Introduction
Alzheimerʼs disease (AD) is a multifarious neurodegenerative disease that causes cognitive
impairment and gradual memory loss. Senile plaques and neurofibrillary tangles (NFTs)
comprised of amyloid β (Aβ) peptides and hyper-phosphorylated tau proteins, respectively, are the classic pathological
hallmarks of AD [1]. Several hypotheses have been put forward to reveal the pathobiology of the disorder
including cholinergic hypothesis, inflammation hypothesis, oxidative stress, mitochondrial
cascade hypothesis, and metabolic hypothesis [2], [3]. According to the World Health Organization, AD is the most common form of dementia
and accounts for about 60 – 70% of all dementia cases [4]. There is more prevalence for people aged over 65 y [5]. Epigenetic variations on the genetic material of neurons can result in neurodegenerative
disorders and these variations in AD genes change from region to region [6]. Familial Alzheimerʼs disease (FAD) and sporadic Alzheimerʼs disease are the 2 specific
types of AD [7]. The combined action of environmental and genetic factors might be culpable for
the SAD and FAD types [8]. Depending on the age of onset, AD can be further grouped into early onset (EOAD)
and late onset (LOAD) [9]. Mutations in some specific genes like amyloid precursor protein (APP), presenilin
I, and presenilin II are responsible for EOAD whereas apolipoprotein E is the only
gene identified that causes LOAD [10]. Approximately 5% of the AD cases is familial early onset type and it develops before
65 y of age, and the remaining 95% accounts for sporadic late onset type and it develops
after 65 y of age [11], [12].
The neuropathophysiology of the neurodegeneration in AD is triggered by anomalous
deposition of amyloid plaques and NFTs in varied regions of the brain involved in
cognition and memory [13]. Amyloid plaques are protein fragments composed of Aβ peptides originated from APP by the synergistic action of enzymes β-secretase and γ-secretase [14]. Polymerization of these Aβ peptides results into insoluble filaments that build up in the walls of cerebral
blood vessels and configure senile plaques. Microglial activation, reactive astrocytosis,
cytokine release, and neuro-inflammation also occur in accordance with the formation
of amyloid plaques [15]. NFTs are made up of tau protein found inside the neurons as a bunch of insoluble
fibers. Hyperphosphorylation of these tau proteins results in the formation of paired
helical filaments and finally forms microscopic tangles that cause cell death [16].
Out of all above pathogenetic pathways, the mechanisms of essential oils (EOs) are
associated with cholinergic hypothesis and oxidative stress hypothesis. As stated
by cholinergic hypothesis, loss of cholinergic neurotransmission in the cerebral cortex
and the destruction of cholinergic neurons in the basal forebrain disturb cognitive
function [17]. Depletion of acetylcholine (ACh) level is usually noticed in dementia patients
and exploratory studies in animals and humans have also confirmed the role of ACh
in learning and memory [18]. Oxidative stress is inevitably linked with various primary AD pathogenesis such
as Aβ-induced neuronal loss, mitochondria dysfunction, tau protein pathology, and disturbance
in metal homeostasis [19]. Senile plaques mediated oxidative imbalance can elevate the levels of lipid peroxidation
byproducts, DNA/RNA oxidation, and protein oxidation in several regions of the brain.
In addition, oxidative stress causes depletion of brain antioxidants level like uric
acid, vitamin C and E and antioxidant enzymes such as catalase, glutathione reductase,
superoxide dismutase, etc. [20].
At present, very few drugs are available for the medical care of AD and are directed
toward symptomatic relief. The currently available U. S. Food and Drug Administration
approved drugs in the market for AD include cholinesterase inhibitors (rivastigmine,
galantamine, and donepezil) and N-methyl-D-aspartate receptor antagonist (memantine)
[21]. Tacrine has been the first approved drug (1993) as a reversible inhibitor of AChE
later on abandoned in 2013 due to its hepatotoxicity, short half-life, and cholinergic
side effects [22]. Huperzin A obtained from Huperzia serrata (Thunb.) Trevis (Lycopodiaceae) is a naturally derived AChE inhibitor used in the
treatment of memory ailments in China [23].
