Download PDF - SAGE Journals

515038
research-article2014
JRA0010.1177/1470320313515038Journal of the Renin-Angiotensin-Aldosterone SystemThakur et al.
Original Article
Beneficial effect of candesartan and
lisinopril against haloperidol-induced
tardive dyskinesia in rat
Journal of the Renin-AngiotensinAldosterone System
2015, Vol. 16(4) 917­–929
© The Author(s) 2014
Reprints and permissions:
sagepub.co.uk/journalsPermissions.nav
DOI: 10.1177/1470320313515038
jra.sagepub.com
Kuldeep Singh Thakur, Atish Prakash, Rohit Bisht and Puneet
Kumar Bansal
Abstract
Introduction: Tardive dyskinesia is a serious motor disorder of the orofacial region, resulting from chronic neuroleptic
treatment of schizophrenia. Candesartan (AT1 antagonist) and lisinopril (ACE inhibitor) has been reported to possess
antioxidant and neuroprotective effects. The present study is designed to investigate the effect of candesartan and
lisinopril on haloperidol-induced orofacial dyskinesia and oxidative damage in rats.
Materials and methods: Tardive dyskinesia was induced by administering haloperidol (1 mg/kg i.p.) and concomitantly
treated with candesartan (3 and 5 mg/kg p.o.) and lisinopril (10 and 15 mg/kg p.o.) for 3 weeks in male Wistar rats.
Various behavioral parameters were assessed on days 0, 7, 14 and 21 and biochemical parameters were estimated at
day 22.
Results: Chronic administration of haloperidol significantly increased stereotypic behaviors in rats, which were significantly
improved by administration of candesartan and lisinopril. Chronic administration of haloperidol significantly increased
oxidative stress and neuro-inflammation in the striatum region of the rat’s brain. Co-administration of candesartan and
lisinopril significantly attenuated the oxidative damage and neuro-inflammation in the haloperidol-treated rat.
Conclusions: The present study supports the therapeutic use of candesartan and lisinopril in the treatment of typical
antipsychotic-induced orofacial dyskinesia and possible antioxidant and neuro-inflammatory mechanisms.
Keywords
Haloperidol, tardive dyskinesia, oxidative damage, candesartan, lisinopril
Introduction
Tardive dyskinesia (TD) is a disabling and potentially irreversible motor complication encompassing all persistent,
abnormal, involuntary hyperkinetic movements occurring
in the setting of chronic therapy with dopamine receptorblocking agents, such as antipsychotic drugs.1,2 Various
theories have been put forward to understand the neuropathology of TD. Some of these include dopaminergic hypersensitivity, disturbed balance between dopamine and
cholinergic systems, dysfunctions of striatonigral
GABAergic neurons and excitotoxicity.3 Unfortunately
the symptoms persist even after the withdrawal of typical
antipsychotic drugs, indicating that these drugs produce
some long term alterations in brain tasks that are no longer
associated with drug usage.4
Recently it has been found that the long term use of
some antipsychotic drugs can also produce some severe
symptoms of TD.5 Haloperidol is an antipsychotic drug
used for the treatment of schizophrenia and is used frequently in animal models to study the pathogenesis of
TD.2,3 It is well established that haloperidol and other
typical antipsychotic drugs (D2 receptor antagonists)
upregulate dopamine D2 receptors. This led to the suggestion that late-onset dyskinesia was a reflection of dopamine receptor supersensitivity.6 However, several
observations indicate that D2 receptor upregulation alone
is not sufficient to account for TD. Therefore the pathophysiological mechanism of haloperidol-induced TD is
still not clear.
Oxidative stress has also been involved in the pathophysiology of TD.3,7 Oxidative stress increases the release
of inflammatory mediators like TNF-α and interleukin1-beta (IL-1β), IL-6 which initiate the apoptotic pathway,
a central mechanism of neuronal cell death.2,8 It has been
Department of Pharmacology, Indo-Soviet Friendship College of
Pharmacy, India
Corresponding author:
Atish Prakash, Pharmacology Division, Indo-Soviet Friendship College
of Pharmacy, Moga, 142001, Punjab, India.
