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Nootropic Activity of Caralluma fimbriata Extract in Mice

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  • SCES's Indira college of pharmacy

Abstract

We investigated the effects of a standardized extract of Caralluma fimbriata Wall (CFE) on learning and memory in mice using various behavioural models. Unusually, CFE exerts both nootropic and anxiolytic effects.
Food and Nutrition Sciences, 2014, 5, 147-152
Published Online January 2014 (http://www.scirp.org/journal/fns)
http://dx.doi.org/10.4236/fns.2013.52019
Nootropic Activity of Caralluma fimbriata Extract in Mice
Ramaswamy Rajendran1, Digambar Balkrishna Ambikar2, Rakesh Arun Khandare2,
Vrushali Dattatraya Sannapuri2, Niraj Sudhakar Vyawahare2, Paul Clayton3*
1Green Chem, Bangalore, India; 2Department of Pharmacology, AISSMS College of Pharmacy, Pune, India; 3Institute of Food, Brain
& Behaviour, Oxford, UK.
Email: *paulrclayton@gmail.com
Received September 30th, 2013; revised October 30th, 2013; accepted November 7th, 2013
Copyright © 2014 Ramaswamy Rajendran et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
In accordance of the Creative Commons Attribution License all Copyrights © 2014 are reserved for SCIRP and the owner of the
intellectual property Ramaswamy Rajendran et al. All Copyright © 2014 are guarded by law and by SCIRP as a guardian.
ABSTRACT
We investigated the effects of a standardized extract of Caralluma fimbriata Wall (CFE) on learning and memory
in mice using various behavioural models. Unusually, CFE exerts both nootropic and anxiolytic effects.
KEYWORDS
Caralluma; Ayurvedic; Nootrope; Anxiolytic; Obesity; Alzheimer’s
1. Introduction
The prevalence of cognitive impairment increases expo-
nentially with advancing age [1,2], and the numbers of
affected individuals are increasing due to demographic
and other trends. Anxiety frequently presents as a co-
morbidity [3], and as the anxiolytic drugs currently
available generally have sedative properties, this poses
problems of clinical management.
We initiated a search for herbs with anxiolytic, non-
sedative properties in the Ayurvedic literature, which
cites a number of plants as being useful in the treatment
of mental symptoms [4]. Some of these have already
been examined and found to have significant pharmaco-
logical activity [5-8]; specific phytochemicals have been
identified as the active constituents [9-11].
Caralluma fimbriata Wall (CF) (Asclepiadaceae), an
edible succulent, grows wild all over India and is a tradi-
tional food plant. Its phytochemical ingredients include
pregnane glycosides, flavone glycosides, megastigmane
glycosides, saponins and various flavonoids [12]. Al-
though many of these compounds exert anxiolytic effects
[13-15], CF is not known to induce sedation. We inves-
tigated its activity on cognition and anxiety in a mouse
model.
2. Methods
2.1. Validation of Active
2.1.1. Plant Material and Preparation of Extract
A voucher specimen of Caralluma fimbriata was col-
lected January 14th 2008 at 200 metres altitude in the
Kolli Hills Forest in Tamil Nadu, India. It was deposited
and identified at the Herbarium of the National Institute
of Science Communication and Information Resources
(NISCAIR) New Delhi, and registered as NISCAIR/
RIIMD/Consult/06-7/945/129/02 on 25th January 2008.
Aerial parts of Caralluma fimbriata Batch CFH/7030
were dried, powdered using sieve 355 and extracted us-
ing a hydro-alcoholic mixture (70:30 ethanol:water). This
was dried to produce Caralluma fimbriata extract (CFE)
containing 25% of pregnane glycosides minimum. These
were assayed using HPLC (instrument Shimadzu LC-10
A VP Gradient system) and HPLC Column: Phenomenex
C-18, Luna, -SS column 250 mm × 4.6 mm, 5-µ particle
size. The mobile phase used was (A) water and (B) ace-
tonitrile at a flow rate of 1.0 ml/min, screened at 205
nm.
2.1.2. HPTLC Fingerprinting of C. fimbriata Samples
Detection by vanillin sulphuric acid reagent.
*
Corresponding author.
OPEN ACCESS FNS
Nootropic Activity of Caralluma fimbriata Extract in Mice
148
A. Fresh Herb; B. Dried Herb; C. Extract CFE/7025; D.
Extract CFE/WS/06/65% (Working Standard equated to
Reference Standard); E. SlimalumasideA Reference Stan-
dard (SLMA/REF/03).
2.1.3. HPLC Analysis
Caralluma fimbriata extract, batch number CFE/10050.
SLIMALUMASIDE A, batch number SLMA/REF/04.
2.2. Pharmaceutical Reference Materials
2.2.1. Chemicals and Drugs
Piracetam (PT) syrup (Nootropil, UCB, Batch no-
V007003) and diazepam injection (Calmpose, Batch no
9059221) were used as reference standards; Piracetam as
a recognised nootrope and diazepam as an anxiolytic. All
other chemicals were AR grade.
2.2.2. Preparation of Drug Solutions
CFE was dissolved in distilled water to prepare a stock
solution from which working solutions allowing dosing
at 100, 250, 500 and 1000 mg/kg were prepared. Doses
were administered by gavage.
2.3. Animals
Male Swiss albino mice (18 - 22 g) used for the study
were purchased from approved supplier (Yash farms,
Pune) and maintained at 25˚C ± 2˚C and relative humid-
ity of 45% to 55% under standard environmental condi-
tions (12 h light 12 h/dark cycle). The animals had free
access to standard food (Chakan Oil Mills, Pune) and
water ad libitum. Institutional Animal Ethics Committee
(IAEC) approved the protocol (CPCSEA/IAEC PC-01/
032K7). All experiments were carried out between 12:00
- 16:00 h.