EOs constitute a blend of enormously complex, volatile, naturally derived compounds
that are obtained as secondary metabolites from plants. They are found to be copious
in leaves, seeds, flowers, barks, and rhizomes and are commonly obtained through cold
pressing, hydro-distillation methods [24]. Its major constituents include monoterpenes hydrocarbon, sesquiterpenes hydrocarbon,
oxygenated sesquiterpenes, oxygenated monoterepenes, and esters [25]. A review on therapeutic and pharmaceutical use of EOs related to cardiovascular
disease, cancer, antidiabetic, penetration enhancer, antimicrobial, massage therapy,
neuroprotective, aromatherapy, and anti-aging effects revealed the immense medicinal
benefits of EOs [26]. Dobetsberger and Buchbauer [27] pointed out the analgesic, anxiolytic, anticonvulsive, and anti-AD effects. Recently,
the anti-aging and neuroprotective effects of numerous EOs and their involvement in
various brain disorders have been outlined [24]. Studies revealed that EOs are classic naturally derived antioxidants and most of
them exhibits cholinesterase inhibitory potential and are relevant in AD pathogenesis
[28]. [Table 1] shows the list of EOs with respect to their anti-Alzheimerʼs intervention.
Table 1 List of EOs with respect to their anti-Alzheimerʼs intervention.
|
Plant/source
|
Study design
|
Results
|
Reference
|
|
AD: Alzheimerʼs disease, ICV: intra-cerebroventricular, Aβ: amyloid β
|
|
C. sativum
|
ICV Aβ(1 – 42)-induced AD in rats
|
Reduced oxidative stress induced by Aβ(1 – 42) and confer neuroprotective effects
|
[31]
|
|
S. aromaticum
|
ICV colchicine-induced AD in rats
|
Reversed memory impairment, restored the levels of ACh and antioxidants, reduced neuroinflammation
and mitochondrial dysfunction in colchicine treated rats.
|
[33]
|
|
Z. multifora
|
ICV Aβ(25 – 35)-induced AD in rats
|
Reversed Aβ-induced learning deficits, exhibited antioxidant, anti-inflammatory and anti-cholinesterase
activities.
|
[35]
|
|
SuHeXiang Wan
|
Drosophila model of AD
|
Neuroprotective effects
|
[39]
|
|
ICV Aβ(1 – 42)-induced AD in ICR mice
|
Reversed Aβ(1 – 42)-mediated memory deficit Suppressed Aβ(1 – 42)-mediated JNK, tau phosphorylation, and p38 in the mice hippocampus.
|
[40]
|
|
A. nemorosa
|
Scopolamine-induced spatial memory impairment in rats
|
Prevented cognitive defects.
|
[42]
|
|
S. officinalis
|
Single blind trial in healthy volunteers
|
Enhanced mood and cognitive performance
|
[45]
|
|
S. officinalis ssp. lavandulifolia (vahl) Gams
|
Single blind trial in healthy volunteers
|
No significant effects.
|
[45]
|
|
Clinical study in healthy volunteers for mood and cognition.
|
Enhanced mood and cognition
|
[50]
|
|
Clinical trial in mild/moderate AD patients
|
Improved memory and cognition
|
[51]
|
|
M. officinalis
|
Double-blind placebo-controlled trial in AD patients
|
Improved agitation and quality of life indices
|
[54]
|
|
Clinical trial in AD patients
|
No significant effects
|
[55]
|
|
Anti-agitation studies
|
Anti-agitation effects
|
[56], [57]
|
|
J. communis
|
ICV Aβ(1 – 42)-induced AD in rats
|
Reduced memory impairment, antioxidant and anti-cholinesterase potential
|
[59], [60]
|
|
C. nucifera
|
Prospective study in AD patients
|
Improved memory status in AD patients.
|
[62]
|
|
In vitro neurotoxicity study in rat cortical neurons
|
Neuroprotective effects
|
[63]
|
|
P. peregrina
|
Scopolamine-induced memory deficits, depression, and anxiety in a rat model of AD
|
Hindered depression, anxiety, and memory deficits.
|
[65]
|
|
L. angustifolia
|
Scopolamine-induced amnesia model in rats
|
Hindered depression, anxiety, and memory deficits.
|
[69]
|
|
Clinical trials
|
Improved mood and cognitive performance.
|
[70], [71]
|
|
R. officinalis
|
Scopolamine-induced dementia model in mice
|
Reduced memory impairment.
|
[75]
|
|
Memory performances in aged and young mice.
|
Improved memory performances
|
[76]
|
|
Clinical trials
|
Improved mood and cognitive performances
|
[70], [71], [76], [77], [78]
|
Methods and Results
Scientific databases such as PubMed, ScienceDirect, Scopus, and Google Scholar from
April 1998 to June 2018 were explored to collect data. The keywords searched were
Alzheimerʼs disease, EOs, amyloid hypothesis, NTFs, antioxidants, acetylcholinesterase,
and dementia. We have conducted wide search on various EOs used in different models
of AD. A total of 540 papers were obtained by scientific search, and 89 papers found
to be relevant to the review. Studies of about 55 EOs were identified for Alzheimerʼs
intervention. Twenty-eight EOs were finally included based on the quality of the study
of which short descriptions of in vivo studies of 13 EOs together with clinical trial data of Salvia officinalis L., S. officinalis L. ssp. lavandulifolia (vahl) Gams, Melissa officinalis L., Lavandula angustifolia Mill., and Rosmarinus officinalis L. were highlighted. Chemical constituents and medicinal benefits of the EOs, animal
models, doses and time of administration, study duration, behavioral parameters, and
biochemical and histological assessments were also summarized. In vitro studies of 15 EOs that possess antioxidant and anticholinesterase potential are also
mentioned.
