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Salvia officinalis extract in the treatment of patients with mild to moderate Alzheimer's disease: A double blind, randomized and placebo-controlled trial

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New treatments were presented for management of Alzheimer’s Disease (AD) in the recent years. However, they were not fully successful. The objective of this study was to assess the efficacy and safety of Salvia officinalis extract in AD at 4 months using fixed dose of the extract. A randomized, double blind, placebo-controlled trial in three centers in Iran was the structure of this study. Patients with mild to moderate AD (n=36, 10 women) with a score of ≤ 12 on the cognitive subscale of Alzheimer’s Disease Assessment (ADAS-cog) and ≤ 2 on Clinical Dementia Rating (CDR) were randomized to placebo or fixed dose of Salvia officinalis extract. Over 16 weeks, the primary outcome measure was the change in ADAS-cog score. Change in CDR (sum of the boxes) was the secondary outcome over the trial. At 4 months, Salvia extract produced a significant better outcome on cognitive function and CDR total score than placebo (ADAS-cog: d.f.: 1 f = 4.77, P = 0.037) (CDR: d.f.: 1, F=10.84, P
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Salvia officinalis extract in the treatment of patients with
mild to moderate Alzheimer’s disease: a double blind,
randomized and placebo-controlled trial
S. Akhondzadeh*PhD, M. Noroozian* MD,M.Mohammadi*MD, S. OhadiniaMD,
A. H. JamshidiPharmD and M. KhaniMSc
*Roozbeh Psychiatric Hospital, Tehran University of Medical Sciences, Tehran, Iran and Institute of
Medicinal Plants, Iranian Academic Centre for Education, Culture and Research, Tehran, Iran
SUMMARY
Background: Alzheimer’s disease is characterized
by a slow, progressive decline in cognitive func-
tion and behaviour. Acetylcholine esterase
inhibitors are the only agents approved by the
Food and Drug Administration for the treatment
of Alzheimer’s disease. All other agents pre-
scribed for the treatment of Alzheimer’s disease
are used on an off-label basis. Current research
into new drugs is focused on agents that will
prevent, slow down and/or halt the progress of
the disease process. Savia officinalis has been
used in herbal medicine for many centuries. It has
been suggested, on the basis of traditional
medicine, its in vitro cholinergic binding pro-
perties and modulation of mood and cognitive
performance in humans, that Salvia officinalis
might potentially provide a novel natural treat-
ment for Alzheimer’s disease. The objective of
this study was to assess the efficacy and safety of
Salvia officinalis extract using a fixed dose
(60 drops/day), in patients with mild to moderate
Alzheimer’s disease, over a 4-month period.
Methods: This was a 4-month, parallel group,
placebo-controlled trial undertaken in three cen-
tres in Tehran, Iran. Patients with mild to mod-
erate Alzheimer’s disease aged between 65 and
80 years (n¼42, 18 women) with a score of 12 on
the cognitive subscale of Alzheimer’s Disease
Assessment Scale (ADAS-cog) and £2 on the
Clinical Dementia Rating (CDR) were random-
ized to placebo or fixed dose of S. officinalis
extract. Over the 16 weeks, the main efficacy
measures were the change in the ADAS-cog and
CDR-Sum of Boxes scores compared with base-
line. In addition, side-effects were systematically
recorded throughout the study using a checklist.
Results: At 4 months, S. officinalis extract pro-
duced a significant better outcome on cognitive
functions than placebo (ADAS-cog: F¼4Æ77,
d.f. ¼1, P¼0Æ03) (CDR-SB: F¼10Æ84, d.f. ¼1,
P<0Æ003). There were no significant differences
in the two groups in terms of observed side-
effects except agitation that appears to be more
frequent in the placebo group (P¼0Æ09).
Conclusions: The results of this study indicate
the efficacy of S. officinalis extract in the mana-
gement of mild to moderate Alzheimer’s disease.
Moreover, S. officinalis may well reduce agitation
of patients but this needs to be confirmed.
