Essential Oils and Their Antioxidant Importance: The In Vitro and In Vivo Treatment and Management of Neurodegenerative Diseases with New Delivery Applications

Abstract

Essential oils are organic volatile oils of plant sources consisting of various compounds with numerous medicinal and pharmacological actions of great importance in other fields. Neurodegenerative diseases are a constellation of conditions depicted by multifactorial processes, as evident in structural and functional neurodegeneration that affect diverse brain parts showing similar cellular and molecular etiologies. The antioxidant properties of essential oils are promising targets in drug discovery to find the solution to incurable neurodegenerative diseases in terms of prevention, treatment and management. The antioxidants in essential oils encounter barriers in their delivery to the central nervous system for effective targeted therapy. These barriers are characterized as limited permeability and solubility, and accumulation of drugs or molecules to the non-targeted site, among others, render neurodegenerative diseases incurable. However, nanotechnology and other approaches in drug delivery to the central nervous system provide promising results in different in vitro and in vivo studies that indicate controlled drug release, increased bioavailability and efficiency in treating and managing neurodegenerative disease.

1. Introduction

Essential oils (EOs) are invaluable secondary metabolites of complex components and liquids mixtures obtained from different parts of aromatic plants. EOs obtained from different plant parts such as the leaves, stem, seed, bark, and root undergo other extraction processes: azeotropic distillation or solvent extraction. Hydrodiffusion, hydrodistillation, and steam distillation extraction, which is a commonly used method of extraction because it is cheap and easily achievable, is a type of azeotropic distillation [1]. These EOs are volatile organic compounds and over 300 different such compounds with a relatively molecular weight below 300 [2]. EOs comprise several chemical constituents, terpenes and phenylpropanoids, the most constituents of the EOs in aromatic plants. The metabolic pathways responsible for forming these major chemical constituents of EOs are methylerythritol, mevalonate and shikimic acid [3].

EOs type, yield, composition or chemistry are determined by different factors. Notably, plant variety, plant nutrition, harvest season, geographical locations, climate and seasonal variations, stress factors, and post-harvest handling and storage are the attributable factors [4]. Naturally, the EOs in plant function to protect the plant from various attacks of insects, fungi, bacteria and viruses. In addition, EOs tends to facilitate pollination in plants because of the odor or smell [5].

The importance of EOs must be considered in different fields of cosmetics, food, and pharmaceutical industries which necessitated and resuscitated the growth of the EOs market. Globally, the approximate contribution of EOs in terms of market value is USD 10.3 billion in 2021. The projection of USD 16.0 billion is the offing for the year 2026 [6] Hence, EOs contribute massively to the GDP because of the awareness of the health benefits of consuming natural food or products. Generally, the bioactive component of EOs from medicinal plants contains an armamentarium of antioxidants that confer an array of potent therapeutic properties. At the same time, the antioxidants contained in EOs have a better safety profile compared to synthetic antioxidants such as butylated hydroxyanisole (BHA), and butyl hydroxytoluene (BHT), among others [7]. The suspected toxic or harmful nature of synthetic antioxidants in human health draws concerns. In addition, natural antioxidants from EOs are very essential in the food industry preventing rancidity and improving the shelf-life of food products. The use of natural antioxidant from EOs become very sacrosanct with increasing or growing interest in medicines because many or nearly all diseases conditions finds their root or are linked to oxidative stress.

Generally, the physiological process allows cell death without resulting in any pathological state or condition; however, most oxidative cell death and tissue damage from the overarching effect of excess oxidants or free radicals or reactive oxygen species (ROS) beyond the body’s mechanism antioxidants defense system (endogenous and exogenous) results to oxidative stress. Free radicals or ROS are highly unstable with a propensity to accept or donate electrons which cause structural and functional modifications to important cellular biomolecules such as the DNA, protein, lipids, and carbohydrates that lead to oxidative stress [8, 9].