Coriandrum sativum
Coriandrum sativum L. (coriander) of Umbelliferae/Apiaceae family has been reported to have anti-anxiety,
anticonvulsive, antioxidative, antispoilage, hypoglycemic, anti-inflammatory, antimutagenic,
diuretic, antihypertensive, carminative, hypolipidemic, antispasmodic, and antidepressant
effects [29]. The major constituents of its EO include linalool (60 – 80%), terpinen-4-ol (3%),
r-cymene (3.5%), γ-terpinene (1 – 8%), α-pinene (0.2 – 8.5%), linalyl acetate (0 – 2.7%), α-terpineol (0.5%), camphor (0.9 – 4.9%), camphene (1.4%), myrcene (0.2 – 2.0%), geranyl
acetate (0.1 – 4.7%), and geraniol (1.2 – 4.6%) [30]. The effects of EO from dried fruits of C. sativum in AD has been studied in an in vivo study by Cioanco et al. [31] AD model was developed in rats by ICV Aβ(1 – 42) injection and the animals of the test group were made inhale C. sativum EO (1% and 3%) daily for 21 d. Cognitive performances were evaluated using radial
arm maze and Y-maze tests. Aβ(1 – 42)-treated rats showed notable cognitive dysfunction, which was significantly
reversed by EO inhalation. Coriander oil inhalation significantly decreased levels
of SOD, LDH, and MDA and increased glutathione peroxidase levels in rat hippocampus.
Presence of amyloid deposits were abundant in rats brain induced with ICV Aβ(1 – 42) and the deposits were less in rats treated with both doses of C. sativum EO. Authors concluded that exposure of C. sativum EO in Aβ(1 – 42)-induced rats could capably rebuild brain antioxidant status and confer neuroprotective
effect possibly due to suppression of oxidative stress caused by Aβ(1 – 42).
Syzygium aromaticum
Syzygium aromaticum (L.) Merr. & L. M. Perry. (clove) is an aromatic flower bud of Myrtaceae family.
Clove oil is a mind stimulant used for medical care in anxiety, insomnia, and depression.
The active constituents of its EO are eugenol (87.34%) and smaller amounts of eugenol
acetate (5.18%) and β-caryophyllene (2.01%) [32]. The neuroprotective potential of clove oil in ICV colchicine-induced memory impairment
in rats has been reported in a study by Kumar et al. [33]. Male SD rats were subjected to intraperitoneal injection of minocycline (25 and
50 mg/kg), clove oil (0.05 mL/kg and 0.1 mL/kg), and their combinations for 21 d.
ICV colchicine-treated rats showed significant cognitive impairment in Morris water
maze (MWM) test and showed an increase in AChE activity, oxidative stress, neuro-inflammation,
and mitochondrial dysfunction as compared to control group. Treatment with clove oil
was found to reverse the memory impairment, restored the levels of ACh and antioxidants,
and reduced neuroinflammation and mitochondrial dysfunction in colchicine-treated
rats. Authors highlighted that the favorable potential of clove oil in reversing memory
impairment and cognitive dysfunction is due to its antioxidative, mitochondrial-restoring,
and microglial inhibitory mechanisms.
Zataria multiflora
Zataria multiflora Boiss (ZM), belonging to Lamiaceae family, is a traditional Iranian herb with anti-inflammatory,
antibacterial, antifungal, spasmolytic, antinociceptive, antiprotozoal, antioxidative,
and immune stimulant properties. The main constituents of its EO include thymol (40.94%),
carvacrol (22.23%), p-cymene (7.73%), linalool (7.92%), caryophyllene (3.95), and
γ-terpinene [34]. Majlessi et al. [35] mentioned the beneficial effects of EO from the leaves of ZM in ICV Aβ(25 – 35)-induced AD model in rats. Seven days after induction of disease, EO was
administered in a dose of 50, 100, and 200 µg/mL (i. p.) 30 min prior to MWM task.
Aβ injection in the rat brain remarkably impaired the ability of rats to locate the
hidden platform in MWM task. Administration of ZM EO significantly reversed Aβ-induced learning deficits. Also, LD50 of EO was determined in male NMRI mice and was found to be 1264.9 µL/kg. Authors
concluded that EO administration remarkably reversed Aβ(25 – 35)-induced cognitive dysfunction in rats due to its antioxidant, anti-inflammatory,
and anticholinesterase activities. Further studies are needed to detect the presence
of amyloid peptides and neurological alterations and more significant results can
be obtained.