Keywords: Alzheimer’s disease, herbal medicine,
Salvia officinalis
INTRODUCTION
Alzheimer’s disease is characterized by profound
memory loss sufficient to interface with social and
occupational functioning. It is the most common
form of dementia, affecting approximately 20 mil-
lion people worldwide (1, 2). Alzheimer’s disease is
characterized by an insidious loss of memory,
associated functional decline and behavioural dis-
turbances. Patients may live for more than a decade
after they are diagnosed with Alzheimer’s disease,
making it the leading cause of disability in the
elderly. The prevalence and incidence of this
disease and its cost to society, increase exponen-
tially with age. The prevalence increases from 0Æ3%
at 65 years of age to nearly 50%after 85 years. The
incidence increases from 0Æ5%at 65 years of age to
Received 5 December 2002, Accepted 14 January 2003
Correspondence: Dr Shahin Akhondzadeh, Roozbeh Psychiatric
Hospital, Tehran University of Medical Sciences, South Kargar
Avenue, Tehran 13334, Iran. Tel.: +98 21 4428388; fax: +98 21
549113; e-mail: s.akhond@neda.net
Journal of Clinical Pharmacy and Therapeutics (2003) 28, 53–59
2003 Blackwell Publishing Ltd 53
8%at 85 years (1–3). The first neurotransmitter
defect discovered in Alzheimer’s disease involved
acetylcholine (ACh). As cholinergic function is
required for short-term memory, the cholinergic
deficit in Alzheimer’s disease was also believed to
be responsible for much of the short-term memory
deficit (4). Clinical drug trials in patients with
Alzheimer’s disease have focused on drugs that
augment levels of ACh in the brain to compensate
for the loss of cholinergic function. These drugs
have included ACh precursors, muscarinic agon-
ists, nicotinic agonists and acetylcholine esterase
inhibitors (AChEIs). The most highly developed
and successful approaches to date have employed
AChE inhibition (5). The first drug approved for
general clinical use in Alzheimer’s disease was
tacrine, followed a few years later by donepezil.
More recently, rivastigmine has been used in sev-
eral countries around the world, and was launched
in the US by June 2000 (6). Pharmacological treat-
ment strategies in Alzheimer’s disease include
three classes of agents: (i) mechanism-based, dis-
ease-modifying therapies such as vitamin E and
selegiline; (ii) mechanism-based therapies that
compensate for transmitter deficits such as AChEIs,
and (iii) psychotropic agents administered to re-
lieve behavioural symptoms of Alzheimer’s disease
(7–10). Although two Food and Drug Administra-
tion approved drugs are available for the man-
agement of Alzheimer’s disease, the outcomes are
often unsatisfactory and there is a place for alter-
native medicine and in particular phytotherapy (3,
6, 10). It has been suggested, on the basis of a ret-
rospective review of the historical role of a number
of European herbs in the improvement of cognition
and in particular, memory, that S. officinalis and
another herb in the labiatae family, Melissa offici-
nalis, might potentially provide natural treatment
for Alzheimer’s disease (11, 12). Salvia officinalis
comes from Europe and is now grown all over the
world. Just as mint, it is known for its soothing and
carminative effects (13). In addition, it has been
reported that S. officinalis exhibits CNS acetylcho-
line receptor activity, with demonstration of both
nicotinic and muscarinic binding properties (14).
Moreover, a recent study showed that M. officinalis
another herb from this family with the same CNS
acetylcholine receptor activity modulated mood
and cognitive performance in acute administration
in healthy young volunteers (15). No side-effects or
symptoms of toxicity were reported with the use of
S. officinalis (13–15). The present study was under-
taken to test the efficacy and safety of S. officinalis
using a fixed dose, in patients with mild to mod-
erate Alzheimer’s disease, over 4 months in a
double-blind, randomized and placebo-controlled
trial for the first time.
METHODS
Trial organization
This was a 4-month, parallel group, placebo-con-
trolled trial undertaken in three centres in Tehran,
Iran during October 2000 to September 2002.
Overall coordination of the trial was by the Insti-
tute of Medicinal Plants, Tehran, Iran. All centres
were required to secure appropriate local ethics or
research committee approval before recruitment
could begin. The trial was approved by the
National Research centre of Medical Sciences,
Tehran, Iran.
Participants
Eligible participations in the study were male and
female outpatients, aged between 65 and 80 years.