The resultant effect of oxidative stress is dangerous to human health as envisioned in the occurrence of autoimmune diseases, cardiovascular diseases and heart attack, cancer, kidney disease, infectious disease, diabetes, and rheumatic diseases, particularly with more imminent concern in neurodegenerative diseases [10]. The disturbed homeostasis in oxidative stress conditions forms the basis of the etiology and pathogenesis of many diseases above. Hence, the right to way go in treating and managing such conditions is preventing and halting the cause of oxidative stress that would ultimately prevent or delay pathological changes or alleviate the disease occurrence.

Given that oxidative stress is associated with the etiology and pathogenesis of many diseases, eliminating the causes of oxidative stress may prevent or delay pathological changes and reduce the occurrence of diseases. The antioxidant is pivotal to ensuring normal homeostasis condition and its actionable characteristics help or come to bear to prevent, halt and ameliorate free radicals or ROS such as superoxide anion (O²⁻), per hydroxyl radical (HOO.), hydroxyl radical (HO.) singlet oxygen (¹O²), and hydrogen peroxide (H₂O₂) that are responsible for oxidative stress.

Antioxidants refer to molecules that fight the imbalances caused by the excess oxidants, free radicals or ROS, thus significantly delaying and preventing the oxidative damage process and conferring defense mechanism against such oxidative damage process in cells. ROS prevention, capture, and blockade, as well as the repair processes that expunge the damaged biomolecules that ROS has initiated, form the basis of the mechanisms of action of antioxidants in combating oxidative stress [11]. Protective or defense mechanism offered by both endogenous and exogenous antioxidants help combat oxidative stress linked to many diseases, particularly neurodegenerative diseases (NDs).

The etiology and progression of NDs are linked to oxidative stress, among other vital factors. The neurons of both the central and peripheral systems are implicated; however, NDs primarily affect neuronal brains. The factors that make neurons in the brain prone to oxidative stress leading to NDs include high oxygen demand, increased peroxidation-susceptible lipid membrane-bound cells, and modest content of antioxidant defense system and related enzymes [12, 13, 14]. Till today many researchers have opined that oxidative stress plays a significant role in different NDs, such as Amyotrophic lateral sclerosis (ALS), Alzheimer’s disease(AD), Parkinson’s disease (PD), Huntington’s disease (HD), Multiple sclerosis (MS) [15].

2. Neurodegenerative diseases and their impact

Essentially, the CNS must be protected from oxidative stress, induced majorly by ROS, with both endogenous and non-endogenous defense systems. The role of endogenous and exogenous antioxidant systems in CNS has been well-reviewed [15]. For example, endogenous enzymatic antioxidants activity in CNS, the superoxide dismutase (SOD) reduces oxidative stress, tau hyperphosphorylation and apoptosis [16] glutathione peroxidase (GPx) induces neuroprotection and activate ferroptosis [17] glutathione synthase (GST) increase the level of GSTα4 for neuroprotection [18] and glutathione (GSH) a non- enzymatic endogenous antioxidant increase GSH/GS-SG to prevent neurodegeneration [19].

NDs are a constellation of disease conditions that are often progressive, chronic, and devastating that affect or induce neurons of the peripheral and central nervous system to be defective. This results to reduce neurons or loss of their activity and integrity (protein tangling and aggregation), loss or lack of transmission or communication, and hence cognitive loss, as well as loss or lack of motor and sensory functions [20, 21, 22]. In other words, neurodegeneration indicates both loss of structure and function of neurons, attributed as the hallmark of most NDs. Although the genesis of most NDs is not definitive or clear, neurodegeneration and neuroinflammation linked to oxidative stress alter the homeostasis of the CNS with various aforementioned pathological characteristics associated with NDs. The possible shared pathophysiology or mechanism of most NDs include oxidative stress, neuroinflammation, autophagy, altered cellular energetics, and calcium overload, among others are attributed to the pathogenesis of PD, AD, ALS, MS, HD, Friedreich’s ataxia spinal muscular atrophy, etc.

