Essential Oils As A Potential Neuroprotective Remedy For Age-Related Neurodegenerative Diseases: A ReviewⅢ

4.5. Current EOs on AD 

Salvia is the largest genus of plants in the family Lamiaceae, with the number of species estimated to range from 700 to nearly 1000. Fifteen species of Salvia (namely, officinalis L., chionantha, chrysophylla Staph, urmiensis, nemorosa L., syriaca, ballsiana, cyanescens, divaricate, hydrangea, kronenburgii, macrochlamys, nydeggeri, pachystachys, pseudeuphratica, and rusellii) were studied for cholinesterase inhibition assay, and happen to be the most widely studied source of EOs. Most of the researchers found that Salvia spp. were weak AChE and BChE inhibitors, except for EO from S. pseudeuphratica, which demonstrated the highest inhibitory activity against AChE, at IC50 = 26.00 ± 2.00 µg/mL compared to S. cyanescens and S. pachystachys. In contrast, BChE activity did not show 50% inhibition even at the highest concentration, where IC50 was reported to be above 80 µg/mL for S. pseudeuphratica and S. hydrangea [96]. Salvia officinalis was studied twice, in 2017 and 2019. 

Click to organic cistanche for neuroprotection

Based on GC– MS and GC–FID analysis, the main components of S. officinalis were α-thujone, camphor, 1,8-cineole, and β-thujone. Salvia has also been used in ex vivo-based research, using the isolated guinea pig ileum method where the major molecule, rosmarinic acid, showed significant contraction responses on an isolated guinea pig ileum. Docking results of rosmarinic acid also showed a high affinity to the selected target, AChE [136]. The author suggested the potential of rosmarinic acid to become a novel therapeutic candidate for the treatment of AD. Other than Salvia spp., EOs from Lavandula spp. have also been studied for the treatment of AD. L. luisieri has been found to comprise high contents of oxygen-containing monoterpenes, mainly necrodane derivatives, which are absent from any other oil. This oil was tested on the endogenous beta-site APP-cleaving enzyme 1 (BACE-1) in cultured cells, being responsible for a reduction in Aβ production, with no significant toxicity. 

Although the study was conducted in vitro, the low molecular weight and high hydrophobicity of terpenoids are properties that provide a good chance for them to cross cellular membranes and the blood–brain barrier, an essential attribute for BACE-1 inhibition in vivo [78]. However, EO from L. angustifolia did not give a required finding because it enhanced the Aβ aggregation based on the thioflavin T method; this effect was further confirmed by atomic force microscope (AFM) imaging. EO of L. angustifolia was also showed to counteract the increase in intracellular reactive oxygen species production and the activation of the proapoptotic enzyme caspase-3 induced by Aβ1–42 oligomers [23,24]. 

Meanwhile, EO from L. pubescens exhibited strong anti-AChE and anti-BChE effects at IC50 of 0.9 µL/mL and 6.82 µL/mL, respectively. Carvacrol (CAR, 2-methyl-5-isopropyl phenol) was also found to be higher in L. pubescens. Carvacrol was found to be abundant among EOs of the Lamiaceae family, and is known for various benefits including antibacterial, antifungal, antioxidant, antinociceptive, anti-inflammatory, anti-apoptosis, and anti-cancer activities [201]. Several studies on EOs have reported that carvacrol exerts some actions on the neuronal system, including AChE inhibition [104,202], anxiolytic [203], and antidepressant [204] properties. In addition, carvacrol has the ability to modulate central neurotransmitter pathways, such as dopaminergic, serotonergic and γ-aminobutyric acid (GABA)-ergic systems [201].

