Role of Phytochemicals in Management of Schizophrenia

Abstract

Bioactive substances derived from plants, created by them for defense, are known as phytochemicals. Alkaloids, glycosides, polyphenols, terpenes and terpenoids, phytosterols, cannabinoids and carotenoids are the different categories of phytochemicals. Schizophrenia is associated with changes in the structure of the brain, decrease of dendritic spines from pyramidal neurons in the cortex, loss of gray matter and enlarged ventricles. Hallucinations, delusions, disorganized behavior and amotivation are some symptoms of schizophrenia. Phytochemicals are a key component of the management of schizophrenia. Alkaloids can operate as cholinergic agonists on muscarinic receptors and improve memory deficits. Glycosides target ErbB signaling, inhibit D3/D4 receptors and change dopamine and serotonin metabolism. Because of their anti-inflammatory, antioxidant and anti-apoptotic properties, polyphenols display neuroprotective and anti-schizophrenic activity. Terpenes and terpenoids act on the glutamate and dopamine pathways and inhibit glycinergic action. Cannabinoids have an anti-schizophrenic effect plus boost GABAergic activity and prevent serotonin uptake. Phytosterols have antipsychotic potential by blocking ketamine-induced biochemical, histological and behavioral changes. Because they regulate brain-derived neurotrophic factor (BDNF), carotenoids show significant potential for treating a variety of central nervous system problems. They are also an excellent antipsychotic medication.

1. Introduction

Phytochemicals are plant-based bioactive compounds produced by plants for their protection. There are many different sources of phytochemicals, including whole grains, fruits, vegetables, nuts and herbs. To date, over a thousand phytochemicals have been identified. Carotenoids, polyphenols, isoprenoids, phytosterols, saponins, dietary fibers and certain polysaccharides are a few of the important phytochemicals. In besides having potent antioxidant properties, these phytochemicals have antiviral, antibacterial, anthelmintic, antiallergic and antidiarrheal properties. Additionally, they support immunology, gap junction communication, gene transcription regulation and protection against lung and prostate malignancies. The properties of functional foods have been broadened by a greater focus on translational research. Following their extraction from a variety of sources, phytochemicals are widely used in the development of nutraceuticals and functional foods. The affinity of phytochemicals for solvents and their heat tolerance vary. The quality of the recovered phytochemical and its use in the creation of food and nutraceutical products are also influenced by the solvent choice [1].

The purpose of the study is to describe the role of phytochemicals in management of schizophrenia which could be beneficial in the improvement of symptoms of schizophrenia in patients, reduction of health issues regarding schizophrenia and maintenance of healthy life style.

1.1 Sources of phytochemicals

Our regular diet We first discuss a few terminologies:

Designer food: processed meals enriched with naturally occurring foods high in compounds that prevent disease.

Functional food: Any food or ingredient that has been improved and may have health benefits in addition to the usual nutrients it contains.

Nutraceutical: Certain substances found in food, such as vitamins and chemicals that may help prevent illness.

Pharmafood: Food or nutrient that claims medical or health benefits, including the prevention and treatment of disease [2].

1.2 Classification of phytochemicals

Phytochemical compounds have primary as well as secondary constituents. Phytochemicals can be classified into various groups. Alkaloids, glycosides, polyphenols, terpenes and terpenoids, phytosterols, cannabinoids and carotenoids are the different categories of phytochemicals (Figure 1) [2].

Figure 1.

The color wheel of phytochemicals [2].

1.2.1 Alkaloids

Alkaloids are a vast group of chemicals that are based on the amino acids that supply their nitrogen atom and a portion of their skeleton; this heterogeneous chemical group is divided into groups. Alkaloids with distinct biosynthesis processes and varying biological activities might arise from alkaloids with comparable origins or sharing an identical basic nucleus. L-phenylalanine, L-tyrosine, L-histidine, L-ornithine, nicotinic acid, anthracitic acid or acetate and L-lysine are the sources of these. They are used in daily life by people from all over the world. Animals can also be the source of alkaloids, either endogenously or exogenously [3].

