International Journal of Nutrition, Pharmacology, Neurological Diseases

REVIEW ARTICLE
Year
: 2020  |  Volume : 10  |  Issue : 2  |  Page : 69--74

The Role of Phloridzin and its Possible Potential Therapeutic Effect on Parkinson’s Disease


Preeja Prabhakar1, Abdul Bakrudeen Ali Ahmed2, Saravana Babu Chidambaram3,  
1 Department of Biochemistry, Centre for Research and Development, PRIST University, Thanjavur, Tamil Nadu, India
2 Faculty of Applied Sciences, Ton Duc Thang University, Ho Chi Minh City, Vietnam
3 Department of Pharmacology, JSS College of Pharmacy, Mysuru, Karnataka, India

Correspondence Address:
Preeja Prabhakar
Department of Biochemistry, Centre for Research and Development, PRIST University, Thanjavur, Tamil Nadu
India

Abstract

Parkinson’s disease (PD) is the second commonest neuro-degenerative disorder in the world and is complex in terms of its etio-pathological mechanisms, symptomatology, diagnosis and progression. Research on animal models, epidemiology, human postmortem analysis and genetic studies suggest that oxidative stress, mitochondrial dysfunction, neuro-inflammation, and derangements in neurochemical pathways regulating protein folding and aggregation, have a role in the etio-pathogenesis and progression PD. However, till date, the treatment options for PD including medication and surgical-interventions are only of symptomatic relief. There is no definite preventive or neuro-protective or disease-modifying cure currently available. The relevance of antioxidant molecules is considered as part of a novel research avenue tackling potential therapeutic adjuncts in the treatment of PD. The beneficial effects of naturally occurring dietary polyphenols provide promising perspectives and are of value in the quest of developing a novel generation of therapeutic agents capable of reducing neuro-inflammation and neuro-degeneration, thereby possibly delaying or preventing or halting the progression of PD. Phloridzin is a dihydrochalcone primarily present in unripe-apples (Malus sp., Rosaceae). There are many proposed mechanisms by which phloridzin mitigates the onset and decrease of the progression of neurodegenerative disorders such as PD. These protective actions of phloridzin include its antioxidant anti-neuro-inflammatory (by reducing pro-inflammatory and pro-apoptotic mediators) and modulation of gene expression including mitochondrial directed flavono-therapy. It is anticipated that further evidence in the efficacy of diet derived phenolic products like phloridzin could lend a novel perspective of the role of nutritional therapeutics in preventing the occurrence of neurodegenerative conditions including PD during the early stages and mitigate its progression in susceptible individuals.



How to cite this article:
Prabhakar P, Ahmed AA, Chidambaram SB. The Role of Phloridzin and its Possible Potential Therapeutic Effect on Parkinson’s Disease.Int J Nutr Pharmacol Neurol Dis 2020;10:69-74


How to cite this URL:
Prabhakar P, Ahmed AA, Chidambaram SB. The Role of Phloridzin and its Possible Potential Therapeutic Effect on Parkinson’s Disease. Int J Nutr Pharmacol Neurol Dis [serial online] 2020 [cited 2020 Jul 11 ];10:69-74
Available from: http://www.ijnpnd.com/text.asp?2020/10/2/69/282291


Full Text



 Introduction



Parkinson’s disease (PD) has been regarded as the second most common progressive neurodegenerative disorder (NDD) affecting the human nervous system. It is characterized by a set of clinical features—both classical and atypical motor and non-motor—that can have functional impact on the patients living within various stages of PD.[1] According to the UK Parkinson’s disease Society Brain Bank Diagnostic criteria, the three cardinal motor symptom-complex in PD patients include bradykinesia or akinesia (slowness or absence of movement) in combination with either tremor at rest and rigidity.[2] These clinical features occur due to histopathological changes in the basal ganglia of the brain wherein there is a progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) and accumulation of protein aggregates composed mainly of misfolded α–synuclein that form intra-cytoplasmic inclusions termed ‘Lewy bodies’.[3] As of today, there are medications and surgical therapies available to relieve symptoms in these patients. However, definite preventive or neuro-protective or disease-modifying cure is the need of the hour.[4] Hence, there is a real challenge in tackling NDDs like PD as the treatment modalities are mainly aimed at symptomatic relief, and unfortunately are not yet successful at delaying or preventing this disease in susceptible individuals.