 Only two types of cell lines, SH-SY5Y and PC-12, were reported to have been used in AD research. The in vitro toxic effects of amyloid peptides are usually examined using the human neuroblastoma-derived SH-SY5Y cell line, because differentiated neuron-like SH-SY5Y cells are extra-sensitive to amyloid peptides compared to non-differentiated cells, because the latter lack long neurites [205]. Z-ligustilide (Z-LIG) EOs effectively protect against fibrillar aggregates of Aβ25–35- and Aβ1–42-induced toxicity in SH-SY5Y and differentiated PC12 cells, possibly through the concurrent activation of the PI3-K/Akt pathway and inhibition of the p38 pathway [105]. Aβ25–35 represents a neurotoxic fragment of Aβ1–40 or Aβ1–42, and retains the toxicity of the full-length peptide [206]. Aβ25–35 is often selected as a model for full-length peptides because it retains both its physical and biological properties [207]. In general, declining levels of PI3K subunits as well as blunted Akt kinase phosphorylation have been observed in the AD brain, which is characterised by Aβ and tau pathologies [208]. There was also a study on the potential therapeutic effect of hybrid EO from Kushui roses. Kushui rose (R. setate × R. rugosa) refers to a natural hybrid of cog rose and traditional Chinese rose that has been cultivated for more than 200 years [209]. 

In this study, transgenic worm strains purchased from the Caenorhabditis Genetics Center (CGC) were used instead of rat or mice models. They found that rose EO (REO) significantly inhibited AD-like symptoms of worm paralysis and hypersensitivity to exogenous serotonin (5-HT) in a dosedependent manner. Although the GC–MS analysis revealed the presence of 40 components, the major components, β-citronellol and geraniol, were found to act less effectively than the oil itself. Intriguingly, REO significantly suppressed Aβ deposits and reduced the Aβ oligomers to alleviate the toxicity induced by Aβ overexpression [209]. Su He Xiang Wan (SHXW) has also been studied for its neurodegenerative remedy potential. SHXW is a distinct EO, and is a patent medicine comprising borneol, styrax resin, musk, aquilaria, frankincense, piper, benzoin, saussurea, cyperus, sandalwood, clove, terminallia, aristolachia fruit, rhino horn, and cinnabar. This ancient prescription was recorded in the He Ji Ju Fang of the Song Dynasty [210].

 For this plant, the researchers evaluated the effects of a modified SHXW (KSOP1009 formulation) intake on the AD-like phenotypes of Drosophila AD models, which express human Aβ1–42 in their developing eyes or neurons. They found that Aβ1–42-induced eye degeneration, apoptosis, and locomotive dysfunctions were strongly suppressed. However, Aβ1–42 fibril deposits in the Aβ1–42 overexpressing model were not affected by treatment with KSOP1009 extract. Conversely, KSOP1009 extract intake significantly suppressed the constitutive active form of hemipterous, a c-Jun N-terminal kinase (JNK) activator, while it induced eye degeneration and JNK activation. In Drosophila, flies with mutations that augment JNK signalling accumulate less oxidative damage and live dramatically longer than wild-type flies [211,212]. Cinnamomum zeylanicum consisting of (E)-cinnamaldehyde (CAL) (81.39%) and (E)- cinnamyl acetate (CAS) (4.20%) as the main compounds showed over 78.0% inhibitory activity in cholinesterase. In MAO-A and MAO-B inhibition assays, EOs from C. zeylanicum (96.44%, 95.96%) and CAL (96.32%, 96.29%) demonstrated comparable activity to rasagiline (97.42%, 97.38%, respectively). 