Email: [email protected]
918
reported that chronic treatment with haloperidol was found
to decrease the expression of the GLT-1 transporter in the
glutamatergic synapses in the rat striatum and also induce
extrapyramidal side effects like Parkinsonism, akathisia,
muscular dystonia and TD.9,10 Furthermore, chronic
administration of haloperidol may mobilize arachidonic
acid, which can produce various inflammatory prostaglandins and cause neuronal cell death.11,12
The renin-angiotensin system (RAS) is one of the
important systems in the body that helps to regulate blood
pressure and fluid homeostasis.13,14 The various antagonists of the RAS have been used as anti-hypertensive
agents but recently the RAS system has been found to play
an important role in various CNS disorders.15–17
Upregulation of the RAS has been reported to occur in
CNS pathological conditions including degenerative disorders.14,18 Moreover blockade of AT1 receptor has been
reported to produce neuroprotection in cerebral stroke and
other neurodegenerative disorders.19,20 Lisinopril (ACE
inhibitor) has also shown neuroprotection through inhibition of the RAS.14 Candesartan (AT1 receptor blocker) has
also been reported to activate PPAR-γ, inhibit microglial
activation and prevent dopaminergic neuronal loss.21
Thus keeping in view of the RAS, the present study
investigated the possible role of the RAS in haloperidolinduced TD in rats and more specifically to study the effect
of candesartan (AT1 receptor blocker) and lisinopril (ACE
inhibitor) in haloperidol-induced TD in rats.
Methods and materials
Experimental animals
Male Wistar rats, weighing 180–250 g (4–6 months old)
were bred in the Central Animal House of I.S.F. College of
Pharmacy, Moga, Punjab and were used in the study.
Animals were acclimatized to laboratory conditions at
room temperature prior to experimentation. Animals were
kept under standard conditions of a 12 h light/dark cycle
with food and water ad libitum in plastic cages with soft
bedding. All the behavioral assessments were carried out
between 9:00 and 15:00 hrs. The experimental protocol
was approved by the Institutional Animal Ethics Committee
(IAEC) with the registration no. ISF/IAEC/73/5/2012 and
were carried out in accordance with the guidelines of the
Indian National Science Academy (INSA) for the use and
care of the experimental animals.
Drugs and treatment schedule
Candesartan (Biocon Ltd., Bangalore, India) and lisinopril
(Ind-Swift Laboratories Ltd., Baddi, Himachal Pradesh,
India) were suspended in 1% Na carboxymethyl cellulose
(CMC) respectively; the suspension was always freshly
prepared and mixed well. Haloperidol was obtained from
Journal of the Renin-Angiotensin-Aldosterone System16(4)
the market under the trade name of Trancodol (Intas
Pharmaceuticals Ltd., Matoda, Dist. Ahmadabad, India).
The vehicle used for haloperidol was distilled water.
Candesartan and lisinopril were given orally and haloperidol given intraperitoneally in a constant volume of 0.5 ml
per 100 g of body weight of rat. Doses were selected on the
basis of previous studies in the laboratory and those
reported in the literature.20–23 The animals were selected
randomly based on their body weight into nine groups and
each group comprised six animals. The study was performed in multiple phases as shown in the experimental
protocol (Scheme 1). The animals were segregated into the
following groups:
Scheme No.
Group
1
Control
2
Haloperidol (1)
3
Candesartan (5) Per Se
4
Haloperidol (1) + Candesartan (3)
5
Haloperidol (1) + Candesartan (5)
6
Lisinopril (15) Per Se
7
Haloperidol (1) + Lisinopril (10)
8
Haloperidol (1) + Lisinopril (15)
9 Haloperidol (1) + Candesartan (3) +
Lisinopril (10)
Induction of TD
Haloperidol at a dose of 1 mg/kg i.p. was administered
chronically to the rats for a period of 21 days to induce TD.