Aging, environmental toxins, genetic mutations, chronic oxidative stress and inflammation are said to be major contributing factors for the onset and progression of NDDs including PD.[5],[6] Among these factors, accumulated oxidative stress has largely been considered a major factor in causing PD. Physiologically, in the substantia nigra (SN) of the normal brain, the energy-metabolism ratio of dopaminergic neurons is high. Hence, dopaminergic neurons are usually at relatively high levels of basal oxidative stress. Neuronal cells are considered hypersensitive to oxidative stress and ROS-induced damage due to their high energy demand and their comparatively higher rate of oxygen consumption.[3] Neuronal damage and death is further exacerbated due to their low regenerative capacity and post-mitotic nature. Even at rest, the brain utilizes about 20% of the total oxygen compared to that of total body consumption leading to the abundant generation of reactive oxygen species (ROS), and being low in antioxidants compared to other body parts, is more prone to oxidative stress.[7] The oxidative damage in the brain increases with age. Aging factor adds on to it by inducing a chronic basal level of inflammatory state in the brain that leads to the activation of neuro-glial cells and finally resulting in enhanced production of pro-inflammatory cytokines.[8] These cumulative factors lead to the onset and progression of neurodegeneration in PD.

The research-based approach to the etio-pathogenesis of PD has shown that genetic and environmental risk factors induce oxidative stress, disrupted mitochondrial dynamics and neuronal excitotoxicity in the brain leading to the degeneration of the dopaminergic system in the mid-brain, causing PD.[9] The mitochondrial membrane potential gets disrupted by the generation of protein aggregates and causes abnormal calcium (Ca2+) influx, impaired membrane respiratory enzyme activities, decreased ATP generation and the accumulation of ROS. Damaged mitochondria abnormally releases cytochrome c which in turn triggers the activation of the signaling cascades for cell-apoptosis in the neurons and the release of enzymes like caspases, resulting in neuronal cell death. The generation of free radicals then results in further cell damage through nitrosylation, oxidation, and peroxidation, to cellular organelles and macromolecules, thus aggravating neuronal damage.[9]

Treatment of NDDs including PD mainly aims to replenish depleted dopamine with dopaminergic medications and modulate the dysfunctional circuit.[3] Discovered in the 1960s, levo-carbidopa forms part of the main stay drug along other treatment options for PD that include dopamine agonists, monoamine oxidase B inhibitors, catechol-O-methyl transferase inhibitors and anti-cholinergics. Surgical modality like deep brain stimulation procedure is also tried in patients meeting specific criteria. However, no neuro-protective treatments are available yet and PD patients usually have poor prognosis and decline. In light of these pathologies and limited clinical treatment options, alternative or preventive therapeutics which can control the incidence, prevalence and limit the progression of PD, are searched for.

Recently, some convincing research has been published regarding the use of plant products, derivatives or phytochemicals to delay the occurrence of neuro-degeneration.[10] There have been reports that a plant-based diet and regular use of phytochemicals and their derivatives can delay the progression of these diseases in susceptible individuals by boosting antioxidant, anti-inflammatory activity and improving mental and physical performance thereby increasing neuronal cell survival.[11] Fruits and vegetables and by-products formed through their processing are some of the richest sources of natural antioxidants, due to the abundance of phenolic compounds such as flavonoids.[10] A promising approach to protect the neuronal functionality comes from the evidence regarding the benefits associated with an appropriate and adequate intake of plant-based food.[12] Extensive studies have been done worldwide looking for a product or substance that is capable of altering the disease course in NDDs. In this regard, the apple is a rich source of bioactive phytochemicals that help improve health by preventing and/or curing many diseases. Apples (Malus sp., Rosaceae) are one of the most widely and abundantly cultivated and consumed fruits worldwide. They form a major part of human diet and are one of the top five fruits consumed in the world.[13] Apples have been identified as an important dietetic source of polyphenols, though there is difference in concentration of these molecules between different apple varieties.[14]

Apples are rich in phloridzin, a dihydrochalcone (bicylic flavonoid).[15] Phloridzin has been widely studied and used in research for its hypoglycemic, antioxidant, anti-inflammatory and anti-cancerous activities in a wide array of preclinical studies. Phloridzin is also called phlorhizin, phlorizin, phlorrhizin, or phlorizoside.[16] When hydrolyzed by the intestinal lactase phloridzin hydrolase, phloridzin forms its aglycone known as phloretin. Following this, it undergoes phase-II metabolism creating conjugates like glucuronides as their major derivatives.[13]