SuHeXiang Wan
SuHeXiang Wan (SHXW) is a conventional Chinese medicinal mixture of about 15 crude
herbs including Cyperus rotundus L., Atractylodes macrocephala Koidz., Boswellia sacra Flueck., Bubalus bubalis Linnaeus L. horn powder concentrate, artificial moschus, Santalum album L., Aquilaria sinensis (Lour.) Spreng, Borneolum, Syzygium aromaticum (L.) Merr. & L. M. Perry, Aucklandia lappa DC., Piper longum L., Terminalia chebula Retz., Liquidambar orientalis Mill., and Styrax tonkinensis Craib ex Hartwich and Cinnabaris [36]. Traditionally, it has been used for seizures, infantile convulsion, CNS depression,
and stroke. Analgesic, anticonvulsant, antioxidative, and sedative effects of its
EO has been reported [37]. Modified SHXW exhibited neuroprotective effects in drosophila model of AD [38], [39]. Jeon et al. demonstrated the memory enhancement effect of SHXW EO in an ICR mice
model of AD. ICV Aβ(1 – 42)- or Aβ(42 − 1)-induced mice were subjected to inhalation of 2 g EO twice daily for 21 d.
Behavioral parameters were assessed by step-through passive avoidance and Y-maze tests.
The signaling mechanism was examined by measuring the phosphorylation status of the
stress stimulated JNK, protein kinases, and p38 in the mice brain. SHXW treatment
significantly reversed the Aβ(1 – 42)-mediated memory deficit by suppressing Aβ(1 – 42)-mediated JNK, tau phosphorylation, and p38 in the mice hippocampus. In addition,
an in vitro investigation was also performed to examine the inhibitory potential of SHXW EO in
Aβ(1 – 42)-incited neurotoxicity in SH-SY5Y cells. Not reported were any toxic effects
on cell viability assays. EO suppressed Aβ-induced apoptosis and exhibited antioxidant effect through an upregulation of Nrf2
and HO-1 expression in SH-SY5Y cells [40].
Anthriscus nemorosa
Anthriscus nemorosa (M. Beib.) Spreng. (chervil) is a common plant genus belonging to the family Apiaceae.
Its EO contains caryophyllene (23.6%), germacrene D (5.6%), α-terpineol (2.7%), β-elemene (4.2%), and trans-pinocarveol (9.8%) as major constituents. The antimicrobial
property of its EO has been reported [41]. The EO obtained from the aerial parts of A. nemorosa has been studied by Bagci et al. [42] for its beneficial effects on anxiety, depression, and cognition in scopolamine-induced
amnesia model in rats. The rats were exposed to inhalation of A. nemorosa EO for 21 d and behavioral parameters were analyzed by Y-maze and radial arm-maze
tasks. Scopolamine (0.7 mg/kg i. p.) was administrated 30 min prior the behavior testing.
Also, anxiety- and depression-like behaviors were tested in elevated plus-maze and
forced swimming tests, respectively. Positive results were obtained for EO-treated
groups in all behavioral tests, suggesting the benefits of A. nemorosa EO against cognitive defects, anxiety, and depression. Even though there was some
behavioral evidence for memory improvement, more findings are required to elaborate
the benefits of A. nemorosa in cognitive dysfunction.
Salvia species
The Salvia genus include around 900 species, of which Salvia officinalis L. (common sage/sage) and Salvia officinalis L. ssp. lavandulifolia (vahl) Gams (Spanish sage) of Lamiaceae family have prominent medicinal benefits
[43]. The active constituents of S. officinalis EO are camphor (95.5%), 1,8-cineole (59.0%), cis-thujone (65.5%), trans- thujone
(40.1%), α-humulene (33.7%), and linalool (35.0%). S. lavandulifoila EO contains 1,8 cineole (34.5%), α-pinene (23.2%), β-pinene (19.2%), limonene (16.6%), camphor (15.4%), and β-caryophyllene (8.1%) as main constituents [44]. In a single-blind randomized controlled trial led by Moss et al. [45], the reputed effects of these EOs on mood and cognition in healthy volunteers have
been evaluated. S. officinalis EO-treated group showed better positive performance compared to control group. Results
confirmed an enhancement in mood and cognitive performance deliberated through Bond-Lader
mood scales and cognitive drug research system, respectively. EO of S. lavandulifolia does not exhibit any significant effects. EO of S. lavandulifolia and its constituents reported antioxidant [46], anti-inflammatory, oestrogenic [47], CNS depressant, and AChE inhibitory potential in bovine erythrocyte and human brain
tissue [48] and in rat brain [49]. In a clinical trial conducted in healthy volunteers, EO treatment reported successive
results on mood and cognition [50]. Oral administration of S. lavandulifolia EO in patients with mild/moderate AD reported significant improvement in memory and
cognition in a pilot open-label study [51]. Even though S. lavandulifolia EO possesses antioxidant, anti-inflammatory, anti-AChE, and memory enhancement potential,
it fails in a clinical study [45] and that might be due to lack of standardization and pharmacokinetics studies of
this EO. The concentration of bioactive components varies in plants based on its region,
climate, etc., and this variation remains a major drawback concerning the properties
of EO and is likely to remain so.