1.2.2 Glycosides

A broad class of secondary metabolites is made up of glycosides. Glycosides have a variety of structural forms, and because of their established bioactivities and historical applications, they are crucial to the pharmacognosy regime. It is composed of two parts, a hydrophilic glycone unit made up of one or more sugar components and an aglycone (genin) unit that is mostly lipophilic [4].

1.2.3 Polyphenols

A class of naturally occurring substances with phenolic structures is called polyphenols. There are four main subclasses within this family which are lignans, flavonoids, stilbenes and phenolic acids. Anthocyanidins, flavanones, flavones and flavonols are other classifications of flavonoids. Artichokes, spinach, broccoli, chicory, apples, plums, pears, grapes and cherries are rich in polyphenols. Red wine, tea and olive oil are regarded as excellent sources of polyphenols [5]. About 350 aglycones and 100 glycosylate forms make up flavanones, which have a flavan nucleus made up of two aromatic rings connected by a dihydropyrone ring [6]. The presence of a double bond between C-2 and C-3, along with the attachment of the B-ring to C-2, characterizes flavones, a vast class of flavonoids [7]. The hydroxyl group at position three sets flavonols apart from flavanones and creates a double bond between C-2 and C-3. The majority of anthocyanidins in nature are found as their sugar-conjugated derivatives or anthocyanins, which gives fruit and flower tissues their characteristic red, blue and purple hues. Polyphenols have been found to provide health benefits such as scavenging free radicals, guarding against cancer, heart disease and other age-related illnesses and preventing allergies and inflammation. Additionally, flavonoids have been shown to help with gastrointestinal disorders, diabetes, rhinitis, angina pectoris, cervical lesions, chronic venous insufficiency, dermatopathy, lymphocytic leukemia, menopausal symptoms and traumatic cerebral infarction [1].

1.2.4 Terpenes and terpenoids

Terpenes are the largest class of secondary metabolites. They are simply made up of five carbon isoprene units that may be put together in thousands of different ways to form multiple isoprene units. Terpenoids are a modified class of terpenes with distinct functional groups and an oxidized methyl group that is relocated or deleted at different places. Terpenes are simple hydrocarbons. Depending on the number of carbon units, terpenoids are classified as monoterpenes, sesquiterpenes, diterpenes, sesterpenes and triterpenes. With their diverse structural variations, the majority of terpenoids are physiologically active and utilized globally to treat a wide range of illnesses. Many terpenoids, including Taxol and its variants utilized as anticancer medications because they suppress certain human cancer cells. Terpenes have a pleasant scent which is why many flavorings and fragrances contain them. Antimalarial medications like artemisinin and similar substances are made from terpenes and their derivatives. In the meantime, terpenoids are used in a variety of products, including hormones, vitamins, medications, meals and cosmetics [8].

1.2.5 Cannabinoids

Cannabis is the first illegal drug as well as the third one if tobacco and alcohol are taken into account. Cannabis is becoming more and more common in our culture, both for medicinal and recreational purposes. An estimated 183.3 million adults between the ages of 15 and 64 smoked cannabis in 2015 (3.8% of the world’s population). Young adults between the ages of 15 and 34 are the most likely to consume cannabis (13.9 percent in the previous year). Cannabis use among students in Europe and the United States between the ages of 15 and 16 was 8 and 15%, respectively [9].

1.2.6 Phytosterols

The collective term for the sterols and stanols found in plants that control their physiological processes is called phytosterol. Olive oil and the oils of corn, sesame, sunflower, peanuts, macadamia, nuts, beans and almonds are abundant in them. Plant stanols include campestanol, sitostanol and stigmastanol, whereas some plant sterols include campesterol, stigmasterol and sitosterol. Campesterol is the most basic sterol, with the exception of the five or six double bonds in the B-ring. Generally speaking, phytosterols have several health advantages, such as increased antioxidant activity, decreased low-density lipoprotein (LDL) cholesterol and support for prostate health and hair development [1].