2.4. Acute Toxicity
Male albino mice (18 - 22 g) were subjected to acute
toxicity studies as per OECD 2001 guidelines (AOT 425).
The mice were administered with the different doses of
CFE or distilled water (10 ml/kg). Dose progression/
reduction was carried out following AOT-425 guidelines.
2.5. Acute Effects of CFE
2.5.1. Object Recognition Test
This was carried out in a multiple open-field box pro-
vided by V.J. Instruments, India. Before training, mice
were individually habituated by allowing them to explore
the open-field box for 2 min on the day prior to testing.
During training sessions, the first trial (T1) was con-
ducted 60 min after drug administration. Two identical
objects were placed in opposite corners of the box and
the time taken by each mouse to complete 20 s of object
exploration was recorded. Exploration of the object was
considered to be when the head of the animal was facing
less than 2 cm from the object or touching the object.
Animals were returned to their home cages immediately
after training. The second trial (T2) was performed 90
min after T1. A new object replaced one of the objects
used in T1 and mice were left in the box for 5 min.
Times spent exploring the familiar (F) and new objects
(N) were recorded separately and discrimination index
(D) was calculated as (N F)/(N + F). The object was
changed randomly and the apparatus thoroughly cleaned
between trials to avoid place reference and the influence
of olfactory stimuli [16,17].
2.5.2. Locomotor Activity
Locomotor (horizontal) activity was measured using a
digital actophotometer (Space-lab, India). Mice were
divided into six groups and subjected to respective drug
treatment. 60 min after drug administration, mice were
placed individually in the actophotometer for 5 min and
OPEN ACCESS FNS
Nootropic Activity of Caralluma fimbriata Extract in Mice
149
activity scores obtained. Diazepam (2 mg/kg, i.p.) was
used as reference standard [18].
2.6. Chronic Effects of CFE
2.6.1. Morris Water Maze
A 100 cm diameter circular tank was used, made of light-
impervious material and filled to 30 cm with water (25˚C
± 2˚C) rendered opaque with a food-grade lipid/water
emulsion. The tank was divided into four equal quadrants
with a small platform concealed 2 cm below the water
level, placed initially at a fixed position and subsequently
randomly to assess the effect of the drugs on spatial ref-
erence and spatial working memory [19,20]. Using the
standard pre-selection test, mice were released into the
tank to find the platform. Mice which failed to locate the
platform in the allotted time of 90 s or refused to search
were excluded [20]. Mice were then given CFE or ve-
hicle for 21 days.
Evaluation for Learning Facilitation Activity
Selected mice were released into the tank individually
and allowed to find the hidden platform at either fixed or
variable locations within a time limit of 90 s. Distances
travelled and times taken to find the hidden platform
(escape latency) at a fixed location (working memory) or
variable location (short term spatial memory) were rec-
orded daily for 21 days, 60 min after drug administration
[20].
2.6.2. Elevated Plus Maze (EPM)
An elevated plus maze (V.J. Instruments, India) consist-
ing of two open arms (50 × 10 × 40 cm) and two en-
closed arms (50 × 10 × 40 cm) was used, elevated to the
height of 40 cm. Mice were placed individually in the
centre of the EPM facing an enclosed arm. Time spent by
the mouse during the next 5 min on the open and en-
closed arms was recorded. The mice received drug
treatment for 14 days. Exploratory activity was measured
on 2nd, 7th and 14th day at 60 min after drug administra-
tion; time spent in the open arm is indication of anxiolyt-
ic activity [16,17].
2.6.3. Radial Arm Maze
A radial arm maze (Vijay Instruments, Pune, India) with
an octagonal central hub of 30 cm in diameter and radial
arms of 55 × 10 × 40 cm was used. Food containers were
mounted at 30 cm into each arm [20].
2.7. Pre-Experimental Food Intake
Mice were provided with excess of weighed food; food
remaining at 24 hours was weighed to ascertain daily
food intake. This was repeated for 7 days, and average
daily food intake assessed. During the experiment 85%
of this quantity was provided to generate food-motivated
performance.
2.8. Experimental Procedure
This comprised two distinct trials, wherein a food pellet
was placed in a fixed arm for spatial reference memory
evaluation and in the variable arm for evaluation of spa-
tial working memory. Each mouse placed on the central
hub was allowed to choose any arm to obtain food. The
session was completed once the mouse had searched all
cups or after 3 minutes, when the mouse was returned to
its home cage. Successful retrieval of food was recorded
as a correct entry; repeat visits to previously emptied
cups as errors. Mice were designated trained once they
found all food with maximum one re-entry on three con-
secutive days. Latency to find food, number of correct
entries before first re-entry and the number of re-entries
of trained mice were measured to evaluate performance.
There was a one-hour interval between spatial reference
and working memory evaluation. The apparatus was
thoroughly cleaned between trials to avoid place prefe-
rence and the influence of olfactory stimuli [20].
2.9. Statistical Analysis
Results are expressed as Mean ± SEM. Comparison of
the drug treated groups against vehicle treated group was
made by one-way analysis of variance (ANOVA) fol-
lowed by Dunnett’s t-test.
3. Results
3.1. Acute Toxicity
CFE was found to be non-toxic up to the dose 2000
mg/kg.
3.2. Effects of Acute CFE
3.2.1. Discrimination Index
Pre-treatment of mice with CFE 250, 500, 1000 mg/kg
increased discrimination index in a dose-dependent
manner compared to controls. Efficacy at the higher dos-
es matched that of a reference dose of the recognised
nootrope piracetam (Table 1).