Melissa officinalis
Melissa officinalis L. (lemon balm) of Labiatae has been used traditionally in nervous system diseases,
cognitive dysfunction, and sedation [52]. Geranial (65.4%), geranyl acetate (7.4), neral (24.7%), (Z)-carveol (0.1%), linalool
(0.8%), myrtenol (0.1%), farnesene (0.1%), 2,3-dehydro-1,8-cineole (0.1%), and caryophyllene
(0.8%) are the active components that have been isolated from the leaves of M. officinalis EO [53]. Agitation is one of the main symptoms of AD. Aromatherapy of M. officinalis EO or placebo (sunflower oil) in a double-blind placebo-controlled trial in 72 Alzheimerʼs
patients (agitation with severe dementia) has been reported by Ballard et al. [54] Patients were advised to apply oil combined with base lotion in faces and arms twice
daily for 4 wk. Treatment analysis like Cohen-Mansfield Agitation Inventory score
and quality of life indices were assessed and the results reflected 35% and 11% improvement
in agitation in EO and placebo-treated groups, respectively. Later in 2011, a clinical
trial report revealed that massaging EO in hands and upper arms of dementia patients
with agitation does not produce any significant results compared to standard drug
donepezil or placebo oil [55]. However, positive results of M. officinalis oil for its anti-agitation potential have also been reported [56], [57]. While all these trials comprised comparatively short duration and small sample
sizes, the significant improvement in agitation with M. officinalis oil appear to explain the importance for further long-term clinical studies, assessment
of adverse effects, appropriate doses, and efficacy compared to standard drugs for
AD.
Juniperus communis
Juniperus communis L. (juniper) belongs to the family Cupressaceae. The chemical compositions of its
EO are α-pinene (41.13%), α-thujene (3.78%), myrcene (10.16%), sabinene (11.73%), γ-terpinene (1.57%), and limonene (8.63%) followed by lower quantities of β-elemene (1.1%), terpinen-4-ol (3.42%), β-caryophyllene (1.03%), eremophylene (1.17%), and germacrene D (1.51%). The EO obtained
from needles and berries of J. communis has been reported to have carminative, diuretic, antianxiety, astringent, rubefacient,
antispasmodic, stimulating, stomachic, blood purifier, antirheumatic, antiseptic,
and tonic effects. [58], [59] Cioanco et al. [59] reported about the multiple exposure of juniper oil inhalation boosted memory defects
in an Aβ-induced rat model of AD. In this study, rats were split up into 4 groups, of which
control group received saline treatment (0.9% NaCl), disease group was subjected to
ICV Aβ(1 – 42) injection, and the other 2 treatment groups were subjected to inhalation
of juniper volatile oil 1% and 3% for 20 d after ICV Aβ(1 – 42) injection. Y-maze and radial arm maze tests were used for the evaluation
of memory status. Juniper oil treated groups showed significantly less memory impairment
in both behavioral tests as compared to Aβ(1 – 42) alone treated group. Later Cioanco et al. [60] demonstrated that antioxidant and anti-AChE potential of juniper volatile oil ameliorates
cognitive dysfunction in Aβ(1 – 42)-induced rat model of AD.