Phloretin is β-(4-hydroxyphenyl)-1-(2’,4’,6’-trihydroxypropiophenone and phloridzin is its glucoside phloretin-2-β-D-glucose [Figure 2] and [Figure 3].{Figure 1}{Figure 2}{Figure 3}

Phloridzin was first isolated in 1835 from the apple tree bark by De Koninck.[17] Phloridzin has been a compound of extensive research for its multitude of in-vitro and in-vivo effects. Various studies have discussed about the effects of phloridzin on diabetes mellitus mainly aiming at glucose metabolism including its absorption and excretion.[17],[18],[19] Unpeeled apples are a richer source of phloridzin than skin peeled ones. The phloridzin content in apple peel is 12–418 mg/kg, whereas that in apple pulp is only 4–20 mg/kg.[18] Also, previous apple cultivars contained relatively higher amounts of phloridzin than the newer ones.[20] Phloridzin is also a novel avenue of research on its role as the precursor in a group of anti-diabetic drugs belonging to the SGLT 1, 2 (sodium-glucose co-transporter 1, 2) inhibitors category.[18],[19],[20],[21]

The polyphenols in an apple are also hydrogen donors, reducing agents, free radical scavengers and singlet oxygen quenchers and they show antioxidant activity by acting as metal ion chelators.[22] The antioxidant potential elicited by phloretin and phloridzin [23] offers an additional mechanism impeding the formation of advanced glycation end products (AGEs), thus ameliorating neuronal inflammation and its consequences.[13] Human studies have measured an increase in antioxidant activity in human serum after apple consumption (300 mL apple juice—comparable to 5 apples—single dose),[24] which could reflect the anti-oxidant effects of phloridzin and its derivatives detected in plasma.[25] A study showed that phloretin and phloridzin also inhibit lipid peroxidation in isolated liver hepatocyte microsomes of rats.[26] The antioxidant protection of omega-3 PUFA and fish oil by apple skin extracts containing phloretin and phloridzin in food chemistry has also been reported.[15],[27] Phloridzin not only possess free radical scavenging properties,[28] dihydrochalcones are considered to have other biological effects too.[29]

A study by Muthuswamy et al., 2004 demonstrated the antimicrobial effects of phloridzin against various pathogenic bacteria.[30] Phloridzin was also utilized in cancer research wherein xenograft tumor growth in athymic nude mice implanted with a variety of human cancer cells had been studied. An additional mechanism by which phloridzin and phloretin can impede the formation of advanced glycosylation end products (AGEs) and decrease intestinal inflammation has also been shown. [12] Mechanistically, phloridzin can form phloretin and glucose. Phloretin is also a Ca2+ channel reducer that can inhibit transport of glucose and fatty acids. Phloretin reduces glucose, fatty acids and glycerol absorption in the small intestine. Hence, phloridzin can be ameliorative in managing the dyslipidemia and hyperglycemia which are very well associated risk factors for onset and poor prognosis in PD. [31],[32],[33]

Possible role of phloridzin on Parkinson’s disease like conditions

There has been considerable public and scientific interest in the use of phyto-constituents for neuro-protection or to prevent neurodegenerative diseases. The proposed mechanisms by which many polyphenols mitigate the onset and progression of neurodegenerative disorders like PD include suppression of lipid peroxidation, inhibition of neuro-inflammation by reducing pro-inflammatory and pro-apoptotic mediators and modulation of gene expression changes including mitochondrial directed flavonoid therapy.[34]

Different polyphenols have been shown to exert neuro-protective action on in vivo and in vitro models of neurological disorders. It is widely known and accepted that polyphenols and their metabolites can exert modulatory actions on proteins/enzymes through direct interaction with receptors or enzymes playing significant roles in signal transduction. Few examples of these are those involved in the lipid kinase and protein kinase signaling pathways.[35] The different neuro-chemical mechanisms explaining the protective effects of plant polyphenols have been described mainly due to their inhibition of neuro-pathological processes,[36],[37] iron chelating properties,[38] modulation of signaling pathways related to neuronal survival and differentiation[35],[39] and regulation of mitochondrial function.[40],[41],[42]