3.2.2. Locomotor Activity
CFE at doses of 100 and 250 mg/kg did not significantly
impact on locomotor activity. Higher doses (500 and
1000 mg/kg) reduced locomotor activity significantly (P
< 0.05) (Figure 1).
3.3. Effects of Chronic CFE
3.3.1. Morris Water Maze Task Performance
In mice pre-treated with CFE at all doses, escape latency
in both spatial reference and spatial working memory
OPEN ACCESS FNS
Nootropic Activity of Caralluma fimbriata Extract in Mice
150
Figure 1. Effect of CFE and diazepam on mean change in
locomotor activity. n = 6 Data was analyzed by one-way
ANOVA followed by Dunnett’s t test *P < 0.05, **P < 0.01.
Table 1. Effect of CFE and piracetam (PT) on discrimina-
tion index in object recognition test.
Treatment Discrimination index
Vehicle (10 ml/kg) 0.25 ± 0.019
CF (100 mg/kg) 0.33 ± 0.035
CF (250 mg/kg) 0.35 ± 0.024*
CF (500 mg/kg) 0.36 ± 0.027*
CF (1000 mg/kg) 0.38 ± 0.035**
PT (150 mg/kg) 0.40 ± 0.008**
n = 6 Data was analyzed by one-way ANOVA followed by Dunnett’s t test.
*P < 0.05, **P < 0.01.
models was significantly reduced (P < 0.01). Distance
travelled by mice pre-treated with CFE 100 and 250
mg/kg in the spatial reference memory model and CFE
100 mg/kg in the spatial working memory model was
also significantly reduced. This effect disappeared at
higher doses, showing a biphasic effect common among
anxiolytics (Figures 2 and 3).
3.3.2. Elevated Plus Maze Task Performance
Mice pre-treated with CFE 250, 500 and 1000 mg/kg
significantly increased the time spent in open arm on the
2nd, 7th and 14th days, with a trend towards dose-depen-
dency (Figure 4).
3.3.3. Radial Arm Maze Task Performance
CFE had no significant effects. The reference standard
piracetam significantly reduced all learned parameters.
4. Discussion
Memory performance depends upon the type of difficulty
Figure 2. Effect of CFE and piracetam (PT) on escape la-
tency using Morris water maze. n = 6 Data was analyzed by
one-way ANOVA followed by Dunnett’s *P < 0.05, **P <
0.01.
Figure 3. Effect of CFE and piracetam (PT) on distance
travelled using Morris water maze. n = 6 Data was analyzed
by one-way ANOVA followed by Dunnett’s *P < 0.05, **P <
0.01.
Figure 4. Effect of CFE and piracetam (PT) on time spent
in open arm using elevated plus maze. n = 6 Data was ana-
lyzed by one-way ANOVA followed by Dunnett’s *P < 0.05,
**P < 0.01.
and the nature of task [18]; hence new drug evaluation is
usually carried out using multiple models, as in our paper.
The significant improvement in discrimination index in
the object recognition test achieved by CFE indicated
facilitation of learning and memory processes in the ab-
sence of cognitive deficit, a major criterion for classify-
ing nootropic agents [21]. This supports its possible use
in disorders related to episodic memory impairment as-
0
5
10
15
20
25
30
35
40
45
Vehicle CF 100 CF 250 CF 500 CF
1000 PT 150
Treatment mg/kg
Escape latency (sec)
Preferential
Working
**
**
**
**
**
**
**
**
0
200
400
600
800
1000
1200
Vehicle CF 100 CF 250 CF 500 CF 1000 PT 150
Treatment mg/kg
Distance travelled (cm)
Preferential
Working
**
**
**
*
**
0
20
40
60
80
100
120
140
160
Vehicle CF 100 CF 250 CF 500 CF 1000 Piracetam
150
Trea tment (m g/kg)
Time spent in open arm (sec)
2nd Day
7th Day
14th Day
*
**
**
**
**
**
**
**
**
**
**
**
OPEN ACCESS FNS
Nootropic Activity of Caralluma fimbriata Extract in Mice
151
sociated with encoding and/or storage disorders and ma-
jor perturbation of recollective judgment [22].
Mazes are traditionally used to evaluate spatial learn-
ing and memory. Spatial memory is a form of short term
memory utilising neuro-circuitry that provides temporary
storage and manipulation of information necessary for
complex cognitive tasks such as language comprehension,
learning and reasoning [23]. Its impairment is analogous
to memory disorder in Alzheimer’s dementia [24].
CFE pre-treatment significantly reduced escape laten-
cy in Morris water maze performance, facilitating learn-
ing and memory processes integral to spatial navigation
[20]. The reduction in distance travelled with lower doses
of CFE does not meet the criteria of a classic nootropic
agent as the effect disappeared at higher doses [20].
However, distance travelled can be reduced either via
improved cognition or a change in swimming behaviour
influenced by serotonergic transmission [25]. In the
present investigation, a significant nootropic effect was
observed with respect to escape latency with all doses of
CFE. We believe that at higher doses, flavonoidal com-
ponents in CFE may have exerted an inhibitory effect on
swimming behaviour via serotonergic mechanisms [26],
and will explore this in future work.
In the Elevated Plus Maze, mice pre-treated with CFE
significantly increased time spent in the open arm, de-
monstrating an anxiolytic action [27] alongside CFE’s
nootropic effects. This is the most important observation
of the present investigation; anxiety is frequently asso-
ciated with and can worsen impaired learning and wea-
kened memory in Alzheimer’s disease, and there are
currently no drugs that adequately treat co-presenting
anxiety and cognitive deficit. Benzodiazepines, the most
widely prescribed anxiolytic agents, have unfavourable
effects on learning and memory processes [16,17] and
selectively impair anterograde episodic memory [28].