3. Essential oils and their antioxidant properties

The innumerable uses or importance of EOs calls for the best and most efficient methods in exploring aromatic plants. The therapeutics and other biological properties of EOs depend on chemical composition, molecular structure, position or location, and stereochemistry of the functional groups inherent in the molecule. It is crucial to get these various chemical constituents of EOs out of the aromatic plants well preserved. The method of steam distillation, solvent extraction, maceration, cold press extraction CO₂, and water distillation are employed. Modern techniques such as supercritical fluid extraction, microwave-assisted extraction, and ultrasound are more efficient, with greater yield for the composition of EOs [23, 24]. The vast chemical constituents of EOs have been expressed to have antioxidant activity. EOs are mainly classified into two structural families of hydrocarbon skeleton, namely, Phenylpropanoid and terpenoids, both of which contain an antioxidant phenolic, a principal compound inherent in several EOs [15]. A few structures of the different chemical components of Eos are given as an example in Figure 1.

Figure 1.

Some structures of different important chemical compounds of EOs.

Today, evaluating chemical components or constituents of natural products is an essential aspect of drug discovery and development. Determining the antioxidant properties of EOs is very important, attributed to the composition of different constituents. Various methods with their unique properties or mechanism are used to determine the antioxidant of EOs. Several scientific works have been done to evaluate antioxidant properties in vitro and in vivo assays, and many methods, especially in vitro assay, give reliable results in a short time without using animals [25]. Different in vitro assays that are commonly used for the determination of the antioxidant activity of natural products, including EOs are 2,2-DPPH (2,2-diphenyl-1-picryl-hydrazyl-hydrate) antioxidant compound’s ability to behave as a hydrogen donor or free radical scavenger, ABTS (2,2′-azinobis-(3-ethylbenzthiazolin-6-sulfonic acid), antioxidant compound stabilize the ABTS radical cation (ABTS·+) acting as electron transfer, FRAP(Ferric reducing antioxidant power) acting as reductant of ferric tripyridyltriazine complex [26] among others.

The identification of the components of EOs is done using chromatographic techniques, and gas chromatography-mass spectrometry (GC-MS) is usually or majorly employed technique to separate and identify EOs from different substances. This identification is possible using a unique fragmentation pattern of each separated component For example, GC-MS was used to identify the chemical composition of the EOs obtained from six Lamiaceae plants. The results revealed 167 components were identified from the six EOs using GC-MS [4]. Basically, in the review of the preclinical and clinical studies, the therapeutic potential of EOs from plants that delineates their biological actions on the CNS is highlighted in Table 1.

Plant	EO	Active ingredient more than 20 (%)	Biological activity
Syzygium aromaticum	Clove oil	Eugenol (76.8%)	GABAA receptor agonist
Boswellia sacra, Bos wellia frereana	Frankincense oil	a-Pinene (2–64.7%), a-thujene (0.3–52.4%), myrcene (1.1–22.4%), limonene (1.3–20.4%)	Unknown, but has synergistic effect
Lavandula angustifolia	Lavender oil	Linalyl acetate (7.4–44.2%), linalool 11.4–46.7%)	GABAergic system interaction Antagonist of NK-1 receptor inhibiting release of substance P reduces peripheral and central nerve excitability Inhibition of voltage-gated calcium channels, reduction of 5-HT1A receptor activity, and increased parasympathetic tone
Cymbopogon citratus	Lemongrass oil	Citral (26.1%), neral (31.5%)	GABAergic system interaction
Cananga odorata	Ylang oil	{3-Caryophyllene (26.8%)	Activation of ANS and has effects on the 5-HT and DAergic system Direct binding onto CB2R receptor
Cinnamomum verum	Cinnamon oil	Transcinnamaldehyde (71.50%)	Unknown
Mentha piperita	Peppermint oil	Menthol (40.7%), iso-menthone (23.4%)	Binds to the nicotinic/GABAA receptor and inhibits acetylcholinesterase
Rosmarinus officinalis	Rosemary oil	p-Cymene (44.02%), linalool (20.5%) 1,8-cineole (26.54%), α-pinene (20.14%),	Improves DA activation and secretion
Salvia sclarea	Sage oil	Camphor (12.8–21.4%), α-thujone (17.2–27.4%), 1–8, cineole (11.9–26.9%),	Acetylcholinesterase inhibition
Santalum paniculatum	Sandalwood oil	a-santalol (34.5–40.4%) and β-santalol (16–24.10%)	Acetylcholinesterase inhibition
Eucalyptus globulus		1,8-cineole (49.07–83.59%), α-pinene (1.27–26.35%)	Acetylcholinesterase inhibition