Research by Murata and co-workers [69] found that kaur16-ene, nezukol, and ferruginol isolated from plants had anti-AChE (IC50) activity at 640, 300 and 95 µm, respectively. Even though ferruginol activity has already been highlighted before, by Gulacti et al. [213], this study documented the activities of kaur-16-ene and nezukol for the first time. Meanwhile, Citrus limon has been found to significantly lower AChE brain depression in APP/PS1 and wild-type C57BL/6L (WT) mice. PSD95/synaptophysin, the synaptic density index, was substantially improved in histopathological shifts [109]. Based on the previous analysis by other researchers, nobiletin 30 ,40 ,5,6,7,8-hexamethoxyflavone was found to be the major component of polymethoxylated flavones in citrus peels, such as C. depressa, C. reticulata, C. sinensis, and C. limon [214,215]. Thus, nobiletin may potentially be the compound that substantially alters the development of these diseases. Other than that, Acori graminei, which was found to be rich in β-asarone, enhanced cognitive function of AβPP/PS1 mice and decreased neuronal apoptosis in the AβPP/PS1 mouse cortex. In addition, a substantial increase in the expression of CaMKII/CREB/Bcl-2 was observed in the cortex of AβPP/PS1 mice treated with β-asarone. In a study conducted by Ayuob et al. [113], Ocimum basilicum up-regulated the serum corticosterone level, the hippocampal protein glucocorticoid receptor, and the brain-derived neurotropic factor (BDNF); however, it down-regulated the neurodegenerative and atrophic changes induced in the hippocampus, which decreased after exposure to chronic unpredictable mild stress (CUMS). 

According to the data collected by Avetisyan and coworkers [216], the major components of O. basil includes methyl chavicol and linalool. Interestingly, many linalool-producing plants are commonly used in folk medicine and aromatherapy to alleviate symptoms and treat multiple acute and chronic diseases [217,218]. Linalool is frequently used in the manufacture of fragrances for shampoos, soaps, detergents, and in pharmaceutical formulations [219,220]. Research conducted by SabogalGuáqueta et al. [221] found that oral administration of monoterpene linalool to elderly mice (21–24 months old) with a triple transgenic form of AD (3x Tg-AD) at 25 mg/kg for three months at an interval of 48 h resulted in enhanced learning and spatial memory and increased risk assessment activity in the elevated plus maze. Hippocampi and amygdalae from 3x Tg-AD linalool-treated mice also showed a large reduction in extracellular βamyloidosis, tauopathy, astrogliosis, and microgliosis, as well as pro-inflammatory marker levels of p38 MAPK, NOS2, COX2 and IL-1β. Thus, linalool is suitable as an AD prevention candidate for pre-clinical studies. Based on the articles that we have selected, linalool is a major volatile component of EOs in a number of aromatic plant species, such as L. angustifolia Mill., M. officinalis L., R. officinalis L., and C. citrate DC. The presence of linalool can also help to reduce the deposits of Aβ, based on a study conducted by Gradinariu et al. [114] where Aβ1–42-treated rats exhibited the following: a decrease in exploratory activity (crossing number); smaller percentage of time spent and fewer entries in the open arm in the elevated plus-maze test; increase in swim time; and decrease in the immobility time within the forced swimming test.

4.6. Current EOs on PD

In terms of PD, the current therapy in practice is applied as a combination of goldstandard dopaminergic reposition with 3-(3,4-dihydroxyphenyl)-L-alanine (L-dopa), along with other agents such as MAO-B, catechol O-methyltransferase (COMT) inhibitors, dopaminergic agonists, and cholinergic blockers [222]. However, the available treatments are subject to consequences of motor and non-motor side effects, which leads to poor efficacy in advanced stages of PD [144]. These arising phenomena are the main reasons that suggest and emphasise the necessity for the synthesis of anti-PD drugs that could delay the progression of neurodegeneration [144]. As mentioned in the results, PD studies included in this review comprise in vitro and in vivo, as well as combinations of in vitro with in vivo or ex vivo research. Cinnamomum sp., Eryngium sp., Myrtus sp., Acorus sp., Eplingiella sp., Foeniculum sp., Pulicaria sp., Rosa sp., Zingiber sp., and Lavandula sp. were among the identified EOs based on the respective included PD studies. Four of the included studies on PD were based on in vitro approaches, with various EOs. 