1.2.7 Carotenoids

Carotenoids are pigments that are found in plants, algae and photosynthetic bacteria. They are vivid yellow, red, and orange. Carotenoids are found in abundance in fruits, but they are also abundant in vegetables. According to reports, fucoxanthin has anti-inflammatory, antihypertensive, anticancer, radioprotective and anti-obesity properties [1].

1.3 Schizophrenia

Schizophrenia, as a long-term mental disorder, affects about one percent of the world’s total population. Early environmental and genetic variables appear to be the primary contributors to this disease, while the existence of other mental diseases may also be involved. It is unclear if schizophrenia is a single condition or a collection of several syndromes due to the wide range of symptom combinations that might occur. There may be a connection between the pathophysiology of schizophrenia and increased oxidative stress. Changes in the structure of the brain associated with this illness include a reduction in dendritic spines from pyramidal neurons in the cortex, an expansion of ventricles and a loss of gray matter. Further potential links between schizophrenia and the prefrontal brain include elevated phospholipid metabolism and decreased dopaminergic function [10].

1.3.1 Symptoms of schizophrenia

A mental illness known as heterogeneous syndrome, schizophrenia can present with a variety of symptoms, including delusions, hallucinations, very disordered thinking or speech, disorganized behavior, flat affect and amotivation. The pathophysiology of the onset and progression of schizophrenia and sensitive and specific biomarkers have not yet been reliably identified [11].

2. Phytochemicals and their role in management of schizophrenia

Approximately 80% of people in Asia and Africa rely on complementary and alternative medicine. Antipsychotic medications that are often used have a number of side effects. Thus, in animal and cell culture models of central nervous system (CNS) diseases, a number of phytochemicals have been studied for their potential to preserve neurons and have antipsychotic properties. The overwhelming majority of research has shown that phytochemicals’ antioxidant activity is what gives them their antipsychotic and neuroprotective properties. Since oxidative stress in the brain is clearly depicted in the pathophysiology of schizophrenia, natural antioxidants in the form of extracts or specific phytochemicals are useful in the treatment of schizophrenia. These phytochemicals’ medicinal usefulness, low side effect rate, improved safety profile and excellent efficacy have drawn attention [12]. Phytochemicals demonstrate efficacy against schizophrenia and are associated with different phytochemical classes such as alkaloids, tannins, glycosides, phenolic acids, flavonoids, terpenes, terpenoids and essential oils [13].

2.1 Role of alkaloids in management of schizophrenia

Alkaloids are present in all plant parts especially in flowers. These are mostly helpful in the treatment of various neurodegenerative illnesses. These phytochemicals are beneficial against schizophrenia via changing acetylcholine concentration, boosting GABA, antagonizing N-methyl-D-aspartate (NMDA) receptors, antioxidant action, anti-amyloid activity and reducing neuro-inflammation [14]. Stepholidine, a protoberberine alkaloid, has a special feature of combined D1 agonist and D2 antagonist effect and is useful in improving memory deficit in schizophrenia [15]. Aporphine alkaloids, including apomorphine, reportedly cause amelioration of schizophrenic symptoms in patients by potently antagonizing dopamine at its receptor site [16]. Anti-schizophrenia studies have also been conducted using isoquinoline alkaloids. The NMDA current in the cortical neurons of rats is increased by galantamine. Additionally, it strengthened the benefits of Ach by positively modulating nAchR, which reduced attention deficit and improved short-term memory and focus [17, 18]. A combination of galantamine and memantine was effective in enhancing cognition in schizophrenic patients [19]. Reticuline has also demonstrated antipsychotic activity through anti-dopaminergic actions [20].

As an alpha nicotinic receptor agonist, nicotine, a pyridine alkaloid, was found to be beneficial in treating attention deficit disorder in people with schizophrenia [21]. Geissoschinzine methyl ether’s partly antagonistic action against NMDA receptors and regulation of dopamine receptors both contributed to its ameliorative effects against schizophrenia [13].