Cocus nucifera
Cocus nucifera L. (coconut) belonging to Arecaceae family, consists of saturated fatty acids (SFA)
92% and medium-chain fatty acids (MCFA) 62 – 70% as major constituents. MCFA can be
transformed into ketone bodies, which are alternative energy source in the brain in
conditions wherein disturbance in brain glucose level and can be favorable to humans
progressing or earlier with cognitive dysfunction [61]. Hu Yang et al. [62] conducted a prospective study in Alzheimerʼs patients in which the test group was
provided with coconut oil (40 mL/day) for 3 wk. The memory test such as lobo cognitive
test and mini test scores pre- and post-involvement were performed in test and control
groups. A statistically appreciable elevation in test score was noticed in patients
taking the oil and therefore a positive improvement in memory status was noted. An
in vitro study conducted by Nafer et al. [63] highlighted the neuron protecting effects of coconut oil in Aβ-incited neurotoxicity in rat cortical neurons. Cells were initially induced with
Aβ for 1, 6, or 24 h and then treated with coconut oil further for 24 h. Survival of
neurons and various cellular parameters (synaptophysin labeling, cleaved caspase 3,
and reactive oxygen species) were assessed. Reports unveiled that coconut oil protects
against Aβ-induced neurotoxicity, inhibits Aβ-induced elevation of cellular stress markers, and in addition provides neuron protecting
effects by activating Akt and ERK signaling pathways
Pimpinella peregrina
Pimpinella peregrina L. is an aromatic herb belonging to Apiaceae family. The major constituents of its
EO are trans-pinocarveol (35.1%), α-cubebene (12.4%), pregeijerene (15.1%), (+)-epi-bicyclosesquiphellandrene (7.5%),
and α-terpineol (6.7%) [64], [65]. EO is widely used in flavored drinks like raki, ouzo, pastis, arak etc. Adyn et
al. [65] reported the effects of inhalation of EO from aerial parts of P. peregrina in scopolamine-induced memory deficits, depression, and anxiety in a rat model of
AD. Rats were exposed to inhalation of EO (1% and 3%) continuously for 21 d. Scopolamine
was injected (i. p.) 30 min before the behavioral tests. Memory impairments were observed
through radial arm-maze and Y-maze tests. Also, elevated plus-maze and forced swimming
tests were used for checking anxiety and depressive behavior, respectively. Successive
results were obtained in EO-treated groups as compared to respective scopolamine-treated
groups, suggesting the neuroprotective effects of P. peregrine EO in the treatment of anxiety, depression, and memory deficits. In conclusion, more
biochemical and histological findings are needed to prove the effect of P. peregrina EO on AD.
Lavandula angustifolia
Lavandula angustifolia Mill. (lavender) belongs to the family Lamiaceae. The dominant components of its
EO are caryophyllene (24.12%), terpinen-4-ol (9.57%), β-phellandrene (16%), and eucalyptol (15.69%) [66]. It has been used in the treatment of anxiety, migraines, stress, irritability,
exhaustion, depression, headaches, digestion, colds, flatulence, insomnia, loss of
appetite, stomach upset, liver diseases, nervousness, and aromatherapy [67], [68]. Hritcu et al. [69] reported the effects of 2 distinct EOs from Lavandula hybrida Rev. and L. angustifolia subsp. angustifolia on neurological capability in scopolamine (0.7 mg/kg)-induced amnesia model in rats.
Lavender EO inhalation for 7 consecutive days notably hindered depression, anxiety
and memory impairment in scopolamine treated rats as observed through various behavioural
tests. A human study led by Moss et al. [70] unveiled that exposure of EOs of Rosmarinus officinalis L. and L. angustifolia significantly affects the mood and cognitive performances of sound volunteers. Aromatherapy
of 4 different EOs from R. officinalis, Citrus limon (L.), Citrus sinensis (L.) Osbeck, and L. angustifolia reported significant improvement in cognitive function in a clinical trial led in
28 elderly people [71].
R. officinalis
Rosmarinis officinalis L. (rosemary) belongs to the family Lamiaceae. The EO of R. officinalis consist of α-pinene (21.3%), 1,8 cineole (28.5%), camphor (27.7%), camphene (8.7%), β-pinene (4.7%), and borneol (2.5%) as major constituents. [72] Antioxidant, antiproliferative, antibacterial, antimutagenic, antiphlogistic, and
chemopreventive, and ANS stimulant potentials of its EO has been reported [73], [74]. Satiou et al. [75] have recently studied the beneficial effects of EO from leaves and flowers of R. officinalis on scopolamine-induced Alzheimerʼs-type dementia model in mice. The results showed
that inhalation of R. officinalis EO (4 µL/L or 8 µL/L air) have shown a positive result in spontaneous alternation
behavior in Y-maze test, and 1,8 cineole, α-pinene, and β-pinene were found in dominant concentration in the mice brain. Asadi et al. [76] have tested the potential of EO from leaf and aerial part of R. officinalis on memory in aged and young mice. The test group were administered EO (200,400,600
and 800 mg/kg i. p.) daily for 7 d and improvement in memory performances were found
in all test groups. Filiptsora et al. [77] reported the effects of R. officinalis EO on the short-term and numerical memory in a study conducted in 79 school students
(aged 13 – 17 y). The result showed positive results as evidenced by increased image
and number memory compared to control groups. The positive correlation of 1,8 cineole
on mood and cognitive performances following inhalation of rosemary oil has been described
in a clinical study conducted in healthy volunteers [78]. As mentioned above, R. officinalis EO reported memory enhancement potential in many clinical studies [70], [71]. Further studies are essential for this oil to verify possibility for drug interactions
and adverse effects in long duration trials and to determine appropriate dose that
can mediate relevant neuroprotective effects.