Patients with a history of cognitive decline that had
been gradual in onset and progressive for at least
6 months were included. Other inclusion criteria
were:
A diagnosis of probable Alzheimer’s disease
according to the criteria of National Institute of
Neurological and Communicative Disorders and
Stroke and Alzheimer’s Disease and Related
Disorders Association (NINCDS ADRDA) (16).
Presence of mild to moderate dementia (score of
12 on the cognitive subscale of Alzheimer’s
Disease Assessment Scale (ADAS-cog) and £2on
Clinical Dementia Rating Scale (CDR) (17, 18).
Patients also had to have regular contact with a
responsible caregiver. Those with concomitant
disease such as hypertension, congestive heart
failure, non-insulin-dependent diabetes mellitus
and hypothyroidism were included in the study,
provided the disease was controlled. Patients were
excluded from the study if they had evidence of
other neurodegenerative disorders, any cardiovas-
cular disease thought likely to prevent completion
of the study, clinically significant psychiatric
2003 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics,28, 53–59
54 S. Akhondzadeh et al.
diseases, urinary outflow obstruction, an active
peptic ulcer, any history of epilepsy, or significant
drug or alcohol misuse. Any other medication
being taken to treat dementia had to be discontin-
ued. The use of other concomitant medication was
permitted, except that, where possible, drugs with
a psychotropic action were discontinued 48 h
before cognitive evaluation. Drugs with anticho-
linergic effects or cholinomimetic effects were
avoided. The ADAS is a 21-item scale used to
assess the severity of cognitive and non-cognitive
impairments that has been validated for use in
patient with Alzheimer’s disease. ADAS-cog is a
subscale of 11 items that evaluates selected aspects
of attention, language, memory, orientation, praxis
and reasoning. Score for ADAS-cog range from 0 to
70 (very severe) (17). Clinical Dementia Rating–
Sum of the Boxes (CDR-SB) provides a consensus-
based global clinical measure by summing the
ratings from six domains: memory, orientation,
judgement, problem-solving, community affairs,
home and hobbies, and personal care. Ratings were
assigned by the function in relation to cognitive
ability and past performance, with an increase in
score denoting deterioration (18). Patients were
randomized to receive S.officinalis extract or pla-
cebo in a 1 : 1 ratio using a computer-generated
code. The assignments were kept in sealed, opaque
envelopes until the point of allocation. The rand-
omization and allocation process was carried out
by the pharmacist of the Roozbeh hospital. The trial
was performed in accordance with the Declaration
of Helsinki and subsequently revised and
approved by ethics committee at National Research
Center of Medical Sciences of Iran. The patient (or a
representative), together with the carer, provided
written informed consent to participate.
Interventions
Patients were randomized to receive S. officinalis
extract 60 drops day or placebo drop 60 drops
day. Throughout the study, the person who
administrated the medications, rater and patients
were blind to assignments.
Extract preparation
Salvia officinalis was obtained from the farm of
Institute of Medicinal Plants, Halejerd, Iran. The
taxonomic identity of the plants was confirmed by
the botanist of the Department of Cultivation and
Development of Institute of Medicinal Plants,
Tehran, Iran. The plant extract was prepared as
1 : 1 in alcohol 45%. In other words, 1 kg dried
herb (leaf) to 1 L of alcohol.
Outcomes
The main efficacy measures were the ADAS-cog
and CDR-SB and outcome measures were the
change in ADAS-cog and CDR-SB scores over the
trail. Patients were assessed by a neurologist at
baseline and every 2 weeks after the medication
started.
Safety evaluations
All adverse events, reported, elicited or observed,
were recorded at each visit. Routine physical
examinations were conducted at each clinic visit.
Complete physical examinations, including 12-lead
electrocardiograph (ECG) recordings, were con-
ducted at week 0, week 8 and week 16.
