The antioxidant and anti-inflammatory properties of Citrus flavonoids can play a key role in their activity against several degenerative diseases and particularly brain diseases. In Brazil promising studies deposited in the patents “pharmaceutical formulation” form was obtained from the inclusion of Citrus sinensis L. (orange) essential oil with β-cyclodextrin and Citrus limon (lemon) compounds and their applications in therapy of Alzheimer’s disease. In this chapter, we report activities of active compounds present in the genus Citrus, which include antioxidant, anti-inflammatory, anxiolytic, insecticidal, and anticholinesterase activities. These activities are associated with some neurodegenerative diseases such as Alzheimer’s disease (AD). Pharmaceutical formulations containing such compounds (for example, inhibitors such as acetylcholinesterase (AChE) of C. limon (5,8-dimethoxy-psoralen and 5,7-dimethoxycumarin) and essential oil from C. sinensis oils are reported in this chapter. These results indicate that the effects of the essential oil and substances of Citrus species are very interesting for further isolation of AChE inhibitors that can be used in the formulation of natural products for neurodegenerative diseases.
- Citrus sinensis
- Citrus limon
- neurodegenerative diseases
Citrus fruits make up the largest sector of the global production of fruits, with more than 100 million tons produced every season .
In this chapter, we report activities of active compounds present in the genus Citrus, including antioxidant, anti-inflammatory, anxiolytic, insecticidal, and anticholinesterase activities, which are associated with some neurodegenerative diseases such as Alzheimer’s disease and we report the pharmaceutical formulation of
2. Acetylcholinesterase activity (AChE) of Citrus species
Alzheimer’s disease (AD) is a multifactorial disease that affects a significant portion of the population and its incidence has grown over the years due to the increasing proportion of elderly people in the world population. Factors such as formation of senile plaques and neurofibrillary tangles, reduction of acetylcholine levels (by inhibiting the enzyme acetylcholinesterase) and oxidative phenomena are related to the development and/or progression of AD [18, 19]. The acetylcholinesterase (AChE), an enzyme inhibitor associated with AD, is widely detected by Ellman’s test. According to the principle of the method of Ellman et al. , the reaction with the thiol has been shown to be sufficiently rapid so as not to be rate limiting in the measurement of the enzyme and in the concentrations used does not inhibit the enzymatic hydrolysis [18, 19].
Some AChE inhibitors are found naturally in medicinal plants. Reversible cholinesterase inhibitors are currently used in clinical trials for treatment of Alzheimer’s disease . The treatment is based on the inhibition of AChE, which hydrolyzes acetylcholine, increasing their availability to cholinergic transmission .
The anticholinesterase activity of extracts from
Studies on the species as
The structural diversity of terpenoids that exert inhibitory activity of AChE is difficult to predict the potential structure-activity relationship. But it is known that some features, such as the presence of a hydrophobic ligand, may be associated with greater effectiveness in the inhibition, since the active site of AChE is known to be susceptible to hydrophobic interactions. The monoterpenes consist of a hydrocarbon skeleton that can be cyclic (α-pinene) or acyclic (linalool), a feature that may also influence their AChE inhibitory activity. For a bicyclic monoterpene skeleton pinene or carene, the potential of AChE inhibition was associated with the position of the double bond . The presence of terminal olefins (H2C=CH2) resulted in decreased inhibition of AChE, as well as the presence of an oxygenated functional group .
Experiments that assess memory evaluate the effects of acute treatment with the essential oil of leaves (EOL) from
The composition of EOL of
The acquisition of memory space is evaluated by time the animal takes to locate the platform after having been trained. The results of the open field were demonstrated that animals do not exhibit motor stimulus when treated with the essential oil of
Activities of active compounds present in the genus Citrus, which include activities such as antioxidant, anti-inflammatory, anxiolytic, insecticidal, and anticholinesterase. These activities are associated with some neurodegenerative diseases such as Alzheimer’s disease .