2.2 Role of glycosides in management of schizophrenia

Glycosidic bonding is the process by which a sugar moiety is joined to a non-sugar molecule in glycosides. Plants have glycosides as secondary metabolites; they are the parts of their “offense and defense” [22, 23]. By enhancing vesicular glutamate transporter 2 in the cingulate gyrus region, a study investigating the effects of bacoside A and B isolated from Bacopa monnieri demonstrated improvement in cognitive deficits in a schizophrenic model [24]. Isothiocyanates, like sulforaphane, shown antioxidant activity by boosting electrophilic response elements, detoxifying phase 2 enzymes and activating the Nrf2 pathway to exhibit antipsychotic activity [25]. Nephthodianthrone or hypericin has antioxidant qualities. Inhibiting D3/D4 receptors, it is a potential medication for the treatment of schizophrenia [26, 27]. Emodin targets ErbB signaling and modifies the metabolism of dopamine and serotonin to reduce symptoms of schizophrenia [28, 29]. Polygala saponin, a saponin glycoside, has anti-schizophrenic activity due to its dopamine and serotonin antagonist activities. Cardenolides and iridoid glycosides are also shown to be useful in treating psychotic symptoms that need more research. Docking experiments also showed that beta-sitosterol blocked NMDA receptors that included GluN2B. Additionally, picroside II demonstrated antipsychotic activity potential in vitro [30, 31].

2.3 Role of polyphenols in management of schizophrenia

Plant secondary metabolites known as polyphenols have been shown to have neuroprotective and anti-schizophrenic properties. These appear to be effective against neurologic and psychotic diseases, according to several studies [32]. Because of its anti-inflammatory, antioxidant and anti-apoptotic properties, kaempferol has shown neuroprotective effects against schizophrenia [33]. It has been observed that baicalin improves cognitive dysfunction and unpleasant symptoms in psychosis. Its anti-inflammatory, antioxidant and anti-prolyl-oligopeptidase properties may be responsible for this psychotic impact [13, 34].

Quercitin is a bioflavonoid that has the ability to alleviate symptoms of schizophrenia by scavenging free radicals [35]. Protein kinase C and nitric oxide are both inhibited by myricitrin. Its antioxidant action is responsible for its anti-schizophrenic properties [36]. Scopoletin and rutin’s inhibitory interaction with the D2 receptor makes them beneficial for reducing positive symptoms of schizophrenia [37]. The anti-schizophrenic properties of xanthones, like magniferin and α-mangostin, have also been investigated. α-mangostin possesses anti-inflammatory and antioxidant properties. In rodent models of schizophrenia, it was also demonstrated to be efficacious and to inhibit phosphodiesterases and 5HT2A receptors. Magniferin’s antioxidant mechanism, preservation of mitochondrial capabilities, anti-inflammatory activity and dopamine decrease all contributed to its better cognitive effects [38, 39]. One cholesterol that has demonstrated neuroprotection against a variety of neurological and psychological conditions is hydroxytyrosol. By activating the Nrf2 pathway, it reduced oxidative stress and improved mitochondrial functioning. When given during pregnancy, it improved learning and memory in fetuses of stressed animals and humans, demonstrating the importance of maintaining neurogenesis and cognitive abilities in offspring [40, 41].

Because curcumin can increase decreased glutathione levels, it has a number of advantageous benefits on the neurological system [42]. In patients with persistent schizophrenia, curcumin enhanced the effectiveness of regular antipsychotic medications. These therapies have improved the negative symptoms associated with schizophrenia. Curcumin modulates NMDA activity and controls the production of genes linked to inflammation, both of which are linked to symptoms of schizophrenia. By increasing GABA activity, Morin also showed antipsychotic-like effects without having an extrapyramidal side effect [43]. The flavonoid nobiletin reduces the cognitive symptoms of schizophrenia by enhancing the hypo-functioning of NMDA receptors through its action on extracellular signal-regulated kinases (ERK) signaling [44].

Diosmin, a flavone, enhances GABA transmission to treat symptoms of schizophrenia [45]. Isoflavone [46], luteolin and apigenin have also shown a great deal of promise in reducing the symptoms of schizophrenia [46].