Statistical analysis
Using data from pilot study and considering a five-
point difference in the change in ADAS-cog score
between patients treated with Salvia and placebo,
we calculated that at least 15 patients were needed
in each arm. A two-way repeated measures ana-
lysis of variance (time-treatment interaction) was
used. The two groups as a between-subjects factor
(group) and the nine measurements during treat-
ment as the within-subjects factor (time) were
considered. This was carried out for ADAS-cog and
CDR-SB scores. In addition, a one-way repeated
measures analysis of variance with a two-tailed
post hoc Tukey mean comparison test were per-
formed on the change in ADAS-cog and CDR-SB
from baseline. To compare the reduction of score of
ADAS-cog and CDR-SB scale at week 16 compared
with baseline, an unpaired two-sided Student’s
t-test was used. Results are presented as mean ±
SEM differences and were considered significant at
P£0Æ05. To compare the baseline data and fre-
quency of side-effects between the protocols,
Fisher’s exact test was performed. A traditional
‘observed cases’ (OC, the patients who completed
2003 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics,28, 53–59
Salvia officinalis extract in the treatment of Alzheimer’s disease 55
the trial) analysis at 16 weeks was the primary
efficacy analysis. In addition, intention to treat
(ITT) analysis with last observation carried forward
(LOCF) procedure was also performed. All results
discussed are based on OC analysis unless other-
wise stated.
RESULTS
A total of 103 patients were screened for the study
and 39 were randomized to trial medication. No
significant differences were identified between
patients randomly assigned to the group 1 or 2
conditions with regard to basic demographic data
including age and gender (Table 1). Thirty patients
completed the trial. In the Salvia extract and
placebo group, the number of drop-outs were four,
and five, respectively. No significant difference was
observed in the two groups in terms of drop-out
(P¼1Æ00) (Fig. 1).
Efficacy
ADAS-cog. The mean ± SEM scores of two groups
of patients are shown in Fig. 2. There were no
significant differences between two groups in week
0 (baseline) on the ADAS-cog rating scale (t¼0Æ10,
d.f. ¼28, P¼0Æ91). The difference between the
two protocols was significant as indicated by the
effect of group, the between-subjects factor
(F¼4Æ77, d.f. ¼1, P¼0Æ03 and F¼4Æ92, d.f. ¼1,
P¼0Æ03 for OC and LOCF analyses, respectively).
The behaviour of the two treatments was not
homogeneous across the time (groups-by-time
interaction, Greenhouse ·Geisser correction;
F¼245Æ37, d.f. ¼2Æ71, P<0Æ0001). In addition, a
one-way repeated measures analysis of variance
showed a significant effect of both protocols on the
ADAS-cog rating scale scores (P<0Æ0001). In both
groups post hoc comparisons showed a significant
change from week 4 on the ADAS-cog rating scale
scores. The difference between the two protocols
was significant at the endpoint (week 16) (t¼5Æ12,
d.f. ¼28, P<0Æ0001 and t¼4Æ64, d.f. ¼37,
P<0Æ0001 for OC and LOCF analyses, respec-
tively). The changes at the endpoint compared with
baseline were: )6Æ60 ± 1Æ63 (mean ± SD) and
5Æ53 ± 1Æ12 for Salvia extract and placebo, respec-
tively. A significant difference was observed on the
change of scores of the ADAS-cog rating scale at
week 16 compared with baseline in the two groups
Fig. 1. Trial profile.
Fig. 2. Mean ± SEM scores of the two protocols on the
ADAS-cog score. ns, non-significant.
Salvia extract Placebo P-value
Age (mean ± SD) 71Æ78 ± 3Æ67 72Æ75 ± 3Æ43 0Æ44
Gender Male: 12, female: 7 Male: 12, female: 8 1Æ00
Table 1. Baseline characteristic
2003 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics,28, 53–59
56 S. Akhondzadeh et al.
(t¼23Æ63, d.f. ¼28, P<0Æ0001 and t¼14Æ72,
d.f. ¼37, P<0Æ0001 for OC and LOCF analyses,
respectively).