In vitro studies
Ayaz et al. [79] reported the cholinesterase inhibitory activities and reactive oxygen species scavenging
potential of EOs from the flowers and leaves of Persicaria hydropiper (L.) Delarbre. In AChE inhibition assay, EO of leaf exhibited IC50 of 120 µg/mL and flower of 220 µg/mL, whereas flower and leaf EOs reported IC50 of 225 and 130 µg/mL, respectively, in butyrylcholinesterase (BChE) inhibitory assay.
In 1,1-diphenyl 2-picrylhydrazyl (DPPH) antiradicals assay, these EOs showed remarkable
radical scavenging potentials. Also, IC50 of 50 and 45 µg/mL for flower oil and 60 and 180 µg/mL for leaf oil was obtained
in hydrogen peroxide and 2,2-azinobis3-ethylbenzthiazoline-6-sulfonic acid (ABTS)
scavenging assays, respectively. Ahmed et al. [80] reported the antioxidant and anticholinesterase activities of EO from Rumex hastatus D. Don. It exhibited significant BChE and AChE inhibitory activities with IC50 of 97.38 and 32.54 µg/mL, respectively. Also, IC50 values of 6.29 and 3.71 µg/mL were obtained for ABTS and DPPH assays, respectively.
Salvia chionantha Boiss EO was analyzed for its antioxidant activity and reported 77.4 ± 0.5% inhibition
in ABTS assay. The anti-AChE and BChE activities were found to be 56.7 ± 1.9% and
41.7 ± 2.9%, respectively [81]. In vitro anti-AChE activity of EO from Acorus calamus L. rhizomes has been studied and exhibited significant AChE inhibitory potential
(IC50 = 10.61 µg/mL) [82]. Ertas et al. [83] reported the anticholinesterase activities of EOs from Anchusa arvensis subsp. Orientalis (L.) Nordh. and Tragopogon latifolius Boiss. Both of them betrayed moderate AChE and BChE inhibitory activities.
EO isolated from leaf and stem of Gynura bicolor (Roxb.ex Willd.) DC. has been screened for anti-AChE activity. These oils have been
evaluated and compared with standard AChE inhibitor pulegone. The leaf and stem oil
inhibited AChE (53%) at a concentration of 0.50 µg/mL with ID50 values of 85 and 92 µg/mL, respectively. Both oils showed better results than pulegone
[84]. EO obtained from fresh Chaerophyllum aromaticum L. root and aerial parts exhibited significant anticholinesterase and antioxidant
activities [85]. Bonesi et al. [86] reported the cholinesterase inhibitory activities of EOs from Pinus nigra J. F. Arnold and Pinus heldreichii Christ. P. heldreichii was more active with IC50 of 80.6 and 51.1 µg/mL toward BChE and AChE inhibitory assays, respectively. EOs
from Cistus libanotis L., Cistus salvifolius L., Cistus creticus L., Cistus villosus L., and Cistus monspeliensis L. were evaluated for antiradicals and anti-AChE activities. In ferric reducing antioxidant
assay, C. libanotis exhibited most potent value of 19.2 l MFe (II)/g. In AChE inhibitory assay C. salvifolius revealed IC50 of 58.1 µg/mL. Meanwhile, C. creticus, C. libanotis, and C. salvifolius exhibited significant anti-BChE effects with IC50 values of 29.1, 23.7, and 34.2 µg/mL, respectively. In b-carotene bleaching test,
C. monspeliensis EO exhibited better results with IC50 of 54.7 µg/mL [87]. Eminent results of all this data suggest the anticholinesterase and antioxidant
potential of EOs for the development of therapeutic remedies targeting AD pathogenesis.
[Table 2] shows the list of in vitro studies of EOs that possess antioxidant and anticholinesterase activities.
Table 2 List of in vitro studies of essential oils that possess antioxidant and anti-cholinesterase activities.
|
Plant/source
|
Study design
|
Results
|
References
|
|
AChE: acetylcholinesterase, BChE: butyrlcholinesterase, H2O2: hydrogen peroxide, ABTS: 2,2-azinobis3-ethylbenzthiazoline-6-sulfonic acid, DPPH:
1,1-diphenyl 2-picrylhydrazyl, FRAP: ferric-reducing antioxidant power, ↓: decreasing/inhibiting.