The first study was focused on the evaluation of protective effects of EOs extracted from Cinnamomum sp. (C. verum and C. cassia) and cinnamaldehyde, in comparison to hydroalcoholic extracts using 6-OHDA-induced PC12 cytotoxicity as the representative model of PD [138]. Cinnamomum sp., or more commonly known as cinnamon, belongs to the Lauraceae family that is composed of almost 250 species and has been acknowledged for extensive health benefits [223,224]. Among the various species, C. verum and C. cassia were the two main species that have been widely applied for their medicinal and culinary applications, especially in Iran [225–227]. It is important to note that cinnamaldehyde represents one of the key components of both species, and EOs were reported to exhibit strong antioxidant properties [223]. The findings of this study indicated that 6-OHDA led to cell death, cell apoptosis, and suppression of the p44/42 pathway. On the whole, the study concluded that synergistic effects of cinnamaldehyde and EOs as well as other extract components could promote cinnamon’s roles as neuroprotective agents, specifically for PD treatment [138]. Eryngium sp. belong to the Apiaceae family, and are recognised for their EOs’ potentials in MAO inhibition [139]. MAO is available in two forms (A, B) where MAO-A inhibition is linked to antidepressant effects, while MAO-B is correlated with PD treatment [228,229]. An in vitro study conducted by Klein-Júnior et al. demonstrated the assessment of Eryngium sp. (E. floribundum: EP, E. horridum: EH, E. pandanifolium: EP, E. eriophorum: EE and E. nudicaule: EN) EOs for their MAO inhibitory effect. Intriguingly, the findings of this study indicated that MAO-A activity was not inhibited by any EOs, while EPEO and EHEO resulted in MAO-B inhibition. 

The literature search has also highlighted that PD patients usually represent elevated levels of MAO-B which arise due to gliosis, and hence contribute towards the collapse of the dopaminergic system [229]. Thus, this study puts forward the claim that Eryngium sp. could have potential applications as CNS bioactive secondary metabolites, particularly for neurodegenerative disease, in relevance to characteristics exhibited by EHEO [139]. Another important aspect that is usually associated with studies on PD is on α-Syn fibrillation. It is presumed that protein structural modifications resulting in amyloid fibril formation progresses towards neurodegenerative disorders [140]. However, the exact factors of α-Syn actions of misfolding and aggregation in the brain are still scarce. In addition, it should also be noted that preventive measures against α-Syn fibrillation are yet to be available; hence, the acceleration of the fibrillation process via certain factors should be avoided. Among some of the common factors are metal ions, small molecules, nanoparticles, and, particularly, toxins that could intensify the aggregation process [140,230–233]. The next two in vitro studies were performed by the same research team, where they highlighted the effects of 15 various Iranian EOs against α-Syn fibrillation [140,141]. Among all the 15 oils tested, it was shown that M. communis demonstrated potential benefits because it elevated the fibrillation in a concentration-dependent manner. However, it is necessary to understand that the major components of this oil are not responsible for the observed changes, suggesting complexity of both extract and synergistic effects of the available compounds, regardless of their amount [140]. In the second study, the investigation on C. cyminum EO signified the presence of cuminaldehyde as the major active compound that plays its role in the inhibition of α-Syn fibrillation. 