All the behavioral assessments were carried out every
week and the last behavioral quantification was done 24
hours after the last dose of haloperidol.24
Behavioral assessments
Assessment of orofacial dyskinesia. On the test day rats were
placed individually in a small Plexiglas cage (30 × 20 × 30
cm) for the assessment of oral dyskinesia. Animals were
given 10 min to get acclimatized to the observation cage
before the behavioral assessments began. To quantify the
occurrence of oral dyskinesia, hand operated counters were
employed to score tongue protrusion and vacuous chewing
movements (VCMs). In the present study, VCMs are
referred to as single mouth openings in the vertical plane
not directed toward physical material. If tongue protrusion
or VCMs occurred during the period of grooming, they
were not taken into account. Counting was stopped whenever the rat began grooming and restarted when grooming
stopped. Mirrors were placed under the floor and behind
the back wall of the cage to permit observation when the
animal faced away from the observer. The behavioral
parameters of oral dyskinesia were measured continuously
for a period of 10 min. In all the experiments, the scorer
was unaware of the treatment given to the animals.2
Thakur et al.
Elevated plus maze. The elevated plus maze consists of
two opposite white open arms (16 × 5 cm), crossed with
two closed walls (16 × 5 cm) with 12 cm high walls. The
arms were connected with a central square of dimensions
5 × 5 cm. The entire maze was placed 25 cm high above
the ground. Acquisition of memory was tested on day 20.
Mice were placed individually at one end of the open arm
facing away from the central square. The time taken by
the animal to move from the open arm to the closed arm
was recorded as the initial transfer latency (ITL). Animals were allowed to explore the maze for 10 s after
recording the ITL. If the animal did not enter the enclosed
arm within 90 s, it was guided to the enclosed arm and the
ITL was recorded as 90 s. Retention of memory was
assessed by placing the mouse in an open arm and retention latency was assessed on day 21 and day 42 of the
ITL, termed as the first retention transfer latency (1st
RTL) and second retention transfer latency (2nd RTL),
respectively.25
Locomotor activity. Locomotor activity was monitored by
using an actophotometer (Medicraft, INCO, Ambala, Haryana, India), which operates on photoelectric cells connected in a circuit with a counter. Before subjecting the
animals to a cognitive task, all the animals were individually placed in the activity meter and the total activity count
was measured for 10 min. The locomotor activity was
expressed in terms of total photobeam counts per 10 min
per animal.8,26
Rota-rod activity. Motor co-ordination was assessed for all
rats on a rota-rod. Rats were placed individually on a rotating rod with a rod of 7 cm (speed 25 rpm). Prior to any
treatment, rats were trained in a single session until they
attained 180 seconds on the rota-rod. Fall off time was
recorded during drug treatment every week.27
Assessment of grip strength. The grip strength test is a
widely-used non-invasive method designed to evaluate
mouse limb strength. It has been used to investigate the
effects of neuromuscular disorders and drugs. It is based
on the natural tendency of the mouse to grasp a bar or grid
when it is suspended by the tail. During this test the mouse
grips with either both forelimbs or hind-limbs to a single
bar or a mesh. Metering is performed with precision force
gauges in such a manner as to retain the peak force applied
on a digital display. The values may be either recorded
manually or automatically via an optional RS-232 interface available on the computerized model(s).28–31
Stereotypic behavior assessment. Different stereotypic
behaviors (rearing, sniffing and grooming) were measured
in different animal groups. Each animal was placed individually in a 1000 ml beaker and various behaviors (rearing, sniffing and grooming) were scored for the time period
919
of 10 min. All three parameters were scored as ++++ =
very high, +++ = high, ++ = moderate, + = low.8
Dissection and homogenization. On day 22, all the animals
were sacrificed by decapitation immediately 24 h after
behavioral assessments. The brains were removed, forebrain was dissected out and cerebellum was discarded.