3. Citrus antioxidants
Oxidative stress produced by free radicals has been implicated in the pathogenesis and progression of a wide variety of clinical disorders such as cancer, cardiovascular disease, inflammation, epilepsy, diabetes, and Alzheimer’s disease . Oxidative stress is the result of natural deficiency of antioxidant defenses, or by increased levels of reactive species derived from oxygen . Reactive oxygen species (ROS) such as superoxide radicals (O2−), hydrogen peroxide (H2O2), and hydroxyl radicals (OH•) are produced as a result of many biochemical reactions and can be considered the main cause of oxidative damage, as protein denaturation and lipid peroxidation mutagenesis [10, 27, 28].
The plants of the Citrus genus are rich in compounds that have antioxidant properties . Phenolic compounds, particularly flavonoids, have shown an important antioxidant activity, which is mainly based on their structural characteristics and other chemical characteristics due to the number and position of phenolic hydroxyl groups .
Natural antioxidants from fruit juices offer an alternative source of dietary ingredients to promote healthy life. A recent study on the juice of
Thirty-four types of essential oils of Citrus and its components were investigated for their antioxidant activity by 2,2-diphenyl-1-picrylhydrazyl (DPPH). The activity of components compared with a standard antioxidant, the trolox showed effects on DPPH scavengers ranging between 18 and 64%. One possible explanation for the difference in efficiency found in this study may be substantial variation in the compounds of the essential oils of citrus. Among the 34 types of essential oils, the radical scavenging activity of the lemon (
The antioxidant effect of α-terpinene, nootkatone, citronellal, citral, γ-terpinene, terpinolene, and geraniol substances result showed greater than trolox (
The low-density lipoprotein plasma (LDL) plays a significant role in the development of atherosclerosis. The antioxidant activity of the essential oil of three Citrus species (
4. Citrus anti-inflammatory activity
The inflammation is typically characterized by an increase in tissue permeability and endothelial leukocyte influx of blood into the interstitium, causing edema. Different mediators influence each step of the cascade of inflammation and characteristically inflammatory agents exhibit therapeutic properties by blocking the action or synthesis of these mediators. While inflammation is a normal response to tissue injury, often it is uncontrolled in chronic autoimmune diseases such as rheumatoid arthritis and Crohn’s disease, or when related to allergic response such as asthma and anaphylactic shock. In these cases, anti-inflammatory compounds are administered therapeutically to control the inflammatory response .
Plants rich in certain flavonoids have traditionally been used for its anti-inflammatory properties, being increasingly reported the isolation of flavonoids, including the Citrus genus with anti-inflammatory potential . Citrus flavonoids appear to impact blood and microvascular endothelial cells .
Studies reported that nobiletin (flavone) is a major component in juice from
Therefore, these results further support the notion that nobiletin is likely to be a candidate for characterization as a novel immunomodulatory and anti-inflammatory drug .
Citrus peels, the dominant residue, possess a large variety of bioactive compounds; they are considered as potential sources of functional components . In traditional herbal medicine in Korea, the dried fruit peels of
5. Citrus insecticidal
The insecticidal properties have been recognized in the essential oil of many species of the Citrus genus and various products containing (+)-limonene, linalool, and crude extract of some species of
Analyses were performed with the potential insecticidal activity by spraying volatile extracts from the bark of species two of orange–
The observed effect of oil extracted from
The herbal extracts to inhibit AChE activities are promising for the symptomatic treatment of Alzheimer’s disease, a neurodegenerative disease that initially affects memory and thinking ability. Research indicates that in the literature, there is a growing search for new inhibitors of AChE activity in plant extracts . This search is directed mainly to plants already used in traditional medicine for the treatment of insomnia, amnesia, depression, and anxiety, or to extend longevity and improve memory and cognitive function. Some plants, such as
The inhibitory activity of AChE is a significant effect induced by coumarins and particularly monoterpenes such as
6. Terpenes acetylcholinesterase inhibitors as perspective for the production of herbal medicines
Pharmacological treatments most commonly employed for Alzheimer’s disease (AD) stands out the use of materials whose action increases central cholinergic function, increasing levels of acetylcholine in the brain through inhibition of the enzyme acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). These enzymes are responsible for the hydrolysis of acetylcholine to acetate and choline, which prevents its action to the neurotransmitter. The inhibition of the enzyme AChE has been investigated for the treatment of various neurological diseases, and are therefore as the most suitable strategy for the treatment of AD and other diseases such as: senile dementia, ataxia, myasthenia gravis, and Parkinson’s disease .