In addition, cytotoxicity assays on PC12 cells indicated the absence of toxic effects with cuminaldehyde treatment throughout α-Syn fibrillation [141]. Apart from in vitro studies, PD studies are also extensively performed under in vivo conditions. EOs of Acorus sp. cover two of the in vivo studies in this review. Both of these studies were conducted by the same research team, and focused on the regulation effect of β-asarone that was isolated from A. tatarinowii Schott on 6-OHDA-induced parkinsonian rats via two distinct endoplasmic reticulum (ER) stress pathways [142,143]. ER is known for its role in protein folding, where the build-up of protein unfolding/misfolding could initiate a phenomenon called ER stress that further activates the cellular process of unfolded protein response (UPR) [234]. ER stress has been noticed in a number of PD experimental models, and is also provoked by an increase in wild-type α-Syn [235–237]. Three main pathways that are categorised as UPR are inositol requiring enzyme 1 (IRE1), protein kinase RNA (PKR)-like ER kinase (PERK), and activating transcription factor 6 (ATF6) [238]. In general, GRP78 functions in the regulation of ER stress, where it binds the three proteins of the UPR pathway and maintains them as inactive when the cells are not exposed to stress conditions. However, under conditions of accumulated protein unfolding or misfolding, GRP78 will bind to the proteins and release them [239–241]. In terms of autophagy, the latest research has claimed that it could be induced due to ER stress [242,243]. Beclin-1 is known for its role in forming autophagosomes and is an essential part of the initial autophagy process. The pro-autophagic role of Beclin-1 could be inhibited via its reaction with Bcl-2, however this interaction is also subject to disruption caused by Bcl-2 phosphorylation that leads to Beclin-1 release and accelerates autophagy [244]. 

As per the second pathway study, it was proven that β-asarone leads to Beclin-1 downregulation, which highlights that Bcl-2 could possibly be the main linkage between autophagy and ER stress. The findings of both studies lead us to conclude that diminishing ER stress via β-asarone regulation is proven to be useful in the impairment of PD pathological progression [142,143]. Another study that also applies the use of 6-OHDA-induced PD mouse models focused on the investigation of the effects of zingerone and eugenol on dopamine concentration, behavioural changes, and antioxidant activities upon 6-OHDA administration and treatment of L-dopa [28]. Zingerone is extracted from the ginger root, while eugenol originates from cloves and was reported to be protective against 6-OHDA-induced depletion of striatal dopamine via increases in SOD activity and elevation of reduced glutathione (GSH) and LAscorbate (Asc) concentration, respectively [245,246]. Although these groups of researchers previously reported positive findings where pre-treatment with zingerone or eugenol inhibited 6-OHDA-induced dopamine depression by preventing lipid peroxidation, the current study, which involved post-treatment with similar compounds, resulted in contradictory findings, where dopamine decrease was more pronounced [28,246]. 

Despite the availability of other findings that propose the benefits of consuming these compounds, Kabuto and Yamanushi [28] suggested that intake of these specific substances upon the onset of PD symptoms should be more carefully monitored to prevent further injury aggravation. In addition to studies among 6-OHDA-induced Parkinson’s rat models, the possibility to achieve positive effects of EOs when complexed with β-cyclodextrin (βCD) was evaluated by Filho and colleagues using reserpine-induced progressive models for PD in mice [144]. Cyclodextrins are cyclic oligosaccharides that could form host–guest complexes with hydrophobic molecules and were also reported to protect EOs from heat, evaporation, moisture, oxidation and light effects along with facilitating easy solubility [247–249]. Complexation effects of cyclodextrins with EOs were shown to be more prominent in exerting positive effects, especially in the treatment of chronic diseases, as published by several studies [250,251]. In this particular study, the same approach was applied using leaf EO extracted from Eplingiella fruticosa (EPL), where one of the key components is 1,8-cineole. Eplingiella sp. belongs to the Lamiaceae family, and was reported for its benefits as antiinflammatory and antioxidant effects [252,253]. 

This research demonstrated and proved the hypothesis whereby both treated groups of EPL and EPL-βCD deferred reserpine effects on catalepsy time. However, this effect was noticed to be more remarkable with EPL-βCD treated mice groups. Another study also applied induction with reserpine, with a different PD model of ovariectomized and non-ovariectomized rats [145]. Reserpine is known as an irreversible inhibitor of the vesicular monoamine transporter 2 (VMAT-2). The approach of reserpine injection to rats as a mode of PD model was proposed in response to its action on the depletion of monoamine and locomotor activities [254]. Ovariectomized rats are subjected to oestrogen deficits, similar to surgically menopaused women, where cognitive damage is highly possible [255]. Lower oestrogen levels are correlated with many side effects, such as mental disorders, memory defects, emotional issues, and other cognitive failures [256]. These incidences have led to much attraction towards phytoestrogens for its protective nature against certain diseases. Fennel plant (Foeniculum vulgare) is classified as in the Apiaceae family, and is known for its phytoestrogen compounds; it showed promising results in the treatment of cognitive disorders, such as dementia and AD [145,257–259]. 