CDR-SB
The mean ± SEM scores of two groups of patients
are shown in Fig. 3. There were no significant dif-
ferences between two groups in week 0 (baseline)
on the CDR-SB (t¼0Æ32, d.f. ¼28, P¼0Æ75). The
difference between the two protocols was signifi-
cant as indicated by the effect of group, the
between-subjects factor (F¼10Æ84, d.f. ¼1,
P<0Æ003 and F¼13Æ10, d.f. ¼1, P<0Æ001 for OC
and LOCF analyses, respectively). The behaviour of
the two treatments was not homogeneous across
the time (groups-by-time interaction, F¼31Æ64,
d.f. ¼8, P<0Æ0001). In addition, a one-way
repeated measures analysis of variance showed a
significant effect of both protocols on the CDR-SB
scores (P<0Æ0001). In both groups post hoc
comparisons showed a significant change from
week 8 on the CDR-SB scores. The difference
between the two protocols was significant at the
endpoint (week 16) (t¼6Æ13, d.f. ¼28, P<0Æ0001
and t¼6Æ27, d.f. ¼37, P<0Æ0001 for OC and
LOCF analyses, respectively). The changes at
the endpoint compared with baseline were:
)1Æ60 ± 1Æ35 (mean ± SD) and 0Æ73 ± 0Æ41 for Salvia
extract and placebo, respectively. A significant
difference was observed on the change of scores of
the CDR-SB at week 16 compared with baseline in
the two groups (t¼6Æ38, d.f. ¼28, P<0Æ0001 and
t¼6Æ95, d.f. ¼37, P<0Æ0001 for OC and LOCF
analyses, respectively).
Clinical complications and side-effects
Six cases of side-effects were observed over the
trial. The difference between the Salvia extract and
placebo in the frequency of side-effects was not
significant except for agitation (P¼0Æ09) (Table 2).
DISCUSSION
This study showed that patients with mild to
moderate Alzheimer’s disease receiving S. offici-
nalis extract experienced statistically significant
benefits in cognition after 16 weeks treatment. The
clinical relevance of these findings was emphasized
by the improvements seen in both the ADAS-cog
and CDR-SB measures in the S. officinalis extract
group on both observed case and ITT analyses. To
the best of our knowledge, this study is the first
clinical trial of S. officinalis extract in the treatment
of Alzheimer’s disease. There is increasing evi-
dence to indicate the possible efficacy of S. offici-
nalis and Melissa officinalis in the management of
Alzheimer’s disease (11, 12). Indeed, a couple of
recent reports indicated the CNS acetylcholine
receptor activity of M. officinalis and S. officinalis
and modulation of mood and cognitive perform-
ance following acute administration of M. officinalis
that are in agreement with the findings of the
present study (14, 15).
The side-effects associated with Salvia in this
study were generally those expected from cho-
linergic stimulation, and similar to those reported
with cholinesterase inhibitors (6, 10). Although, we
cannot consider agitation as a side-effect, frequency
of agitation appeared higher in the placebo group
and this may indicate an additional advantage for
Fig. 3. Mean ± SEM scores of the two protocols on the
CDR-SB score. ns, non-significant.
Table 2. Observed side-effects over the trial
Side-effects Salvia extract Placebo P-value
Vomiting 3 1 0Æ34
Dizziness 2 2 1Æ00
Wheezing 2 0 0Æ23
Agitation 1 6 0Æ09
Abdominal pain 2 0 0Æ23
Nausea 1 0 0Æ48
2003 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics,28, 53–59
Salvia officinalis extract in the treatment of Alzheimer’s disease 57
Salvia officinalis in the management of patients with
Alzheimer’s disease.
Implications for research
The limitations of present study including the
small number of patients and a relatively short
period of follow-up should be taken into account.
Further research is therefore needed.
CONCLUSIONS
The results of this study indicate the efficacy of
Salvia officinalis extract in the management of mild
to moderate Alzheimer’s disease. Moreover Salvia
officinalis may reduce agitation in patients with
Alzheimer’s disease. Further investigations to val-
idate the results are necessary.
The trial group
Shahin Akhondzadeh (principal investigator and
statistical support, clinical neuropsychopharma-
cologist from October 2000 to September 2002)
Mohammad Reza Mohammadi (clinical coordina-
tor, psychiatrist from October 2000 to September
2002)
Maryam Noroozian (trial programmer, neurologist
from October 2000 to September 2002)
Sina Ohadinia (trialist, medical doctor from
October 2000 to September 2002)
Amir Hossein Jamshidi (pharmacognosist from
October 2000 to September 2002)
Mousa Khani (botanist from October 2000 to
September 2002)
ACKNOWLEDGEMENTS
This study was supported by two grants from
National Research Centre of Medical Sciences,
Tehran, Iran and Iranian Academic Centre for
Education, Culture and Research to Dr Shahin
Akhondzadeh. The authors would like to thank Dr
Margaret Tejerizo for editing the manuscript.