2.4 Role of terpenes and terpenoids in management of schizophrenia

Tutin is a sesquiterpene that inhibits glycinergic activity and blocks GABA-A receptors. In addition, 1, 8 cineole is a monoterpenoid that influences the glutamate and dopamine pathways. Sesquiterpene caryophylline, which is extracted from essential oils and functions as a phytocannabinoid, has been successfully studied in a clinical study on schizophrenia [47].

2.5 Role of cannabinoids in management of schizophrenia

As members of the terpenoid class, cannabinoids are useful in the management of neurodegenerative illnesses. A meta-analysis’s findings indicate that people with schizophrenia have higher levels of the endocannabinoid anandamide in their blood, CSF fluids and immune cells’ cannabinoid 1 receptor (CB1) [48]. Using cannabinoids has been shown to improve cognition and reduce disease-positive symptoms in three randomized trials [49].

In order to have an anti-schizophrenic effect, cannabinoids, a kind of cannabinoid, boost GABAergic activity and prevent serotonin uptake. Cannabis-using schizophrenic individuals also showed this effect. Furthermore, compared to other antipsychotics, cannabinoids have demonstrated a definite advantage in clinical trials because they did not cause any movement-related side effects [50].

Another cannabinoid, tetrahydrocannabinol, also improved the symptoms of schizophrenia due to its effect on the endocannabinoid receptors [51]. However, some investigations claimed that the administration of 9-tetrahydrocannabinol had exacerbated psychotic symptoms. However, tetrahydrocannabinol may have effects that vary in dose, according to the study. When taken in large quantities, it caused disturbance to brain circuits that exacerbated psychotic symptoms, while at modest dosages, it alleviated the symptoms of psychosis [51].

2.6 Role of phytosterols in management of schizophrenia

Many plants naturally produce phytosterols and oxyphytosterols, which are the byproducts of phytosterol oxidation. Due to a rise in the consumption of plant-based foods enhanced with phytosterol and oxyphytosterol, exposure to these natural agents is increasing [52]. One type of phytosterol found in vegetables, legumes, nuts, herbs and seeds is stigmasterol. It has been demonstrated to suppress the biochemical, histological and behavioral changes brought on by ketamine in mice, suggesting that it may have antipsychotic potential [52].

2.7 Role of carotenoids in management of schizophrenia

The active ingredients of saffron (Crocus sativus L.), such as crocins and safranal, have demonstrated great promise in the treatment of a number of illnesses affecting the central nervous system, including anxiety, depression and memory loss [53]. A carotenoid called crocin has demonstrated efficacy as an antipsychotic medication by controlling brain-derived neurotrophic factor (BDNF) in the hippocampal tissues [54]. Growing preclinical data shows that crocins, at doses of 15–50 mg/kg, alleviated the memory impairment, hypermotility and social isolation that ketamine generated in rats [55]. Additionally, it was discovered that crocins prevented rats’ apomorphine-induced impairment in a novel object identification test linked to dopaminergic dysfunction [56]. Based on a better safety profile and the preclinical evidence of efficacy against psychosis, there is a strong need for controlled clinical studies of these agents against schizophrenia [57].

2.8 Role of other phytochemicals in management of schizophrenia

Dopamine D2 and/or D1 receptor antagonistism is the mechanism via which alpha asarone, an essential oil from the polypropanoid class, exhibits anti-schizophrenic effects [58]. In a human open trial, the amino acid glycine reduced the unpleasant symptoms associated with schizophrenia. This effect is attributed to its potentiating effect on NMDA receptors. When used as an adjuvant to other medical therapy, it has been shown to be beneficial against treatment-resistant schizophrenia, negative symptoms and cognitive issues. Another amino acid that reduces the symptoms of schizophrenia is leucine, which works on dopaminergic receptors [59].

Because kava contains kavapyrone, which has been shown to have efficacy against a number of neurological illnesses, kava is a well-known herb. Because kavapyrone inhibits glutamate release and increases the density of GABA-A receptors, it may be used to treat schizophrenia. Withaferin A, Withanolide A, Withanolide B and Withanolide D are steroidal lactones that have shown favorable effects on NMDA receptors through docking studies and can be useful in schizophrenia following further examination [31]. The effect of various phytochemicals on positive, negative and cognitive symptoms is summarized in Figure 2 [13].