Table 1.

Summary of biological actions of some EOs antioxidant constituents on the CNS.

This is adapted and modified [24].

4. The potential of essential oils in neurodegenerative disease treatment

Considering the improved life expectancy, NDs are undoubtedly debilitating conditions affecting older populations or people. Because NDs remain incurable, efforts towards discovering and developing molecules with preventive and neuroprotective potential of neurodegeneration are important. EOs effectiveness and their respective antioxidant components are never in doubt in age-related NDs as they can halt OS. The neuroprotective and anti-aging characteristics of EOs have been explored in many kinds of research, having been adjudged as relatively non-toxic compared with other conventional therapy of NDs [27, 28, 29]. Efforts have been made in this chapter to majorly review various in vitro and in vivo studies using EOs as preferred candidates for managing and treating NDS in particular AD, PD, ALS and HD in Table 2.

NDs	Sources of the EOs	Major constituent of the EOs	Findings	References
AD (in Vitro)	Ajuga chamaecistus subsp scoparia (Boiss.) Rech.f	Spathulenol (18.0%), thymol (15.1%), octen-3-ol (14.3%) and linalool oxide (11.2%).	↓ Acetylcholinesterase and butylcholestrase activities	[30]
AD (in ivitro)	Allium tuncelianum (Amaryllidaceae)	Diallyl disulfide (49.8%), diallyl trisulfide (27.9%) and allyl methyl trisulfide	↓ Lipid peroxidation activity and acetylcholestrase and butylcholestrase activities	[31]
AD (in ivitro)	Artemisia macrocephala	a-humulene (46.3%), (β-caryophyllene (9.3%), α-copaene (8.2%), β-myrcene (4.3%), Z(E)-α-farnesene (3.7%), and calarene (3.5%)	↓ Acetylcholestrase activities	[32]
AD (in ivitro)	Artemisia maderaspatana	α-humulene (46.3%), β-caryophyllene (9.3%), α-copaene (8.2%), β-myrcene	↓ Acetylcholestrase activities	[33]
		(4.3%), Z(E)- a-farnesene (3.7%), and calarene (3.5%)
AD (in ivitro)	Boswellia dalzielii	3-carene (27.72%) and α-pinene (15.18%). 2,5-Dihydroxy acetophenone and β-D-xylopyranose	↓ Acetylcholestrase activities and inflammation properties	[34]
AD (in ivitro)	Daucus aristidis Coss	Contain majorly α-pinene (49–74.1%) and β-pinene (19.2–11.9%).	↓ Acetylcholestrase and butylcholestrase activities	[35]
AD (in ivitro)	Panax ginseng; Panax japonicas; P. notoginseng; P. quinquefolius	Spathulenol (8.82%), bicyclogermacrene (6.23%), β-elemene (3.94%), and α-humulene (3.69%	↓ Acetylcholestrase, butylcholestrase and β-Secretase activities.	[36]
AD (in vivo)	Lavandula angustifolia mill.	—	↓ Acetylcholestrase activity and MDA level, ↑SOD and GPx activities. Neuroprotective effect.	[37]
AD (in vivo)	Lavandula angustifolia Mill.	—	↓ SOD and GPx activities, ↓MDA level, ↑synapse plasticity-related proteins, calcium-calmodulin-dependent protein kinase II (CaMKII), p-CaMKII, BDNF, and TrkB	[38]
AD (in vivo)	Lavandula luisieri	—	↓ BACE-1 is an aspartic protease involved in the conversion of amyloid precursor protein (APP) to Aβ.	[39]
AD (in vivo)	Salviae aetheroleum	—	↑ Antioxidant enzymes activity. Thus, prevent neurodegeneration.	[40]
AD (in vivo)	SHXW	—	↑ A/31-42 induced memory impairment and suppressed A/31-42 induced JNK, p38 and Tau phosphorylation	[41]
PD (in ivitro)	Eryngium sp.	(E)-caryophyllene (4.9–10.8%), germacrene D (0.6–35.1%), bicyclogermacrene (10.4–17.2), spathulenol (0.4–36.0%), and globulol (1.4–18.6%) are major compounds.	↓ MAO activity	[41]
PD (in ivitro)	Cinnamomum verum Cinnamomum cassia	—	↑ Cell viability ↓ ROS and apoptosis. Hence, neuroprotection	[42]
PD (in ivitro)	Cuminum cyminum	Cuminaldehyde	↑ Cell viability ↓a-SN fibrillation	[43]
PD (in ivivo)	Eplingiella fruticosa	β-caryophyllene, bicyclogermacrene and 1,8-cineole	↓ Catalepsy and decreased membrane lipid peroxides levels	[44]
PD (in invivo)	Acorus tatarinowii Schott (Shi Chang Pu)	—	c mRNA levels of GRP78 and CHOP, ↓ expressions of phosphorylated IER1 (p-IRE1) and XBP1	[45]
PD (in invivo)	Pulicaria undulata	Carvotanacetone	↑ Dopamine, ATP levels and glutathione striatal contents. ↓ Striatal interleukin-1β (IL-l/β), tumor necrosis factor-α (TNF-a), and inducible nitric oxide synthase (iNOS) and MDA	[46]
PD (in invivo)	SHXW		↑ Dopaminergic neurons and dopamine levels, ↑ Phosphorylation levels of cAMP-response element-binding protein	[47]