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Salvia officinalis extract in the treatment of Alzheimer’s disease 59
... Isorosmanol and 7-methoxyrosmanol isolated from S. officinalis have been previously reported to inhibit AChE by 50-65% at concentrations of 500 µM [39,46]. Cytoprotective effects of sage against Aβ in neuronal cells have been reported [45], and oral administration of its essential oil to patients improves cognition and memory with no adverse effects [47,48]. Interestingly, we also found that, from all the extracts tested herein, S. officinalis achieved the highest BACE-1 inhibitory activity (up to 76%). ...
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ISESER2020 which will be held on 04-05 July 2020, Manisa, Turkey. The purpose of the symposium is to give information about the environmental sciences and engineering to participants. In this symposium all participants will take advantage about environmental topics with the help of foreign participants and several poster and oral presentations. Also, this symposium aims to provide connections for students and to provide opportunities for experts to share and discuss their experiences.
... Mild to moderate cases of AD aged 65-80 years were included to take certain doses of Salvia officinalis extract or placebo. After 4 months, Salvia officinalis extract showed a considerably better effect on cognitive functions compared to placebo (Akhondzadeh et al., 2003). Abozaid et al. evaluated the possible effect of Mg-Salvia officinalis nanoparticles on the treatment of aluminum chloride (ALCL3) induced AD in rats. ...
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Hundreds of millions of people around the world suffer from neurological disorders or have experienced them intermittently, which has significantly reduced their quality of life. The common treatments for neurological disorders are relatively expensive and may lead to a wide variety of side effects including sleep attacks, gastrointestinal side effects, blood pressure changes, etc. On the other hand, several herbal medications have attracted colossal popularity worldwide in the recent years due to their availability, affordable prices, and few side effects. Aromatic plants, sage (Salvia officinalis), lavender (Lavandula angustifolia), and rosemary (Salvia Rosmarinus) have already shown anxiolytics, anti-inflammatory, antioxidant, and neuroprotective effects. They have also shown potential in treating common neurological disorders, including Alzheimer's disease, Parkinson's disease, migraine, and cognitive disorders. This review summarizes the data on the neuroprotective potential of aromatic herbs, sage, lavender, and rosemary.
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Background Alzheimer's disease is a debilitating neurological brain disease with memory impairment among the first signs. Scopolamine (SCO), a muscarinic receptor antagonist that disrupts cognition and memory acquisition, is considered a psychopharmacological AD model. We investigate the effectiveness of medicinal plants in mitigating the SCO-induced neurobehavioural damage in rats.Materials and Methods Animals were injected with Scopolamine hydrobromide trihydrate (2.2 mg/kg IP.) daily for 2 months. Each treatment group was administered one of four medicinal spice extracts (Nigella sativa, 400 mg/kg; rosemary, 200 mg/kg; sage, 600 mg/kg and ginseng;200 mg/kg 90 minutes after SCO injection. Animals were subjected to cognitive-behavioral tests (NOR, Y-maze, and MWM). After the experiment, we extracted the brains for histopathological examination and biochemical assessment for oxidative stress (levels of TT, CAT and TBARS) and gene expression of acetylcholinesterase and brain monoamines.ResultsAs expected, SCO treatment impaired memory and cognition, increased oxidative stress, decreased neurotransmitters, and caused severe neurodegenerative changes in the brain.Conclusion Surprisingly, these effects were measurably moderated by the administration of all four plant extracts, indicating a neuroprotective action that we suggest could alleviate AD disease manifestations.