|
|
P. hydropiper
|
AChE, BChE inhibition DPPH, ABTS, H2O2 assay
|
↓AChE, BChE, DPPH, ABTS, H2O2 activity
|
[79]
|
|
R. hastatus
|
AChE, BChE inhibition DPPH, ABTS, H2O2 assays
|
↓AChE, BChE, DPPH, ABTS activity
|
[80]
|
|
S. chionantha
|
AChE, BChE inhibition ABTS assays
|
↓AChE, BChE, ABTS activity
|
[81]
|
|
A. calamus
|
AChE inhibition
|
↓AChE activity
|
[82]
|
|
A. arvensis subsp. Orientalis
T. latifolius
|
AChE, BChE inhibition
|
↓AChE, BChE activity
|
[83]
|
|
G. bicolor
|
AChE inhibition
|
↓AChE activity
|
[84]
|
|
C. aromaticum
|
AChE inhibition Antioxidant assay
|
↓AChE activity Significant antioxidant activity
|
[85]
|
|
P. nigra P. heldreichii
|
AChE, BChE inhibition
|
↓AChE, BChE activity
|
[86]
|
|
C. creticus C. libanotis C. salvifolius C. monspeliensis C. villosus
|
AChE, BChE inhibition FRAP assay, β-carotene bleaching assay
|
↓AChE, BChE acitivity Significant antioxidant activity
|
[87]
|
Discussion
This literature review displayed promising evidence that supports the use of EOs for
reversing cognitive and memory impairment of AD. EOs obtained from numerous medicinal
plants are reported to possess anti-AD potential. EOs of S. officinalis, S. officinalis ssp. lavandulifolia (vahl), M. officinalis, L. angustifolia, and R. officinalis have proven their putative effects in clinical studies. EOs are rich in various bioactive
markers in different concentrations and it changes from place to place. Linalool,
thymol, β-caryophyllene, carvacrol, α-pinene, α-terpineol, α-terpinene, and eugenol are some of the components that are common in above-mentioned
oils. [Fig. 1] depicts the chemical structure of some of the main constituents of EOs. Some are
present in higher amount like linalool (60 – 70%) in C. sativum, caryophyllene (23.6%) in A. nemorosa, and 1,8 cineole (46.0%) in R. officinalis while others are in minor amounts. Monoterpenes like pinene, limonene, sabinene,
etc., are found to be responsible for the antioxidant and anticholinesterase properties
[88]. Therefore, it seems to be important to screen the main constituents of EOs based
upon the strength of the biologic potential and more findings are needed to establish
the required dose and proportions that are necessary to protect the brain from degenerative
diseases.
Fig. 1 Some of the main bioactive constituents of EOs.
Majority of the clinical as well as animal studies prefer inhalation as the route
of administration of EO for AD therapy. Aromatherapy for AD are used since long back
and found to be very effective. The aroma of EO acquired through inhaling or massaging
directly affects mood and cognition. These oils are supposed to enter the blood stream
through lung mucosa, nasal, or even diffuse directly into the olfactory nerve and
reach limbic system in the brain [89]. The EOs mentioned in this review is mostly nontoxic at the recommended doses. Most
of the EOs possess anticholinesterase property. In vitro studies of 15 EOs that displayed both AChE and BChE inhibitory potentials are mentioned.
ACh is the brain neurotransmitter involved in regulating memory and cognition and
cholinesterase inhibitors prevent degradation of ACh and maintain its synaptic concentration.
Hence, assessment of the potential shown by EOs on cholinesterase adds up a useful
approach for developing new drugs for AChE/BChE inhibitor with fewer cholinergic side
effects. Oxidative stress plays a major role in the pathophysiology of AD. Imbalance
in oxidants/antioxidants defense generates free radical that causes cell/neuron damage.
Antioxidant-rich EOs can hence counteract the free radical mediated oxidative stress
and thereby protects brain form neuronal damage. The ability of EOs to cross blood
brain barrier remains as a main reason for activity in brain regions
However, it is important to initiate further studies on pharmacokinetics and toxicities
of EOs and their bioactive markers responsible for anti-Alzheimerʼs action. More cell
culture and in vivo studies are essential. All these findings result in the establishment of good interventions
and subsequent development of safer and more effective anti-Alzheimerʼs drug.
There are numerous natural resources with reputed ethnobotanical uses shown to ameliorate
memory impairment in different Alzheimerʼs studies. However, comparatively only few
are explored to determine any therapeutic support for their putative effects. Our
literary survey revealed encouraging results regarding various EOs being studied in
preclinical and clinical studies of AD with significant effects in modulating the
pathology through anti-amyloid, antioxidants, anti-AChE, and memory enhancement activity.
The literature studies disclosed many drugs that showed positive results in animal
studies but failed in clinical trial. This demands more studies focused on human physiology,
pharmacokinetics, dose, and route of administration. Thus, the establishment of potential
targets and optimization of safety and efficacy of EOs in AD remain as a promising
area for future research.