The evaluation of this study indicated that protective oestrogen effects against neurodegenerative disorders were significantly decreased among reserpine-induced ovariectomized rats. Injection of reserpine resulted in a more remarkable observation on limb movement disorder among ovariectomized rats. Fennel treatment at various doses for both groups gave better results on the motor activity, which stressed the importance of oestrogens and phytoestrogens as a protective measure of dopaminergic neurons and improved PD symptoms [145]. Rotenone administration to rats, as induction of a PD model, is an alternative approach where it induces nigrostriatal dopaminergic neuron degeneration that is associated with α-Syn Lewy bodies [260]. Rotenone is an insecticide with high lipophilic nature, and is known to inhibit mitochondrial complex-1 along with causing oxidative stress [261,262]. This rotenone-induced model was reported in the study by Issa and colleagues, based on the neuroprotective effects of Pulicaria undulata EO in male Wistar rats [146]. P. undulata belongs to the Asteraceae family, which is commonly distributed in Asia, Europe, and North Africa [263]. From this study, it was shown that EO of P. undulata could exert its neuroprotective effects via anti-inflammatory and antioxidant properties. The mechanisms involved in neuroinflammation suppression include downregulation of induced nitric oxide synthase (iNOS) expression, followed by lower gene expression of α-Syn [146]. 

Compared to individual studies, there are also several approaches that examine combined effects that could incorporate in vitro, in vivo, and also ex vivo applications. One such attractive research is on the combined in vitro/in vivo evaluation of SHXW EO with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice and SH-SY5Y cell lines [147]. In this study, SHXW was a Chinese herbal formulation that consisted of 15 crude herbs called KSOP1009, composed of eight medicinal plants of different families (Hamamelidaceae, Myristicaceae, Umbelliferae, Santalaceae, Piperaceae, Myrtaceae, Typhaceae, and Lamiaceae). MPTP is known to cause fast degeneration of dopaminergic neurons, and as such, it was believed that the use of this specific model could assist in explaining certain aspects of PD disease mechanisms [147,264]. Positive findings of the study demonstrated that ingestion of KSOP1009 was successful in the protection of MPTP toxicity, where this could be correlated with dopamine reduction that also decreases ROS and restores mitochondrial roles [147]. 

In terms of in vivo and ex vivo combinatorial approaches, two articles were highlighted in this review, with several authors originating from the same team [148,149]. Both studies explored the approach of L-dopa induction of oxidative toxicity. L-dopa has been recognised as the most effective symptomatic treatment of PD for more than 30 years; however, toxicity issues that were raised via in vitro studies seem to be an unresolved challenge [148]. It was also mentioned that prolonged L-dopa treatment is often associated with side effects that often result in a delay in its administration [148]. Past studies have claimed that L-dopa therapy in combination with antioxidants could lessen the possible side effects. As such, efforts were taken to evaluate the effects; this research team investigated the combined effects of EOs from Lavandula angustifolia, Rosa damascena, vitamin C and Trolox in the initial study [148], followed by another study in 2019 on the combined effects of pre-treatment with Rosa damascena and vitamin C [149]. 

For the first study, the obtained results indicated that both EOs from herbal plants showed noticeable radical scavenging and antioxidant properties against L-dopa toxicity. Similarly, the second study also put forward equivalent claims with R. damascena characteristics where it was in parallel to vitamin C, and exhibited a significant role of rose oil in its interference against the acute oxidative toxicity of L-dopa [148,149]. Based on all the collective studies, it could be observed that PD treatments remain centralised among several parameters that include mainly α-Syn fibrillation, MAO-B, β-asarone regulation of ER stress pathways, toxicity-induced models with 6-OHDA, MPTP, L-dopa, reserpine, and rotenone with common animal models of rats and mice. Although the regulation mechanisms involved in each of the parameters may differ, the main focus remains towards effective and improved treatments for PD patients.