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Green synthesis of zinc oxide nanoparticles (ZnO NPs) using plant extracts have recently attracted considerable attention due to their environmental protection benefits and their easy and low cost of fabrication. In the current study, ZnO NPS were synthesized using the aqueous extract of Ochradenus arabicus as a capping and reducing agent. The obtained ZnO NPs were firstly characterized using ultraviolet visible (UV-Vis) spectroscopy, Fourier transform infrared (FTIR), transmission electron microscope (TEM), X-ray diffraction (XRD), energy dispersive X-ray absorption (EDX), zeta potential, and zeta size. All these techniques confirmed the characteristic features of the biogenic synthesized ZnO NPs. Then, ZnO NPs were evaluated for their effects on morphological, biochemical, and physiological parameters of Salvia officinalis cultured in Murashige and Skoog medium containing 0, 75, 100, and 150 mM of NaCl. The results showed that ZnO NPs at a dose of 10 mg/L significantly increased the shoot number, shoot fresh weight, and shoot dry weight of Salvia officinalis subjected or not to the salt stress. For the shoot length, a slight increase of 4.3% was recorded in the plant treated by 150 mM NaCl+10 mg/L ZnO NPs compared to the plant treated only with 150 mM of NaCl. On the other hand, without NaCl, the application of both concentrations 10 mg/L and 30 mg/L of ZnO NPs significantly improved the total chlorophyll content by 30.3% and 21.8%, respectively. Under 150 mM of NaCl, the addition of 10 mg/L of ZnO NPs enhanced the total chlorophyll by 1.5 times, whilst a slight decrease of total chlorophyll was recorded in the plants treated by 150 mM NaCl + 30 mg/L ZnO NPs. Additionally, ZnO NPs significantly enhance the proline accumulation and the antioxidative enzyme activities of catalase (CAT), superoxide dismutase (SOD), and glutathione reductase (GR) in plants under salinity. Our findings revealed that green synthesized ZnO NPs, especially at a dose of 10 mg/L, play a crucial role in growth enhancement and salt stress mitigation. Hence, this biosynthesized ZnO NPs at a concentration of 10 mg/L can be considered as effective nanofertilizers for the plants grown in salty areas.
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The deterioration in cognitive function that is characteristic of Alzheimer’s disease is related to a reduction in cholinergic transmission in the basal forebrain, and the appearance of neurofibrillatory tangles and plaques containing β-amyloid (Aβ). Some plaques are neurotoxic and contain acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). AChE consists of different molecular forms: G1, G2 and G4. In the cortex and hippocampus, G4 is located presynaptically and comprises about 70 to 80% of the AChE present. The remainder is in the G1 form which is present in postsynaptic neurons. G4 is the predominant type of AChE that is reduced in Alzheimer’s disease. Skeletal muscle contains mainly G4 and G2. Eight cholinesterase inhibitors that reduce the inactivation of acetylcholine (ACh) have been tested in placebo-controlled trials in patients with Alzheimer’s disease. All these agents were found to improve cognitive function, or delay its rate of decline, in a significant proportion of patients. Tacrine, eptastigmine and rivastigmine also significantly improved activities of daily living. Furthermore, most of these drugs increased cerebral blood flow and glucose metabolism, parameters that are decreased in the basal forebrain of individuals with Alzheimer’s disease. This latter effect may contribute to the therapeutic effect of cholinesterase inhibitors and may delay the formation of Aβ. Currently available cholinesterase inhibitors differ in the incidence and severity of adverse effects produced at clinical doses. Reversible liver damage, seen with tacrine and velnacrine, and cholinergic hyperactivity, such as nausea, vomiting and muscle cramps, with these and other drugs can prevent the attainment of an optimum dose. The selectivity of cholinesterase inhibitors for AChE versus BuChE, and for the different molecular forms of AChE, may have an influence on both therapeutic and adverse effects. Donepezil and galantamine (galanthamine) are selective inhibitors of AChE, while the other agents also inhibit BuChE. The adverse effects associated with cholinergic hyperactivity are not due to blockade of BuChE as previously suggested, since they are seen with the AChE-selective inhibitors and not with those inhibitors that only inhibit BuChE. The advantage of nonselective inhibitors is that they may also increase ACh levels by inhibiting BuChE in glial cells. Selective inhibitors of the G1 form of AChE, such as rivastigmine, are more likely to elevate ACh levels in the brain of patients with Alzheimer’s disease and may be less likely to cause skeletal muscle cramps than nonselective inhibitors such as metrifonate.
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The cause of Alzheimer's disease is closely associated with the accumulation of β-amyloid in the neocortex. The neurochemical factors responsible for precipitating this otherwise normal, soluble protein are contentious. Nevertheless, in the absence of any other curative treatment for Alzheimer's disease, the majority of the research effort has focussed on inhibiting the production of β-amyloid (using secretase inhibitors) or destroying the protein (vaccination with synthetic peptide). Both approaches assume that the protein serves no purposive function. In contrast, a new alternative has recently emerged employing small metal complexing agents that inhibit the neurotoxic hydrogen peroxide produced by β-amyloid, and which facilitate the dissolution of brain amyloid deposits in vivo in transgenic mice. Currently in clinical trials, this class of agent may interdict the Alzheimer disease process at its most generic biochemical level.