Furthermore, benzodiazepines induce tolerance following
repeated dosing [29] due to adaptive receptor changes in
the central nervous system [30]. CFE pre-treatment
showed significant and consistent anxiolytic action even
after daily administration for 14 days, without behavioral
toxicity; together with sustained cognitive enhancement.
Locomotor activity is considered to be an index of
alertness and decreased activity indicates sedation. Lo-
comotor activity was significantly decreased with CFE
500 and 1000 mg/kg pre-treatment, indicating a degree of
sedation at the higher doses. Nootropic effects were
shown at the lower two doses of CFE, which did not in-
duce any sedation.
The radial arm maze (RAM) is used to evaluate hun-
ger-motivated spatial memory in lab animals [20]. CFE
did not impact on RAM performance at any dose, a
null-result that had been anticipated due to CFE’s docu-
mented appetite-suppressant effects [31,32].
5. Conclusion
When administered chronically, CFE has significant
nootropic and anxiolytic activity in mice. The combina-
tion of these usually mutually exclusive effects together
with an absence of toxicity makes CFE an interesting
candidate for the treatment of cognitive impairment co-
presenting with anxiety in the elderly; and its nootrop-
ic/anxiolytic/anorexogenic profile makes it a candidate
treatment for Prader-Willi Syndrome also. Further work
is underway to extend our understanding of its mechan-
ism of action, including a study in aged animals.
Authors’ Contributions
NSV conceptualized and designed the study, drafted the
manuscript, and has given final approval of the version to
be published. RR, DBA, PRC and VDS made substantial
contributions to the conception and design of the study
and to the analysis and interpretation of data. RAK as-
sisted with the acquisition of data and the statistical
analysis. All authors read and approved the final manu-
script.
Declaration of Interests
R. Rajendran is employed by Green Chem, which manu-
factured the CFE. P. Clayton provides occasional con-
sultancy services to GenCor Pacific, which intends to
develop CFE as a commercial product. Neither organiza-
tion was involved in the preparation of this paper.
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OPEN ACCESS FNS
... The time spent by the animal for exploring the new object (tB) and the familiar (tA) objects was recorded during 5 min (Kulkarni et al., 2011). The discrimination index (DI) was calculated as (tB/tB+tA) (Ennaceur and Delacour, 1988;Rajendran et al., 2014). ...
... Thus, scopolamine-induced memory impairment is a valid model for the evaluation of anti -amnesic effects of new drugs. Diverse behavioral animal models are usually used for the evaluation and validation of new drugs against dementia (Rajendran et al., 2014). ...
... In the EPM test, D. integrifolia significantly reduced the initial transfer latency on day 10. These results suggest that D. integrifolia has a nootropic effect because it ameliorates the retention of informations in absence of any memory impairment inducer (Itoh et al., 1990;Rajendran et al., 2014). Furthermore, D. integrifolia significantly reduced the retention transfer latency on day 10 after scopolamine injection suggesting that D. integrifolia ameliorates learning and retention of information and plays a role in memory formation (Itoh et al., 1990;Sharma and Kulkarni, 1992;Joshi and Parle, 2007;Kulkarni et al., 2011;Rajendran et al., 2014). ...
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Alzheimer’s disease the most common form of dementia in the elderly is a neurodegenerative disease that affects 44 millions of people worldwide. The first treatments against Alzheimer’s disease are acetylcholinesterase inhibitors; however, these medications are associated with many side effects. Dichrocephala integrifolia is a traditional herb widely used by indigenous population of Cameroon to treat and prevent Alzheimer’s disease and for memory improvement. In this study, we evaluated the effect of the decoction prepared from leaves of D. integrifolia, on scopolamine-induced memory impairment in mice. Seven groups of six animals were used. The first two groups received distilled water for the distilled water and scopolamine groups. The four test groups received one of the four doses of the decoction of the plant (35, 87.5, 175 or 350 mg/kg p.o.) and the positive control group received tacrine (10 mg/kg), a cholinesterase inhibitor used in the treatment of Alzheimer’s disease, during 10 consecutive days. Scopolamine (1 mg/kg), a cholinergic receptor blocker, administered 30 min after treatments, was used to induce memory impairment to all groups except the distilled water group on day 10 of drug treatment. The behavioral paradigms used to evaluate the effects of the treatment were the elevated plus maze for learning and memory, Y maze for spatial short-term memory, the novel object recognition for recognition memory and Morris water maze for the evaluation of spatial long-term memory. After behavioral tests, animals were sacrificed and brains of a subset were used for the assessment of some biomarkers of oxidative stress (malondialdehyde and reduced glutathione levels) and for the evaluation of the acetylcholinesterase activity. From the remaining subset brains, histopathological analysis was performed. The results of this study showed that, D. integrifolia at the doses of 87.5 and 350 mg/kg significantly (p < 0.01) improved spatial short-term and long-term memory, by increasing the percentage of spontaneous alternation in the Y maze and reducing the escape latency in the Morris water maze. Furthermore, the results of histopathological evaluation showed that D. integrifolia attenuated the neuronal death in the hippocampus induced by scopolamine. The main finding of this work is that D. integrifolia improves learning capacities and counteracts the memory impairment induced by scopolamine. Thus, D. integrifolia can be a promising plant resource for the management of Alzheimer’s disease and memory loss.
... [22] Animal studies have demonstrated dose responsive appetite suppression and significant nootropic and anxiolytic effects in rats. [23] With regard to toxicology, the powdered extract has been investigated at extremely high doses (5,000 mg/kg bw/day) and over a long treatment period with no significant toxicological effect. [21,23] ...