Brains were put on the ice and the cortex and striatum
regions were separated and weighed. A 10% (w/v) tissue
homogenate was prepared in 0.1 mol/1 phosphate buffer
(pH 7.4). Homogenate was centrifuged for 20 min at
20,000 rpm and supernatant was stored in 80°C for assessing the biochemical parameters.
Biochemical assessment. Biochemical tests were conducted
24 hours after the last behavioral test. The animals were
sacrificed by decapitation. Brains were removed and
rinsed with ice-cold isotonic saline. Brains were then
homogenized with ice-cold 0.1 mmol/L phosphate buffer
(pH 7.4). The homogenate (10% w/v) was then centrifuged
at 10,000 g for 15 min and the supernatant formed was
used for the biochemical estimations.
Estimation of lipid peroxidation assay. The extent of lipid
peroxidation in the brain was determined quantitatively by
performing the method as described by Wills.32 The
amount of malondialdehyde (MDA) was measured by
reaction with thiobarbituric acid at 532 nm using a Perkin
Elmer Lambda 20 spectrophotometer. The values were
calculated using the molar extinction co-efficient of
chromophore (1.56 × 105 (mol/l)-1cm-1).
Estimation of nitrite. The accumulation of nitrite in the
supernatant, an indicator of the production of nitric
oxide, was determined by a colorimetric assay with
Griess reagent (0.1 % N-(1-napththyl) ethylene diamine
dihydrochloride, 1% sulphanilamide and 5% phosphoric
acid).33 Equal volumes of the supernatant and the Griess
reagent were mixed and the mixture was incubated for
10 min at room temperature in the dark. The absorbance
was measured at 540 nm using a Perkin Elmer Lambda
20 spectrophotometer. The concentration of nitrite in the
supernatant was determined from sodium nitrite standard curve.
Estimation of reduced glutathione. Reduced glutathione
was estimated according to the method described by Ellman.34 Supernatant (1 ml) was precipitated with 4% sulphosalicylic acid (1 ml) and cold digested for 1 hour at
4°C. The samples were then centrifuged at 1,200 g for 15
min at 4°C. To 1 ml of the supernatant obtained, 2.7 ml of
phosphate buffer (0.1 mmol/l, pH 8) and 0.2 ml of 5, 5’
dithio-bis (2-nitrobenzoic acid) (DTNB) was added. The
yellow color developed was measured at 412 nm using a
Perkin Elmer Lambda 20 spectrophotometer. Results
920
Journal of the Renin-Angiotensin-Aldosterone System16(4)
were calculated using molar extinction co-efficient of the
chromophore (1.36 × 104 (mol/l)-1cm-1).
between groups were made using Tukey’s test. P<0.05 was
considered significant.
Estimation of antioxidant enzyme activity
Results
Estimation of superoxide dismutase activity. Superoxide
dismutase (SOD) activity was assayed by the method of
Kono.35 The assay system consists of EDTA 0.1 mM,
sodium carbonate 50 mM and nitro blue tetrazolium
(NBT) 96 mM. In the cuvette, 2 ml of the above mixture,
0.05 ml of hydroxylamine and 0.05 ml of the supernatant
was added and auto-oxidation of hydroxylamine was
measured for 2 min at 30 s intervals by measuring absorbance at 560 nm using a Perkin Elmer Lambda 20
spectrophotometer.
