Essential Oils As A Potential Neuroprotective Remedy For Age-Related Neurodegenerative Diseases: A ReviewⅡ
Mar 14, 2023
4. Discussion
EOs contain the essence of different scents and the properties of their originating plants. These volatile oils display various biological activities [154]. They are mainly used in the beverage, fruit, cosmetic, and fragrance industries [155]. EOs derived from the steam distillation process are mainly used in pharmacological activities and food products, while the extracts from lipophilic solvents are utilized in the fragrance industry [156]. Several EOs have been well-known for their usage in fragrances and flavors for hundreds of years. EO usage in the fragrance industry is mainly due to its attractive odor. The extensive benefits offered by EOs signify the continuous demand that is seen to be increasing steadily.
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4.1. The Source of EOs
As mentioned before, EOs can be extracted and obtained from various parts of plants. Clove’s EO derived from the Syzygium aromaticum tree’s aromatic flower buds with origin from Maluku, Indonesia contains the powerful scent used in spiced foods [154,155]. Eucalyptus globulus oil is mint-like, with properties such as a decongestant, pain reliever, antimicrobial agent, immunostimulant, flu, and cold/cough treatment, as well as for mental clarity in aromatherapy [157,158]. One of the most influential EO is from Lavandula angustifolia, which is also known as English lavender. Lavender oil possesses strong antioxidant, anti-inflammatory, antibacterial, and antimicrobial properties, and can be used to treat various skin diseases (e.g., eczema, ringworm, acne), improve the digestive system, minimize sore muscle swelling, and additionally, alleviate pain [157,158]. Citrus limon EOs are used as antimicrobial and antifungal agents, pain relievers aid in weight loss, and to reduce extreme nausea as well as for usage as soaps, hair shampoo, furniture polishes, and fresheners [157,158].
Oregano (Origanum vulgare) EOs are often used for skin care, menstrual problems, stomach problems, and to control flu and cold infections [157,158]. Rosemary’s EO originates from the Rosmarinus officinalis evergreen shrub with characteristics of a crisp woody, herbal, and balsamic odor, similar to camphor. The usage of rosemary oil ranges from various treatments of skin care, dandruff, and scalp health, as well as to cold prevention and boosting the immune system [157,158]. EO from Mentha piperita is called peppermint oil, which is mainly used in the prevention of flu and colds, reduces headache symptoms, and also in relieving muscle and joint pains [157,158]. Apart from the general usage of EOs, their extensive benefits have also been noticed and reported in relevance to age-related neurodegenerative disorders. Based on available studies, EOs have been proposed as an effective preventive and treatment approach for anti-aging and neurodegenerative disorders. Therefore, we attempted to describe and highlight the various EOs, and the effectiveness of their components concerning the four common neurodegenerative diseases (AD, PD, HD, and ALS), as mentioned above.
The different parameters that are commonly used for the evaluation of each disease are explained, accordingly. Based on Table 1, a total of sixty-nine types of EOs from different genera of plants were evaluated for their effectiveness against neurodegenerative diseases among studies conducted between 2010 and 2020. About all the compiled literature, we observed that the IC50 results were presented in several formats, in particular to the units of measurement. Among the units that were reported included mg gallic acid equivalents/g [64,76], the percentage [65,74], mg/mL or mg/L [26,67,68,73,75], µm [69], and µg/mL [18,70–72]. This diversity, however, was considered troublesome because direct comparison among studies with different measurement units is not possible without conversion.
4.2. Major Component of EOs
The chemical structures of several major components commonly found in EOs that have been reported to have anti-neurodegenerative properties are presented in Figure 3. Based on our review, 1,8-cineole has been identified as one of the major components found in various types of EOs. The compound 1,8-cineole is a saturated monoterpene that can originate from several plant species (e.g., Eucalyptus, Rosmarinus, and Salvia), with Eucalyptus leaves recognized as the key source [159]. Sometimes called eucalyptol due to its natural source, 1,8-cineole should not be confused with eucalyptus oil, a combination of many other components [160]. Due to its excellent aroma and taste, 1,8-cineole is mostly used in fruit, fragrances, and cosmetics.
Furthermore, pure monoterpene 1,8-cineole is used as an alternative sinusitis remedy for respiratory tract infections, such as the common cold or bronchitis [161]. It was indicated as one of the most potent free radical scavengers that may influence anticholinesterase activity based on a study reported by El Euch and colleagues [88] The antioxidant activity was measured using the free radical 1,1-diphenyl2-picrylhydrazyl (DPPH) test. Essential oil concentration providing 50% inhibition (IC50) of the initial DPPH concentration was calculated using the linear relationship between the compound concentration and the percentage of DPPH inhibition. Ascorbic acid was used as a standard. In the study by Abuhamdah et al. [66], EO extracted from the leaves of Aloysia citrodora Palau showed neuroprotective activity, and a higher presence of 1,8-cineole was reported (23.66%).
In another study performed by Cutillas and his team [97] on EO from Thymus masti china L., it was asserted that among all four compounds (α-pinene, β-pinene, limonene, and 1,8-cineole), 1,8-cineole was the best AChE inhibitor with an IC50 of 35.2 ± 1.5 µg/mL. They tested the antioxidant activity using five different methods such as the oxygen radical absorbance capacity (ORAC) assay, the 2,20 -azino-bis (3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) antioxidant method, the 2,2-diphenyl-1-picrylhydrazyl (DPPH) method, the thiobarbituric acid reactive substances (TBARS) method, and the chelating power (ChP) method. All the methods recorded that 1,8-cineole was one of the compounds highest in antioxidant capacity. This finding was similar to several other types of research, which suggested the efficacy of 1,8-cineole as the dominant anticholinesterase agent from EOs of different sources [8,21,25,152].