Figure 2.

How different phytochemicals targets on different drug for schizophrenia [13].

3. Importance of vitamins in treatment of schizophrenia

Vitamins are often obtained through diet because many of them cannot be produced by the human body at sufficient levels. Many researchers have linked vitamin deficits to schizophrenia, either in the early stages of the condition or after diagnosis [60]. Vitamin B is necessary for cellular metabolism, which includes oxidation-reduction and trans-methylation [61]. Antioxidants like vitamins C and E guard against cellular damage brought on by highly reactive oxygen-containing molecules or inflammation. Schizophrenia Patients showed decreased fasting vitamin C levels and poorer urinary vitamin C excretion following 1.0 g oral vitamin C load in a small cross-sectional research with 20 schizophrenia patients and 15 controls [62]. Retinoic acid, produced from vitamin A and essential for neuronal migration and differentiation, is thought to be part of the pathophysiology of schizophrenia. Within some subgroups, vitamin supplementation, especially with folic acid, vitamin B12 and vitamin D, may be crucial to the management of schizophrenia [63]. Vitamin D supplementation may be protective against psychosis in patients who are deficient in vitamin D (darker skin, living in a latitude with less sunlight). Supplementing patients with particular genetic variations in the folate metabolic pathway with both folate and vitamin B12 can be helpful, particularly when it comes to alleviating bad symptoms [64].

4. Conclusions

More than a thousand phytochemicals have been discovered to date and can be derived from various sources such as whole grains, fruits, vegetables, nuts and herbs. Some of the significant phytochemicals are carotenoids, polyphenols, isoprenoids, phytosterols, saponins, dietary fibers and certain polysaccharides. These phytochemicals possess strong antioxidant activities and exhibit antimicrobial, antidiarrheal, anthelmintic, antiallergic, antispasmodic and antiviral activities. Schizophrenia is a condition that is related to alterations in brain structures involving loss of gray matter, expanded ventricles and reduction of dendritic spines from pyramidal neurons of the cortex and can manifest with delusions, hallucinations, extremely disordered thinking, disorganized behavior, flat affect, amotivation, energy and failure to maintain hygiene along with many more symptom domains. Alkaloids are effective against schizophrenia by affecting acetylcholine concentration, increasing GABA, antagonizing NMDA receptors, antioxidant action, anti-amyloid activity and preventing neuro-inflammation. Glycosides target ErbB signaling and alter dopamine and serotonin metabolism to exhibit ameliorating effects against schizophrenia symptoms. Polyphenols demonstrate neuroprotective effects against schizophrenia due to their anti-inflammatory, antioxidant and anti-apoptotic effects. Terpenes and Terpenoids inhibit glycinergic activity and block GABA-A receptors. Cannabinoids is a cannabinoid that blocks serotonin uptake and increases GABAergic activity to exert anti-schizophrenic effect. Cannabinoids is a cannabinoid that blocks serotonin uptake and increases GABAergic activity to exert anti-schizophrenic effect. Phytosterols manage psychosis by ameliorating inflammation and oxidative stress and by altering dopaminergic, acetylcholinergic and GABAergic neurotransmission. Carotenoids have shown high potential for treatment of various central nervous system disorders such as anxiety, depression and memory deficit. Hence, phytochemicals play a vital role in management of schizophrenia.

Acknowledgments

The authors wish to thank the Research Centre College of Pharmacy and Deanship of Scientific Research at King Saud University Riyadh, Saudi Arabia.

Conflict of interest

The authors declare no conflict of interest.

Acronyms and abbreviations

BPH	benign prostatic hyperplasia
CNS	central nervous system
NMDA	N-methyl-D-aspartate
Nrf2	nuclear factor E2-related factor 2
GABA	gamma-aminobutyric acid
ERK	extracellular signal-regulated kinases