Effect of candesartan and lisinopril on orofacial
dyskinesia in haloperidol-treated rats
Estimation of catalase activity. Catalase activity was
assessed by the method of Luck,36 wherein the breakdown
of H2O2 is measured. Briefly, the assay mixture consists of
3 ml of H2O2 phosphate buffer and 0.05 ml of the supernatant of the tissue homogenate. The change in absorbance
was recorded for 2 min at 30 s intervals at 240 nm using a
Perkin Elmer Lambda 20 spectrophotometer. The results
were expressed as micromoles of hydrogen peroxide
decomposed per min per mg of protein.36
Protein estimation. The protein was measured by the Biuret method using bovine serum albumin (BSA) as a
standard.37
Estimation of TNF-α and IL-1β levels. The quantification of
TNF-α and IL-1β was completed with the help and instructions provided by Ray Biotech. Inc. Quantikine rat TNF-α,
IL-1β immunoassay kits. The assays employ the sandwich
enzyme immunoassay technique. A monoclonal antibody
specific for rat TNF-α and IL-1β are pre-coated in the
microplate. Standards, control and samples were pipetted
into the wells and any rat-TNF-α or IL-1β present is bound
by the immobilized antibody. After washing away any
unbound substance an enzyme-linked polyclonal antibody
specific for rat TNF-α and IL-1β is added to the wells. Following a wash to remove any unbound antibody-enzyme
reagent, a substrate solution is added to the wells. The
enzyme reaction yields a blue product that turns yellow
when the stop solution is added. The intensity of the color
measured is in proportion to the amount of rat TNF-α and
IL-1β bound in the initial steps. The sample values are then
read off the standard curve.
Statistical analysis. Values are expressed as mean ± S.E.M.
The behavioral assessment data were analyzed by repeated
measures two-way analysis of variance (ANOVA) with
drug-treated groups as between and sessions as the withinsubjects factors. The biochemical estimations were separately analyzed by one-way ANOVA. Post hoc comparisons
Chronic administration of haloperidol resulted in timedependent increases in VCMs, tongue protrusion and
facial jerking in rats. However, concomitant administration of candesartan (3 and 5 mg/kg) and lisinopril (10 and
15 mg/kg) alone significantly improved the haloperidolinduced behavioral abnormalities in rats (P<0.05). Further,
a combination of subtheraputic doses of candesartan and
lisinopril (3 and 10 mg/kg) significantly potentiated the
therapeutic effects as compared to treatment with one drug
alone. Candesartan (5 mg/kg) and lisinopril (15 mg/kg)
per se did not produce any significant change in the orofacial dyskinesia as compared to control (Figures 1, 2 and 3).
Effect of candesartan and lisinopril on
stereotypic rearing behavior in haloperidoltreated rats
Chronic administration of haloperidol showed a timedependent decrease in stereotypic rearing behavior up to
the 7th day which there after increased time dependently up
to the last behavioral quantification. However, concomitant administration of candesartan (3 and 5 mg/kg) and
lisinopril (10 and 15 mg/kg) alone significantly improved
the stereotypic (rearing, sniffing and grooming) behavior
in haloperidol-induced rats (P<0.05). Further, combination of subtheraputic doses of candesartan and lisinopril (3
and 10 mg/kg) significantly potentiated the therapeutic
effect as compared to treatment with one drug alone.
Candesartan (5 mg/kg) and lisinopril (15 mg/kg) per se did
not produce any significant change in the stereotypic rearing behavior as compared to control (Figure 4).
Effect of candesartan and lisinopril on body
weight in haloperidol-treated rats
Body weight was significantly decreased in chronically haloperidol-treated (21 days) rats. However, co-administration
of candesartan (3 and 5 mg/kg) and lisinopril (10 and 15mg/
kg) alone significantly attenuated the body weight of haloperidol-treated rats dose dependently (P<0.05). Further,
combination of subtherapeutic doses of candesartan and
lisinopril (3 and 10 mg/kg) significantly potentiated the
therapeutic effect as compared to treatment with one drug
alone. Candesartan (5 mg/kg) and lisinopril (15 mg/kg) per
se did not produce any significant change in body weight as
compared to control (Figure 5).
921
Thakur et al.
Figure 1. Effect of candesartan and lisinopril on vacuous chewing movements in haloperidol-treated rats.
Data are expressed as mean ± SEM. ap≤0.05 as compared to control group; bp≤0.05 as compared to haloperidol-treated group; cp≤0.05 as compared
to Halo (1) + Cand (3) group; dp≤0.05 as compared to Halo (1) + Lisino (10) group.
Halo: haloperidol; Cand: candesartan; Lisino: lisinopril; VCMs: vacuous chewing movements.