... [23] With regard to toxicology, the powdered extract has been investigated at extremely high doses (5,000 mg/kg bw/day) and over a long treatment period with no significant toxicological effect. [21,23] ...
... One could speculate that long-term CFE administration may contribute to a less habituated obsessive compulsive demeanor due to the nootropic and anxiolytic effect of CFE demonstrated in mice. [23] Another limitation was that many of the younger children in our cohort had lower hyperphagic scores at baseline, which corresponded with the timeline of appetite behavior in the PWS phenotype. HQ question 12 pinpointed the onset of the initial hyperphagic behavior as mean 5.5 ± 2.5 years. ...
Article
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Background: Prader-Willi syndrome (PWS) results from a deletion of the paternal genes in the region of chromosome 15q11-q13. PWS develops hyperphagia, which when left unmanaged, leads to an excessive ingestion of food. To date there is inadequate pharmacological treatment or supplementation for modification of the PWS hyperphagia and/or the associated behaviors. Therefore, the best practice is familial supervision and restriction of diet and environment. Aim: We aimed to determine if the natural supplement of Caralluma fimbriata extract (CFE) could attenuate hyperphagia or the associated appetite behaviors in children and adolescents with PWS over the 4-week pilot trial period. Materials and methods: We conducted a placebo-controlled, double-blind, randomized crossover trial over a 10-week period to investigate the effects of CFE on hunger control, in a cohort of children and adolescents with confirmed PWS (n =15, mean age 9.27 ± 3.16 years, body weight 43.98 ± 23.99 kg). Participants from Australia and New Zealand ingested CFE or a placebo of maltodextrin/cabbage leaf over a 4-week period, with a 2-week washout before the crossover to the other treatment. Weekly comparisons in appetite behavior, severity, and drive were recorded by parents, as scaled time-point measures on a hyperphagia questionnaire validated for PWS. Results: CFE administration was found to induce a significant accumulative easing of hyperphagia (P = 0.05), with decreases evident in one-third of the participants. Furthermore due to CFE supplementation, a significant decrease (P ≤ 0.05) was recorded in the category of behavior and a decrease in hyperphagia (n = 8, P = 0.009) was observed at the highest dose 1,000 mg/day (recommended adult dose). There were no reported adverse effects at any dose. Conclusion: We demonstrate that an extract of the Indian cactus succulent Caralluma fimbriata eases hyperphagic appetite behavior within a cohort of children and adolescents (n = 15) with PWS without notable adverse effects. The outcomes of this study will have a potential positive impact on PWS management.
... Studies in animals report similar attenuation of food intake, and importantly comprehensive toxicity assessments assure the safety of treatment CFE (Odendaal et al., 2013;Sakore, Patil, & Surana, 2012). However, characterization of the mechanism of action of CFE remains hypothetical (Kamalakkannan, Rajendran, Venkatesh, Clayton, & Akbarsha, 2010Komarnytsky, Esposito, Rathinasabapathy, Poulev, & Raskin, 2013;Rajendran et al., 2014). Observations in animals include improvements in the lipid profile and reduction in levels of leptin and/or blood glucose (Ambadasu, Dange, & Wali, 2013). ...
... Further, in mouse-derived 3T3-L1 cell lines, CFE has inhibited preadipocyte cell division during adipogenesis in a dose and time-dependent manner (Kamalakkannan, Rajendran, Venkatesh, Clayton, & Akbarsha, 2010). It is proposed that CFE's mechanism of action involves the pregnane glycosides, both as an antihyperglycemic (Priya, Rajaram, & Sureshkumar, 2014) and as an antinociceptive (Rajendran et al., 2014) and that the various steroidal glycosides increase stimulation of the anorexigenic melanocortin pathway (Komarnytsky et al., 2013). These specific hypothalamic appetite pathways are believed to be disturbed due to genetic modifications, one specifically involved in modifying the genetic translation of the 5-HT2c receptor. ...
Article
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Introduction In Prader–Willi syndrome (PWS), nonprotein coding small nucleolar (sno) RNAs are involved in the paternally deleted region of chromosome 15q11.2‐q13, which is believed to cause the hyperphagic phenotype of PWS. Central to this is SnoRNA116. The supplement Caralluma fimbriata extract (CFE) has been shown to decrease appetite behavior in some individuals with PWS. We therefore investigated the mechanism underpinning the effect of CFE on food intake in the Snord116del mouse. Experiments utilized appetite stimulants which included a 5‐hydroxytryptamine (5‐HT) 2c receptor antagonist (SB242084), as the 5‐HT2cR is implicated in central signaling of satiety. Methods After 9‐week chronic CFE treatment (33 mg or 100 mg kg⁻¹ day⁻¹) or placebo, the 14‐week‐old Snord116del (SNO) and wild‐type mice (n = 72) were rotated through intraperitoneal injections of (a) isotonic saline; (b) 400 mg/kg of 2‐deoxyglucose (2DG) (glucose deprivation); (c) 100 mglkg beta‐mercaptoacetate (MA), fatty acid signaling; and (d) SB242084 (a selective 5HT2cR antagonist), with 5 days between reagents. Assessments of food intake were from baseline to 4 hr, followed by immunohistochemistry of neural activity utilizing c‐Fos, neuropeptide Y, and alpha‐melanocyte‐stimulating hormone within hypothalamic appetite pathways. Results Caralluma fimbriata extract administration decreased food intake more strongly in the SNO100CFE group with significantly stimulated food intake demonstrated during coadministration with SB242084. Though stimulatory deprivation was expected to stimulate food intake, 2DG and MA resulted in lower intake in the snord116del mice compared to the WT animals (p = <0.001). Immunohistochemical mapping of hypothalamic neural activity was consistent with the behavioral studies. Conclusions This study identifies a role for the 5‐HT2cR in CFE‐induced appetite suppression and significant stimulatory feeding disruptions in the snord116del mouse model.