Table 2.

The biological activities of EOs on selected NDs.

Note: ↑ Improved/increased.

↑ Decreased/inhibited.

5. New delivery applications for essential oils

Till date, NDs are incurable despite many scientific efforts in drug discovery and development in NDs. Most drugs discovered successfully treat the symptoms without curing the pathogenesis or root cause of the NDs with their attendant toxicities or side effects. Hence, in NDs, most molecules are for managing the conditions and are not curative. Antioxidants are adjudged safe that serve as very potent and effective molecules to many diseases by abrogating oxidative stress implicated in most disorders.

NDs most especially affect neurons of the CNS and the brain. The nature of the architecture of the CNS accounts for the innumerable hindrances to drug delivery for effective actions. The blood-brain barrier (BBB) limits the permeability and solubility of antioxidant molecules [48]; hence the antioxidant cannot reach the target CNS. In addition, antioxidants are sometimes unstable and prone to gastrointestinal degradation [14, 49]. The BBB of the brain function as the structure that controls the movement of substances (regulatory role) in the neural microenvironment. This is the interface between the blood and neural tissue, bringing about regulation [48]. Different lines of evidence suggest that BBB breakdown contributes to the pathogenesis of NDs such as ALS, MS, PD, AD, etc. This is because BBB is highly sensitive to OS-induced damage and distortion evident in physiological factors like neural aging, vascular disorder, molecular irregularities and anatomical pathologies [13].