Various terpenes present in plant essential oils are reported in the literature showing inhibitory activity against AChE and BuChE for example: ethyl bornila (1) α-pinene (2), β-pinene (3) γ-terpinene (4),
Promising studies show that terpenes can have their activity potentiated by complex with cyclodextrins making it a promising source of possible pharmaceutical formulations. The inclusion complex obtained between β-cyclodextrin and
7. Pharmaceutical formulation of citrus
The cyclodextrins (CDs), for example β-cyclodextrins (Figure 4), are composed of complex carbohydrates glucose units (α-D-glucopyranose) joined by α-1,4 linkages type, with a structure similar to a trunk cone. In 1903 Franz Schardinger identified cyclodextrins, as products resulting from the degradation by the action of amylase enzyme. Cyclodextrin starch glycosyl is a compounds of CDs that have played an important role in Medicinal Chemistry with regard to controlled release technology of drugs, currently represents one of the boundaries of science involving different aspects multidisciplinary knowledge. The delivery systems, often described as a “drug delivery systems,” offer numerous advantages when compared to other conventional dosage .
In the pharmaceutical industry, the CDs are used mainly to improve stability and bioavailability of the active principle and its organoleptic properties such as taste and smell in pharmaceutical formulations. The CDs can also be used to mask the unpleasant smell and taste of certain drugs, transforming solid liquid compounds, reduce volatility, and avoid undesirable mismatches. The increased solubility, dissolution, modification of the pharmacokinetics, and controlled release of drugs are other CD applications. The CDs have been used successfully in the management and drug delivery by various routes and/or administration sites such as oral, vaginal, rectal, nasal, ophthalmic, pulmonary, dermal, and transdermal . Figure 4 shows the structure of β-cyclodextrin is widely used as an excipient in pharmaceutical industry at low cost and the size of the cavity, which is suitable for encapsulating most substances
In Brazil a pharmaceutical formulation from the essential oil inclusion complex of
For the characterization inclusion complex of cyclodextrin and EOLCS was held the infrared spectroscopy and differential scanning calorimetry with three proportions, β-CD, and EOLCS, denominate of misture physical. It proved the formation of EOLCS complex with β-cyclodextrin through the analysis of differential scanning calorimetry, infrared spectra disappearance of the groups, and thermogram and it can be concluded that the ratio is 6:94 IC greater stability. It was shown in preliminary studies that the EOLCS significantly inhibits acetylcholinesterase a total of 73% in group 50 mg kg−1, 83% in group 100 mg kg−1, and 76% 200 mg kg−1 and significantly improves memory of the animals in promising preclinical studies.
The composition of the active fraction in
Citrus species are very interesting for further isolation of AChE inhibitors which can be used for neurodegenerative diseases for example Alzheimer’s disease application (Figure 5).
Promising preclinical studies were conducted with compounds isolated from some of these Brazilian species others namely
8. Concluding remarks
The results confirm that AChE inhibitors as alternatives for preparation of phytomedicines are used in therapeutic treatment of AD, being plants the principal source of these inhibitors. Recent studies show that the terpenes may have intensified activities through inclusion complexes with cyclodextrins excipient pharmaceutical, making them a promising source for potential pharmaceutical formulations.
In general, the formulations reported in this chapter from essential oils or their constituents is in progress, as they contribute to various activities of plants and open perspectives regarding the chemical composition of bioactive metabolites of the studied species and are considered promising alternatives to discoveries of new chemical compounds of pharmaceutical interest.