... Another study was conducted to check the limitation of CFE, resulted in no reported adverse effects at the recommended dose of 1000 mg/kg [30]. Moreover, an efficacy study revealed that it was found to be nontoxic even up to the dose of 2000 mg/kg body weight [103]. ...
Article
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Metabolic syndrome (MS), commonly known as syndrome X or insulin resistance syndrome, is a collection of risk factors for cardiovascular diseases and type II diabetes. MS is believed to impact over a billion individuals worldwide. It is a medical condition defined by visceral obesity, insulin resistance, high blood pressure, and abnormal cholesterol levels, according to the World Health Organization. The current dietary trends are more focused on the use of functional foods and nutraceuticals that are well known for their preventive and curative role against such pathological disorders. Caralluma fimbriata is one such medicinal plant that is gaining popularity. It is a wild, edible, succulent roadside shrub with cactus-like leaves. Besides its main nutrient contents, various bioactive constituents have been identified and linked with positive health outcomes of appetite-suppressing, hypolipidemic, antioxidant, hepatoprotective, and anticancer potentials. Hence, such properties make C. fimbriata an invaluable plant against MS. The current review compiles recent available literature on C. fimbriata’s nutritional composition, safety parameters, and therapeutic potential for MS. Summarized data in this review reveals that C. fimbriata remains a neglected plant with limited food and therapeutic applications. Yet various studies explored here do prove its positive health-ameliorating outcomes.
... The time spent by the animal exploring the novel (tB) and familiar (tA) objects was measured over the course of 5 min (Mali et al. 2021). (tB/tBCtA) was used to construct the discrimination index (DI) (Ennaceur and Delacour 1998;Rajendran et al. 2014). ...
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Neurocognition is a severe, neurological challenge caused due to sevoflurane application for induction of anaesthesia. The plan of this study is to investigate the effect of fingolimod loaded niosomes on the cognitive impairment induced by sevoflurane. Span 40 and cholesterol were used in reverse phase evaporation techniques for the preparation of fingolimod -loaded niosomes. The positively charged niosomes were obtained by using chloride salts of 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP). The Fingolimod loaded niosomes has average particle size of 223.5 nm and the surface charge measured as + 8.7 ± 1.2 mV in presence of DOTAP. The Fingolimod loaded niosomes formulation shows higher entrapment efficiency. Fingolimod loaded positively charged niosomes were efficiently retained drug and increase the sustain release property. Fingolimod niosomes increases the spontaneous alternation in Y maze and reduces the escape latency in the Morris water maze test, which leads to significant (p < 0.01) improvement in spatial short-term and long-term memory. The neuronal death in the hippocampus due to the sevoflurane exposure was attenuated by fingolimod loaded niosomes, which was proved by histopathological study. It could be defined that fingolimod loaded niosomes attenuates the sevoflurane induced cognitive impairment.
... On the second day of the test, one of the objects presented in the first day was replaced with a new object and the time spent by the animal to explore the new object (tB) and the familiar (tA) objects was recorded for 5 min (Kulkarni et al., 2011). The discrimination index (DI) was calculated as (tB/(tB + tA) (Ennaceur and Delacour, 1988;Rajendran et al., 2014). ...
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Melissa officinalis L. is used in traditional European and Iranian folk medicines to treat a plethora of neurological diseases including epilepsy. We utilized the in vitro and in vivo models of epilepsy to probe the anticonvulsant potentials of essential oil from M. officinalis (MO) to gain insight into the scientific basis for its applications in traditional medicine for the management of convulsive disorders. MO was evaluated for effects on maximal electroshock (MES) and pentylenetetrazole (PTZ) -induced seizures in mice, on 4–aminopyridine (4-AP)-brain slice model of epilepsy and sustained repetitive firing of current clamped neurons; and its ameliorative effects were examined on seizure severity, anxiety, depression, cognitive dysfunction, oxidative stress and neuronal cell loss in PTZ-kindled rats. MO reversibly blocked spontaneous ictal-like discharges in the 4-AP-brain slice model of epilepsy and secondary spikes from sustained repetitive firing, suggesting anticonvulsant effects and voltage-gated sodium channel blockade. MO protected mice from PTZ– and MES–induced seizures and mortality, and ameliorated seizure severity, fear-avoidance, depressive-like behavior, cognitive deficits, oxidative stress and neuronal cell loss in PTZ–kindled rats. The findings warrant further study for the potential use of MO and/or its constituent(s) as adjunctive therapy for epileptic patients.
... In spite of its traditional use, the scientific evidence on the C. fimbriata efficacy is poor, and the majority of the available literature should be examined critically since a high proportion of studies are sponsorized and/or funded just by the company involved in preparation and/or M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 2 marketing of the C. fimbriata commercial extracts (Kuriyan et al., 2007;Odendaal et al 2013;Lakshmi et al, 2014;Rajendran et al, 2014;Sudhakara et al., 2014). ...
Article
Caralluma fimbriata Wall. is currently used as a “natural slimming” food supplement, likely due to its content in pregnane glycosides. In the present study, a commercially available Caralluma fimbriata extract (Slimaluma®; CFE, 100 mg/kg) has been evaluated for its ability to affect the ingestive behaviour in female rats, also with reference to the modulation of brain neuropeptides NPY and ORX.The interference of CFE with α-amylase and lipase has been investigated in vitro, as possible peripheral mechanism of action. Also, the chemical composition of CFE has been assessed by NMR and spectrophotometric analysis.