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The present review examines the current issues involving the use of drugs in the treatment of the various dementia syndromes. With the introduction of a new cholinesterase inhibitor, galantamine, during 2000, a recap of the symptomatic treatment issues reported during the past year leads on to early attempts at disease modification. Observational reports of the effect of oestrogen and anti-inflammatory drugs have led to therapeutic trials, which have mostly been negative. This may be due to incomplete understanding of mechanism and inappropriate trial design. Statins and vitamin E have been reported as beneficial, and an amyloid vaccine has entered into a clinical trial. The review finishes with some published experience in treating behavioural components of the dementia syndrome, and overall demonstrates how our understanding of the treatment issues continues to unfold.
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The use of complementary medicines, such as plant extracts, in dementia therapy varies according to the different cultural traditions. In orthodox Western medicine, contrasting with that in China and the Far East for example, pharmacological properties of traditional cognitive- or memory-enhancing plants have not been widely investigated in the context of current models of Alzheimer's disease. An exception is Gingko biloba in which the gingkolides have antoxidant, neuroprotective and cholinergic activities relevant to Alzheimer's disease mechanisms. The therapeutic efficacy of Ginkgo extracts in Alzheimer's disease in placebo controlled clinical trials is reportedly similar to currently prescribed drugs such as tacrine or donepezil and, importantly, undesirable side effects of Gingko are minimal. Old European reference books, such as those on medicinal herbs, document a variety of other plants such as Salvia officinalis (sage) and Melissa officinalis (balm) with memory-improving properties, and cholinergic activities have recently been identified in extracts of these plants. Precedents for modern discovery of clinically relevant pharmacological activity in plants with long-established medicinal use include, for example, the interaction of alkaloid opioids in Papaver somniferum (opium poppy) with endogenous opiate receptors in the brain. With recent major advances in understanding the neurobiology of Alzheimer's disease, and as yet limited efficacy of so-called rationally designed therapies, it may be timely to re-explore historical archives for new directions in drug development. This article considers not only the value of an integrative traditional and modern scientific approach to developing new treatments for dementia, but also in the understanding of disease mechanisms. Long before the current biologically-based hypothesis of cholinergic derangement in Alzheimer's disease emerged, plants now known to contain cholinergic antagonists were recorded for their amnesia- and dementia-inducing properties.
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The malignancy of Alzheimer disease is a phenomenon well known to neurologists. Katzman and Karasu estimate that the senile form of Alzheimer disease may rank as the fourth or fifth most common cause of death in the United States. Yet the US vital statistics tables do not list 'Alzheimer disease', 'senile dementia', or 'senility' as a cause of death, even in the extended list of 263 causes of death.
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Clinically diagnosed Alzheimer's disease and other dementing illnesses were assessed in a geographically defined US community. Of 3623 persons (80.8% of all community residents over 65 years of age) who had brief memory testing in their homes, a stratified sample of 467 persons underwent neurological, neuropsychological, and laboratory examination. Prevalence rates of Alzheimer's disease were calculated for the community population from the sample undergoing clinical evaluation. Of those over the age of 65 years, an estimated 10.3% (95% confidence limits, 8.1% and 12.5%) had probable Alzheimer's disease. This prevalence rate was strongly associated with age. Of those 65 to 74 years old, 3.0% (95% confidence limits, 0.8 and 5.2) had probable Alzheimer's disease, compared with 18.7% (95% confidence limits, 13.2 and 24.2) of those 75 to 84 years old and 47.2% (95% confidence limits, 37.0 and 63.2) of those over 85 years. Other dementing conditions were uncommon. Of community residents with moderate or severe cognitive impairment, 84.1% had clinically diagnosed Alzheimer's disease as the only probable diagnosis. These data suggest that clinically diagnosed Alzheimer's disease is a common condition and that its public health impact will continue to increase with increasing longevity of the population. (JAMA. 1989;262:2551-2556)