroinflammatory events either by direct contact with the resident glial and neuronal cell populations or by a product of their activities. Finally, a potential solution to the problem is by using dietary supplements or functional foods that include anti-inflammatory factors to suppress neuroinflammatory reactions, thus reducing the PD symptoms and easing the general burden of neuronal death.

Molecular Docking of Phenolic Glycosides with Various Key Targets in the Pathophysiology of Parkinson’s Disease

Molecular docking studies have increasingly highlighted the therapeutic potential of phenolic glycosides in targeting multiple pathological pathways involved in PD. Several investigations demonstrate that compounds such as arbutin, acetoside, salidroside, and verbascoside display strong binding affinities toward key dopaminergic, inflammatory, and apoptotic proteins implicated in PD progression,[35,36,37] as shown in Figures 2-6. The calculated binding energies of arbutin and acetoside with their respective target proteins are summarized in Table 1, highlighting their comparative binding affinities and interaction strengths.

Figure 2.

Three-dimensional representation of different interactions of acetoside in the binding sites of (1A) catalase (CAT) and (2A) dopamine. Two-dimensional representation of different interactions of acetoside in the binding sites of (1B) CAT and (2B) dopamine

Figure 6.

Three-dimensional representation of different interactions of arbutin in the binding sites of (1A) Tumor necrosis factor-alpha (TNF-α), (2A) Acetylcholinesterase (AChE), and (3C) Caspase. Two-dimensional representation of different interactions of arbutin in the binding sites of (1B) TNF-α, (2B) AChE, and (3D) Caspase

Table 1.

Binding energy of arbutin and acetoside with various proteins

Molecule	Protein name	PDB ID	Binding energy (kcal/mol)
Arbutin	AChE	4PQE	−7.6
Arbutin	Dopamine	6CM4	−7.0
Arbutin	Caspase	3DEI	−7.0
Arbutin	CAT	1DGF	−9.0
Arbutin	TNF-α	1TNF	−8.8
Acetoside	AChE	4PQE	−8.7
Acetoside	Dopamine	6CM4	−10.0
Acetoside	Caspase	3DEI	−8.9
Acetoside	CAT	1DGF	−9.7
Acetoside	TNF-α	1TNF	−8.9

TNF-α=Tumor necrosis factor-alpha, AChE=Acetylcholinesterase, CAT=Catalase

Figure 3.

Three-dimensional representation of different interactions of acetoside in the binding sites of (1A) Tumor necrosis factor-alpha (TNF-α) and (2A) Acetylcholinesterase (AChE). Two-dimensional representation of different interactions of acetoside in the binding sites of (1B) TNF-α and (2B) AChE

Figure 4.

Three-dimensional representation of different interactions of acetoside in the binding sites of (1A) caspase-3. Two-dimensional representation of different interactions of acetoside in the binding sites of (1B) caspase-3

Figure 5.

Three-dimensional representation of different interactions of arbutin in the binding sites of (1A) Catalase (CAT) and (2A) Dopamine. Two-dimensional representation of different interactions of arbutin in the binding sites of (1B) CAT and (2B) Dopamine

Docking Analysis and Amino Acid Interaction Profiling of Arbutin and Acetoside with Multiple Key Molecular Targets Implicated in Parkinson’s Disease

The molecular docking investigations reveal that arbutin provides a broad-pin area of hydrogen bonding with active-site residues of monoamine oxidase B, hence suggesting its possible ability to disrupt dopamine catabolism and oxidative stress.[13,32] Acetoside also shows a strong affinity toward AChE and butyrylcholinesterase, showing strong hydrophobic contact and π–π interactions, implying a possible modulatory effect on the cholinergic disturbances of the cognitive impairments linked to PD.[34,38] Several studies have documented that the phenolic glycosides target the interface of the α-synuclein fibrils, thus preventing aggregation and protecting the dopaminergic neurons against the toxicity of aggregated protein species.[39,40] Besides, docking simulations have suggested caspase-3, caspase-9, and Bax; such constituents might suppress the apoptotic pathways by stabilizing inactive conformers of pro-apoptotic proteins.[41,42] Further docking studies provide evidence of strong binding between the compounds and the major inflammatory mediators, such as TNF-α, NF-κB, and cyclooxygenase-2, which implicates the possible ability to restrain neuroinflammatory signaling.[30,31,43] Last but not least, binding affinities to mitochondrial respiratory-chain constituents and Nrf2-Kelch-like ECH-associated protein 1 regulatory axis additionally suggest the capacity of these agents to boost antioxidant defences but not harm to mitochondrial integrity.[44,45] Collectively, these computational insights support the hypothesis that phenolic glycosides act as multitarget neuroprotective agents that modulate dopaminergic, inflammatory, oxidative, and apoptotic pathways in PD.[46] However, further experimental validation is required to fully delineate their mechanistic relevance in vivo.