... In spite of its traditional use, the scientific evidence on the C. fimbriata efficacy is poor, and the majority of the available literature should be examined critically since a high proportion of studies are sponsorized and/or funded just by the company involved in preparation and/or marketing of the C. fimbriata commercial extracts (Kuriyan et al., 2007;Odendaal et al., 2013;Lakshmi et al., 2014;Rajendran et al., 2014;Sudhakara et al., 2014). ...
Article
Caralluma fimbriata (Apocynaceae) is mainly employed as nutritional supplement to reduce body weight (Dutt et al, 2012) due to the presence of pregnane glycosides, also contained in other plants, all used as “natural” slimming essences. Nowadays, there is only few scientific evidence over the efficacy and safety of C. fimbriata. (Odendaal et al, 2013) The aim of this study is to investigate the effects of a standardized extract of C. fimbriata (Slimaluma ®) for a prolonged treatment (58 days). 18 normal weight female Wistar rats were randomly assigned to a control and a C. fimbriata treated groups. Animal body weight, food and water consumption were recorded three times a week. Blood, liver, intestine and brain (hypothalamus and cerebral cortex) samples were collected and used for clinical chemical tests, histomorphological and ultrastructural investigations and also immunohistochemical evaluation of NPY expression. The results have not highlighted any significant effect in control and treated rats on body weight, haematic and metabolic parameters (insulin, glycaemia, HOMA-IR, AST, ALT, GGT, ALP, LDH, HDL, total cholesterol, triglycerides, amylase, lipase, total proteins), liver and gut structure and ultrastructure. A significant increase in food and water consumption was found in treated rats without any increase of animal body weight; moreover an increase of NPY was found in the cerebral cortex and hypothalamic arcuate nucleus. The C. fimbriata administration seems related to a modified distribution of NPY, as orexigenic neuromediator, in CNS.
Article
The analgesic, antidiarrheal, and neuro-pharmacological potentials of Medicago denticulata leaves extract were screened in animal models. Potential analgesic response was noted (*P<0.05, **P<0.01, ***P<0.001) in formalin, acetic acid and heat-induced pain models in a dose-dependent manner. Maximum activity by means of writhing inhibition was documented for Medicago denticulata at 300mg/kg that was found to be 71.79 % (17.43±1.31). In first phase, the Medicago denticulata at a dose of 150 and 300mg/kg showed analgesic activity and reduced the pain by 54.18% (18.39±1.67) and 62.90% (14.89±1.56), respectively. In second phase, the Medicago denticulata at a dose of 150 and 300mg/kg showed analgesic activity and reduced the pain by 69.48% (19.78±1.44) and 70.89% (18.86±1.58), respectively. In hot plate method, the Medicago denticulata at a dose of 150 and 300mg/kg showed the maximum response of 61.16% (8.47±1.23) and 67.39% (10.09±1.04), respectively at 60min. Scopolamine significantly reduces spontaneous alteration in Y-maze model for antiamnesic activity. Medicago denticulata significantly increased the discrimination index in a dose-dependent manner using novel object recognition test (NORT) model. Exploration time in sec for the novel object was increased significantly (P<0.001) by donepezil decreased for familiar one with a discrimination index (DI) of 62.18%. Medicago denticulata significantly increased the discrimination index by 60.86% and 57.24% at 300 and 150 mg/kg b.w, respectively. The lowest DI of 53.80% at 75 mg/kg was observed in comparison to the amnesic group. The Medicago denticulata significant decreased the elevated levels of acetylcholinesterase (AChE) and malondialdehyde (MDA and enhancing level of acetylcholine (ACh), superoxide dismutase (SOD) and catalase (CAT) acting as an antioxidant agent. Medicago denticulata reduced the total number of diarrheal feces to lesser extent at dose-dependent manner. From the study results, it is suggested that the Medicago denticulata extract possess good analgesic and antiamnesic activity however the antidiarrheal effects of plant were negligible. In the current study, the traditional use of the plant as a source of medicine has been validated.
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Alzheimer's disease (AD) is an age‐associated neurodegenerative disease, which is developed by oxidative stress and acetylcholine contraction in the synaptic cleft of the neurons. This leads to dementia, memory loss, and decrease in learning ability and orientation. In this research work, we aimed to explore the neuroprotective effect of neferine on AlCl3‐induced AD in rats. The results of our study revealed that the increased reactive oxygen species (ROS) and nitric oxide in the hippocampus leads to the development of AD in the rats. The oral treatment of neferine done the following occurrences such as; it potentially inhibited the ROS formation and acts as a scavenging molecule by preventing the neurodegeneration. It also improved the memory and learning ability to complete the maze activity in the AD rats and significantly increased the antioxidants superoxide dismutase, catalase, and reduced glutathione in neferine treated AD rats. It aggressively declined the activity of acetylcholine esterase and Na+K+ATPase in the neurodegenerative rat models. The gene expression pattern of neuroinflammatory cytokines such as tumor necrosis factor α (TNF‐α), interleukin‐6 (IL‐6), and interleukin‐1β (IL‐1β) were decreased in the neferine‐treated rats. The neuroinflammatory proteins such as inducible nitric oxide (iNOS), cyclooxygenase‐2 (COX‐2), and nuclear factor kappa β (Nf‐κβ) were decreased and Nf‐κβ inhibitor IKBα was increased in the neferine‐treated AD rats. Finally, the histology study proved that the neferine treatment possibly prevents neurodegeneration in the hippocampus tissue of the AD models. Hence, these all findings concluded that the neferine could be a potential neuropreventive as well as neurodegenerative therapeutic compound in neurological and cognitive dysfunction.