The important aspect or standard for drugs or molecules is ensuring a delivery system that will circumvent the mentioned hindrances and hence promote potency, stability, specificity and safety. However, the BB is the main obstacle of CNS targeted therapies in NDs, which is addressed primarily through technology. Nanotechnology is an emerging and highly innovative field with tremendous potential in different areas, such as pharmaceuticals and medicine, thanks to distinctive physical and chemical features, such as minimal size and functionalized surface characteristics of materials [50, 51]. Nanomaterials are used in nanotechnology, which have unique physical, chemical, and biological properties due to their nanoscale dimensions (typically between 1 and 100 nm). These materials come in different sizes, shapes, compositions, surface chemical features, and hollow or solid structures, which can be adjusted to produce optical, electronic, magnetic, and biological characteristics suitable for their applications. The advantage of this nanotechnology is that it made possible the interaction of specific molecules or cellular targets by creating an excellent drug delivery system and hence targeted treatments, especially in ND conditions. This drug delivery system permits concerted multifunctional qualities such as bioactivity, targeting, imaging capabilities and gene delivery. Based on these characteristics, nanotechnology in drug delivery systems is now widely accepted.

The neuroprotective properties of EOs are attributed to their unique anti-free radical and antioxidant properties, as revealed in past research or studies. The improvement of cholinergic neuron deterioration that is eminent in most NDs conditions using EOs containing antioxidants improves cognitive function and prevents brain damage. Thus, these improved mental functions are evident in memory, attention span, planning, decision-making, judgments, speech and overall coordination [52]. EOs quickly find their way across the BBB, reaching the CNS after systemic absorption and could bring some neurological intoxications. Some molecules though lipophilic (solubility) in nature, show very poor permeability across the BBB, resulting from the active efflux mechanism in the membranes of BBB. There could be instances of improved drug accumulation that are non-target sites specific, although there is improved or increased lipid solubility in the BBB [53, 54]. Additionally, the exposure of molecules bound across the cerebral endothelial membrane to degrading enzymes [54], recognition of neuropeptide and their quick degradation by BBB itself and the reinforcement of high amount concentrations of P-glycoproteins (Pgp) that remove or prevent a range of molecules from passing across brain parenchyma [55, 56] are recognized barriers to CNS drug delivery.

Over the years, many enhanced strategies for enhanced CNS drug delivery have been developed. These strategies involve pharmaceutical manipulation, BBB disruption and other methods using nanocarriers, which would help transport molecules to target sites in the brain. Some strategies are viral vectors, polymeric nanoparticles, liposomes, dendrimers, micelles, carbon nanotubes, carbon dots and carbon nano-onions, which have been exhaustively reviewed [56]. These approaches increase therapeutic responses of natural products, including EOs, with overall effectiveness in the treatment and management by increasing bioavailability and ensuring effectiveness. For example, circumventing or overcoming BBB in NDs treatments is achievable through a nanoparticles-mediated brain drug delivery approach, as revealed in AD and HD [57, 58, 59].

Over the years, increasingly published works suggest the importance of EOs and drug delivery systems in medicine, food and pharmaceuticals. Although different applications could be adopted, this chapter focuses on the strategy of encapsulating EOs. The encapsulation is advantageous, which helps to overcome the fragility and volatility, enzymatic reactions, and preserve the biological activity that confers increased activity and decreased toxicity. The overall effect of the encapsulation EOs in drug delivery systems would be the avenue for controlled drug release, increased bioavailability and efficiency [60]. The vesicular and nanoparticles lipid–based delivery formulations vis a vis micro- and nanoemulsion, liposomes, solid lipid nanoparticles (SLN), and nanostructured lipid carriers approaches have unique characteristics.

6. Conclusion

EOs are natural products with diverse biological importance in different fields due to the inherent chemical constituents or components. The crux of this chapter is the antioxidant properties of EOs immensely contribute to the prevention, treatment and management of NDs. The multiple mechanisms of action of EOs antioxidants match or counter the multifactorial processes such as oxidative stress, neuroinflammation, excitotoxicity and others involved in NDs pathology. Although attaining the most effective therapeutics is essential, the CNS’s molecule or drug delivery barrier is a significant concern in treating and managing NDs. Many approaches using modern technology supported by research evidence, no doubt, have tremendously contributed to finding near or total solutions to incurable NDS. Therefore, effort must be channeled towards discovering and developing novel EOs and drug delivery systems through innovative and holistic research and collaboration towards finding lasting solutions to NDs.

Conflict of interest

The authors declared no conflicts of interest.