4.3. Cholinesterase Activity in EOs
The most common criteria used in the determination of AD is related to the anti-cholinesterase activity. Cholinesterases (ChEs) are specialized carboxylic ester hydrolases that catalyze the hydrolysis of choline esters. Two types of ChE activity have been identified in mammalian blood and tissues, which are distinguished according to their substrate specificity and sensitivity to selective inhibitors. The first is acetylcholinesterase (AChE), which is systematically known as acetylcholine acetylhydrolase [172]. The second is butyrylcholinesterase (BChE), which is systematically referred to as acetylcholine acyl hydrolase [173–176]. The preferred substrate for AChE is acetylcholine (ACh), while butyrylcholine (BCh) and propionyl choline (PCh) are ideal for BChE [175–177]. AChE activity is known to be inhibited by several compounds, with toxins and drugs as the major inhibitors [178].
AChE activity is used in verifying treatment effects, especially in AD [177]. Both AChE and BChE possess active sites at the bottom of 20 Å-deep gorges with 50% identical amino acid sequence, whereas the gorge entrance locates at the peripheral site [179]. The active site for both enzymes comprises a catalytic triad, acyl-binding pocket, and choline-binding site [180]. A total of 14 aromatic amino acids are found in the active site of AChE, whereas six of these are substituted by aliphatic amino acids for BChE [181]. The binding and hydrolysis processes of bulky ligands are restricted in AChE due to the presence of phenylalanine residues in the acyl binding pocket. In contrast, these residues are substituted with two flexible amino acids that are selective for BChE and allow the binding of bulkier ligands [182]. The different mechanisms involved in relevance to the active gorge site specific for each enzyme have been investigated via molecular modeling, structure-based virtual screening, or even crystallographic studies [181–184].
Generally, traditional Ellman assay is used with some modifications, applied for the determination of anti-cholinesterase activities [185,186]. This technique is a simple, accurate, and rapid method of measuring ChE activity, that is based on the reaction between thiocholine with the sulfhydryl group of a chromogen such as 5,50 -dithiobis-(2-nitrobenzoic acid) (DTNB or Ellman’s reagent). The shift of electrons to sulfur atoms yields a yellow substance called 5-thio-2-nitrobenzoic acid (TNB), which is measured by monitoring absorbance at 410 nm [187–190]. DTNB is a water-soluble compound and is useful for its fast reaction with thiocholine and minor side effects at neutral pH [185,187–191]. This technique, however, is also subject to certain limitations; it is restricted to testing antidots against organophosphorus AChE inhibitors or measuring AChE activity in samples of such treated individuals [190]. In addition to the Ellman assay, another method that can also be used for measuring ChE activities is the electrometric method of Michel [192]. This technique is applied based on pH changes that arise from H+ synthesis via cholinesterase hydrolysis [175,176,193].
4.4. Extracellular Plaque Deposits
Extracellular plaque deposits of the Aβ-peptide and flame-shaped neurofibrillary tangles of the microtubule-binding protein tau are the two hallmark pathologies required for AD patients. Familial early-onset forms of AD are associated with mutations either in the precursor protein for Aβ (APP) or in presenilin-1 (PS1) or presenilin-2 (PS2). Peptide generation pathways synthesize γ-secretase with either PS1 or PS2 as the catalytic subunit. APP is sequentially cleaved, where β-secretase first cleaves APP to release a large, secreted derivative, sAPPβ, followed by γ-secretase that cleaves a fragment of 99 amino acids (CTFβ) to generate Aβ. The process of γ-secretase cleaving can be inaccurate, leading to C-terminal heterogeneity of the resulting peptide population that generates numerous Aβ species, with Aβ1—40 of the highest abundance followed by Aβ42. The slightly longer forms of Aβ, particularly Aβ1–42, are the principal species deposited in the brain that are more hydrophobic and fibrillogenic [193].
Given their vital role in Aβ synthesis, both β- and γ-secretase are considered key components in anti-AD pharmaceutical developments [193,194]. Normal pathology tests refer to the density in the affected brain regions of neuritic amyloid plaques and neurofibrillary tangles of tau protein. AD diagnosis involves the presence of large neuritic plaque portions, consisting of highly insoluble Aβ in the brain parenchyma. There are also deposits of tau protein, although they occur among less common neurodegenerative disorders, especially in the absence of neuritic plaques. There are some distinctive morphological features of the neurofibrillary tangles in various diseases and may exhibit a distinct composition of tau isoforms that vary from AD [195].
It is not only humans which have amyloid beta; non-human primates (NHPs) have the same Aβ sequences as humans, an almost identical APP sequence, and they overlap with related human biochemical pathways in many aspects, however surprisingly with aging, they develop relatively few AD-like neuropathologies. Aged canines also develop severe amyloid deposition; canines tend to demonstrate extensive amyloid deposition from about ten years of age, unlike in aged NHPs, where it could take several decades [196]. Amyloid deposition in canines is also interrelated with age-related cognitive dysfunction [197], although little neuronal loss is detected. Due to a poor understanding of AD and the human brain complexity, it has been deduced that there is no natural animal model of the disease [198]. For the past 25 years, pharmacological and genetic AD models, as well as various animal species (primates, dogs, rodents, etc.), have been used in AD research activities [199,200]. The resurgence of interest in rats as the appropriate animal model for AD led to the usage of various types of rat models. As of current practice, transgenic mice have been extensively used in studies on AD. In any selected models, all need the introduction of some combined familial AD mutation into APP or PS1, or even in both [200].