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The roots and rhizomes of Glycyrrhiza glabra (Leguminosae) have been used in the traditional system of medicine for their antiinflammatory, antiulcer, expectorant and antimicrobial activities.They are also reported to have anxiolytic and antidepressant properties in mice.The present study was under taken to investigate the effect of Glycyrrhiza glabra on learning and memory in rats.Spatial learning T-maze and passive avoidance paradigm were employed to test learning and memory.Three doses of(100,200,300mg/ kg p.o) of the aqueous extract of Glycyrrhiza glabra were administered for 15 days in separate group of animals. The aqueous extract significantly improved spatial learning performance and retention of memory in rats. Furthermore 300mg/kg p.o of this extract significantly reversed the amnesia induced by scopalamine(0.5mg/kg i.p.)Anti oxidant property of Glycyrrhiza glabra may be contributing favourably to the memory enhancement effect.Since scopolamine induced amnesia was reversed by Glycyrrhiza glabra, it is possible that the beneficial effect on learning and memory was due to facilitation of cholinergic.
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Learning is a continual process and our brain keeps track of events taking place in our lives, consciously or subconsciously. The capacities of learning, understanding and memory are all crucial for one's growth. Scientists are trying their level best to find out the root cause of Alzheimer's disease. We have endeavored to throw light on neurochemical mechanisms of learning and memory. The implication of cholinergic system, adrenergic system, dopaminergic system, serotonergic system, GABA-ergic system, benzodiazepine-receptors, NMDA, neuropeptides, histamine, insulin, estrogens, nitric oxide, oxygen free-radicals and platelet activating factor have all been discussed in the updated review article. Future drugs and new strategies for prevention of Alzheimer's disease have also been incorporated at the end.
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The term working memory refers to a brain system that provides temporary storage and manipulation of the information necessary for such complex cognitive tasks as language comprehension, learning, and reasoning. This definition has evolved from the concept of a unitary short-term memory system. Working memory has been found to require the simultaneous storage and processing of information. It can be divided into the following three subcomponents: (i) the central executive, which is assumed to be an attentional-controlling system, is important in skills such as chess playing and is particularly susceptible to the effects of Alzheimer's disease; and two slave systems, namely (ii) the visuospatial sketch pad, which manipulates visual images and (iii) the phonological loop, which stores and rehearses speech-based information and is necessary for the acquisition of both native and second-language vocabulary.
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The above article has been retracted by agreement between the author, the Editor-in-Chief of Phytotherapy research (PTR) and John Wiley & Sons,Ltd. The retraction has been agreed due to inclusion of data in this paper from that published in the Indian Journal of Physiology and Pharmacology, 1992 36(1) 29-34 (PMID: 1597339) by SK Kulkarni and A. Verma 'Evidence for notropic effect of BR-16A (Mentat), a herbal psychotropic preperation, in mice' . The origin of the material in question was not correctly attributed to the authors Kulkarni and Verma
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Benzodiazepines present problems related to both unwanted and withdrawal effects. Dosage adjustments usually obviate unwanted effects except for paradoxical reactions such as hostility. Patients with apparent benzodiazepine dependence need careful assessment with respect to personality, social situation and psychiatric disorder. The patient must be motivated and carefully prepared for withdrawal and taught anxiety management techniques. Withdrawal must always be gradual over at least 6 weeks but very prolonged schedules are counter-productive. Substituting a long-acting for a medium-acting benzodiazepine may be helpful in the more intractable cases. An antidepressant may be needed if a depressive disorder supervenes, but other adjunctive therapies are usually unhelpful.
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To investigate whether an elevated plus-maze consisting of two open and two closed arms could be used as a model of anxiety in the mouse, NIH Swiss mice were tested in the apparatus immediately after a holeboard test. Factor analysis of data from undrugged animals tested in the holeboard and plus-maze yielded three orthogonal factors interpreted as assessing anxiety, directed exploration and locomotion. Anxiolytic drugs (chlordiazepoxide, sodium pentobarbital and ethanol) increased the proportion of time spent on the open arms, and anxiogenic drugs (FG 7142, caffeine and picrotoxin) reduced this measure. Amphetamine and imipramine failed to alter the indices of anxiety. The anxiolytic effect of chlordiazepoxide was reduced in mice that had previously experienced the plus-maze in an undrugged state. Testing animals in the holeboard immediately before the plus-maze test significantly elevated both the percentage of time spent on the open arms and the total number of arm entries, but did not affect the behavioral response to chlordiazepoxide. The plus-maze appears to be a useful test with which to investigate both anxiolytic and anxiogenic agents.
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A novel test for the selective identification of anxiolytic and anxiogenic drug effects in the rat is described, using an elevated + -maze consisting of two open arms and two enclosed arms. The use of this test for detecting such drug effects was validated behaviourally, physiologically, and pharmacologically. Rats made significantly fewer entries into the open arms than into the closed arms, and spent significantly less time in open arms. Confinement to the open arms was associated with the observation of significantly more anxiety-related behaviours, and of significantly greater plasma corticosterone concentrations, than confinement to the closed arms. Neither novelty nor illumination was a significant contributor to the behaviour of the rats on the + -maze. A significant increase in the percentage of time spent on the open arms and the number of entries into the open arms was observed only within clinically effective anxiolytics (chlordiazepoxide, diazepam and, less effectively, phenobarbitone). Compounds that cause anxiety in man significantly reduced the percentage of entries into, and time spent on, the open arms (yohimbine, pentylenetetrazole, caffeine, amphetamine). Neither antidepressants nor major tranquilisers had a specific effect. Exposure to a holeboard immediately before placement on the + -maze showed that behaviour on the maze was not clearly correlated either with exploratory head-dipping or spontaneous locomotor activity.