4.7. Current EOs on Other Neurodegenerative Diseases 

Our review findings also revealed that several studies did not specify the studied disease, and instead examined general neurodegenerative disorders. The in vitro study conducted by Costa et al. [150] using Lavandula pedunculata subsp. lusitanica (Chaytor) Franco EO suggested the ability of L. pedunculata as a suitable choice to prevent neurodegenerative disease. A study performed by Elmann et al. [151] with Pelargonium graveolens EO showed that some constituents may depend on synergistic interactions to function. Geranium oil from Pelargonium graveolens inhibited nitric oxide (NO) production, as well as the expression of the proinflammatory enzymes cyclooxygenase-2 (COX-2) and induced nitric oxide synthase (iNOS) in primary cultures of activated microglial cells. 

The finding showed that none of the major constituents could inhibit NO production when examined at natural relative oil concentrations, with excellent inhibitory activity of citronellol at higher concentrations. The findings indicated that the presence of synergistic interactions between these components are of considerable importance. Thus, geranium oil can be useful in neurodegenerative disease prevention where neuroinflammation is part of pathophysiology [151]. EOs could also be applied as inhalation-based treatment, which could signify a natural way to heal one’s mind, body, and soul [265]. In Bagci et al.’s study [153], it was investigated whether inhalation of the Anthriscus nemorosa EO leads to behavioural changes that indicated significant memory improvement and exhibited both anxiolytic- and antidepressantlike effects in dual-treated rats. The results suggested that A. nemorosa EO inhalation can prevent scopolamine-induced memory impairment, anxiety, and depression [153]. In the in vivo research conducted by Satou et al. [118], mice were administered Rosmarinus officinalis EO (EORO) by inhalation and it was concluded that the rate of spontaneous alternation activity was significantly improved. 

The key components (1,8-cineole, α-pinene and β-pinene) were detected in the brain in a concentration-dependent manner upon EORO inhalation, which indicated its possible exerted effects. However, in several other interpretations, it was proposed that 1,8-cineole might require synergistic interaction effects. This was highlighted by Costa et al. [150], where α-pinene and 1,8-cineole from Lavandula pedunculata subsp. Lusitanica were shown to be effective cholinesterase inhibitors even at low concentrations and are likely to contribute to this behaviour. The synergistic and antagonistic interactions between certain terpenes that could result in combined effects should also be taken into consideration. Although this compound was also mentioned in a study conducted by Hritcu et al. [112], the study focused more on the positive effect of linalool in the improvement of spatial memory deficit in a scopolamine-induced dementia rat model instead of the 1,8-cineole effect on neurodegeneration. In addition, a study by Kaufmann and colleagues [104] signified the potential of myrtenal as an effective AChE inhibitor, compared to 1,8-cineole with EOs of Artemisia annua L. (Asteraceae) or Glycyrrhiza glabra L. (Fabaceae).

5. Conclusions 

In conclusion, our review highlighted that EOs provide many other benefits apart from its common usage as fragrances and flavours, especially for its significant role in neurodegenerative disease therapy. Their roles in reducing disease severity are exerted by different mechanisms that vary respective of their origin. Although human studies were not obtained as part of our search, we strongly believe that the presence of essential components such as 1,8-cineole, carvacrol, or β-asarone could play significant roles in efforts towards the prevention and treatment of neurodegenerative disorders. Therefore, it is vital that the search for novel species of EOs are continued, to explore oils which could be applied towards the application of EO-based therapies or treatment strategies intended for age-related neurodegenerative disorders.