A recent review also discussed other benefiting effects of dietary polyphenols for better cognition and brain health.[34] Phytochemicals like phloridzin have been considered to bring about anti-parkinsonian effects through several similar mechanisms. The mechanisms of action include diminishing loss of dopaminergic neuronal cells and the depletion of the neurotransmitter dopamine, suppressing apoptosis (via the reduction of caspase-3,8 and 9, Bax/Bcl-2 and α-synuclein accumulation), modulating nuclear and cellular inflammatory signaling, reducing the expression of pro-inflammatory cytokines (IL-6, IL-1β, and NF-κB), increasing the expression of neuro-trophic factors (NTFs) and antioxidant activities. Other mechanisms by which flavonoids can be neuro-protective include their improvement in circulatory status on peripheral and cerebrovascular blood flow thereby positively influencing synaptic plasticity processes and cognition.[43]

Experimental and epidemiological studies have clearly suggested that dietary polyphenols such as phloridzin can activate Nrf2/HO1 antioxidant pathways and down regulate PPAR, NFκB, HIF- 1, MMPs and STAT pathways. They can also act as immune response modulators by inhibiting pro-inflammatory biomarkers like, CXCL(9, 10, 11), CCR1, CCR2, CCL22, CCL17, IL(1β,6,17A,22), MIP1α, MIP 1β, IFN-γ and TNF- α.[34] All of these mechanisms are put in use to combat the main pathogenic mechanisms in neurodegenerative disorders, i.e. oxidative damage, neuronal inflammation and mitochondrial damage leading to apoptosis and neuronal death [Figure 3] and [Figure 4].{Figure 4}

Results from a population-based study suggested that patients suffering from diabetes are at 23% higher risk of PD after adjusting for the different confounding factors like age, gender, occupation, co-morbidities, drug history and associated morbidities and complications.[44] Blood glucose levels during the post prandial state can be lowered by inhibition of digestion and decreasing the absorption of carbohydrates in the small intestine. Carbohydrate digestion in the small intestine can be reduced by inhibition of alpha-amylase and also by blocking carbohydrate absorption via SGLT1 and SGLT2 transporters, the sodium dependent sugar transporter systems.[45],[46] Studies have showcased the properties of phloridzin including the inhibitory effects of SGLT1 (sodium-glucose transport protein 1) and SGLT2 (sodium-glucose transport protein 2).[18],[47],[48] Hence, phloridzin shows a promising role in improving, to a great extent, the morbidities associated with the diabetic state along with the higher risk for PD like conditions.

Aging remains the biggest risk factor for developing idiopathic PD.[49] Studies have shown that the phloridzin in yeast has anti-aging effects.[50] Mechanism studies revealed that phloridzin mediates life span extension in yeast via the SIR2 signaling pathways and SOD gene and an increase in SIRT1 activity, thus providing supportive evidence for future research on the anti-aging effects of phloridzin on mammalian cells and in experimental animals.[26]

 Conclusion



Current scientific research and its evidences suggest that neuro-degenerative diseases such as PD are accompanied by the accumulation of ROS and oxidative stress, neuro-inflammation and mitochondrial functional derangements. The prevention and treatment of this second most common NDD, with complex etio-pathologic mechanisms, requires novel therapeutic strategies targeting varied etio-pathologies and mechanisms involving multiple genes and proteins. Polyphenol flavanoids such as phloridzin are naturally occurring plant derivatives from apple with secondary metabolites which exhibit remarkable multi-potent ability to reduce oxidative stress and ROS, metal toxicity, inflammatory markers, apoptosis, signal transduction, modulate ion channels, and neurotransmitters. Studies showing significant anti-diabetic and anti-aging effects of phloridzin give promise to the potential role of this flavanoid polyphenol in mitigating the onset and progression of PD.

However, future research on this novel therapeutic agent combating PD needs to aim towards clinical acceptance directed at pre-clinical, in vitro and in vivo models. It would also be essential for research to focus on human clinical trials of this potent polyphenol and its derivatives in PD should be carried out after finding out the effect on pre-clinical studies. Furthermore, phloridzin must be investigated for risk assessment and safety evaluation to observe any undesirable effects. Aside from this, research in this field would still remain incomplete without studying the pharmacological interactions between anti- parkinsonian drugs and flavonoid supplements. Hence, many questions remain unanswered, especially regarding the translation of findings from in-vitro studies to in-vivo application in order to clearly associate phloridzin with improvements in neurological well-being and health.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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