Clinical Trials of Arbutin and Acetosides

Currently, no clinical trials have evaluated arbutin or verbascoside (acetoside) specifically for PD. However, several human studies have investigated these compounds in other clinical contexts. Arbutin has mostly been researched in the field of dermatology. In their randomized controlled trial, Morag et al. explored that the topical β-arbutin was an essential and safe depigmenting agent in patients with skin hyperpigmentation, as shown by an 8-week trial.[47] On the same note, Crocco et al. demonstrated that a new cream preparation with arbutin lowered the melasma area and severity index score and epidermal melisma.[48] More recently, Gabhane et al. demonstrated that a combination of arbutin and sunscreen was much more effective in preventing dark spots on the face in Indian women and that it was tolerated well.[49] Other human studies, not related to the neurological field, have investigated verbascoside (acetoside). The randomized clinical study by Campo et al. revealed that oral verbascoside (100 mg) decreased platelet aggregation in 2 weeks, indicating the anti-inflammatory and cardiovascular protective activities.[50] Mestre-Alfaro et al. also demonstrated that verbascoside-containing Lippia extract supplementation enhanced antioxidant enzyme activities in people undergoing exercise-induced oxidative stress.[51] Combined, the above studies suggest that both arbutin and acetoside have been clinically proven to exhibit antioxidant and anti-inflammatory effects in humans; the therapeutic efficacy of these two in the treatment of PD is yet to be established by means of specific neurological clinical trials.

Future directions

Arbutin and acetoside demonstrate promising multitarget neuroprotective effects in preclinical and computational studies; substantial work is required before clinical translation. Future investigations should focus on rigorous mechanistic explanations, employment of current state of art in vivo systems, human-induced pluripotent stem cell-produced dopaminergic neurons, and pathway-specific molecular measurements to support target interaction. A detailed pharmacokinetic review, which includes blood–brain barricade stimulability, pharmacokinetics, and dose optimization, is vital. To enhance the bioavailability of the CNS, novel methods of delivery, such as nanoencapsulation, lipid carrier systems, and prodrug modalities, should be explored. In addition, a careful analysis of the combinatoric regimens using verified dopaminergic medications such as levodopa or dopamine agonists is justified to assess the possible synergistic neuroprotective activity, improved efficacy, and reduced adverse consequences. The present proposal outlines a mechanistic/translational framework that is to be engineered to guide future studies that can validate phenolic glycosides as disease-modifying agents in PD.

Conclusion

Parkinson’s disease is a multifaceted neurodegenerative condition stimulated by an intersective set of actions such as oxidative stress, mitochondrial dysfunction, neuroinflammation, and gradual degradation of dopaminergic neurons. Recent preclinical studies have shown that phenolic glycosides, especially acetoside and arbutin, have neuroprotective actions by a variety of mechanistic pathways. At the same time, these compounds also show significant anti-inflammatory potentials as they suppress pro-inflammatory cytokines, prevent microglial activation, and alter the signaling cascades that mediate chronic neuroinflammation related to PD. These results are further supported by computational docking studies, which show that they have high-affinity interactions with a wide range of targets, such as AChE and α-synuclein, caspase 3, and TNF-α, thus highlighting their suitability as a tool in multimodal therapeutic intervention. On this basis, arbutin and acetoside can be discussed as effective multipotent neuroprotective agents in the environment of PD. Future research projects must focus on rigorous mechanistic validation, complete pharmacokinetic profiling, and BBB penetrance studies in addition to optimizing drug-delivery systems and meticulously designed clinical trials in order to define their translational feasibility.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Figures preparation

All figures in this manuscript were created using Microsoft PowerPoint.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.