Figure 2. Effect of candesartan and lisinopril on tongue protrusion in haloperidol treated rats. Data are expressed in mean ± SEM.
ap≤0.05 as compared to control group; bp≤0.05 as compared to haloperidol treated group; cp≤0.05 as compared to Halo (1) +
Cand (3) group; dp≤0.05 as compared to Halo (1) + Lisino (10) group. Halo- Haloperidol; Cand- Candesartan; Lisino- Lisinopril.
Effect of candesartan and lisinopril on
locomotor and rota-rod activity in haloperidoltreated rats
A significant decrease of total locomotor activity and
motor (rota-rod) activity was recorded in rats given chronic
treatment with haloperidol. However, co-administration of
candesartan (3 and 5 mg/kg) and lisinopril (10 and 15 mg/
kg) alone significantly improved the total locomotor activity and motor (rota-rod) activity of haloperidol-treated rats
dose dependently (P<0.05). Further, combination of subtheraputic doses of candesartan and lisinopril (3 and 10
mg/kg) significantly potentiated the therapeutic effect as
compared to treatment with one drug alone. Candesartan
(5 mg/kg) and lisinopril (15 mg/kg) per se did not produce
any significant change in total locomotor activity and
motor (rota-rod) activity as compared to control (Figures 6
and 7).
Effect of candesartan and lisinopril on elevated
plus maze in haloperidol-treated rats
Rats given haloperidol treatment for 21 days showed a
time dependent decrease in retention time as compared to
922
Journal of the Renin-Angiotensin-Aldosterone System16(4)
Figure 3. Effect of candesartan and lisinopril on facial jerking in haloperidol-treated rats.
Data are expressed as mean ± SEM. ap≤0.05 as compared to control group; bp≤0.05 as compared to haloperidol-treated group; cp≤0.05 as compared
to Halo (1) + Cand (3) group; dp≤0.05 as compared to Halo (1) + Lisino (10) group.
Halo: haloperidol; Cand: candesartan; Lisino: lisinopril.
Figure 4. Effect of candesartan and lisinopril on sniffing and grooming in haloperidol-treated rats.
Data are expressed as mean ± SEM. ap≤0.05 as compared to control group; bp≤0.05 as compared to haloperidol-treated group; cp≤0.05 as compared
to Halo (1) + Cand (3) group; dp≤0.05 as compared to Halo (1) + Lisino (10) group.
Halo: haloperidol; Cand: candesartan; Lisino: lisinopril.
the control group on the day of behavioral assessment.
However, co-administration of candesartan (3 and 5 mg/
kg) and lisinopril (10 and 15 mg/kg) dose dependently
increased the retention time in haloperidol-treated rats
(P<0.05). Further, combination of subtherapeutic doses of
candesartan and lisinopril (3 and 10 mg/kg) significantly
potentiated the therapeutic effect as compared to treatment
with one drug alone. Candesartan (5 mg/kg) and lisinopril
(15 mg/kg) per se did not produce any significant change
in retention time as compared to control (Table 1).
Figure 5. Effect of candesartan and lisinopril on body weight
in haloperidol-treated rats.
Data are expressed as mean ± SEM.ap≤0.05 as compared to control
group; bp≤0.05 as compared to haloperidol-treated group; cp≤0.05 as
compared to Halo (1) + Cand (3) group; dp≤0.05 as compared to Halo
(1) + Lisino (10) group.
Halo: haloperidol; Cand: candesartan; Lisino: lisinopril.
Effect of candesartan and lisinopril on grip
strength in haloperidol-treated rats
Grip strength was significantly decreased in chronically
haloperidol-treated rats. However, co-administration of
candesartan (3 and 5 mg/kg) and lisinopril (10 and 15 mg/
923
Thakur et al.
Figure 6. Effect of candesartan and lisinopril on total locomotor activity in haloperidol-treated rats.
Data are expressed as mean ± SEM. ap≤0.05 as compared to control group; bp≤0.05 as compared to haloperidol-treated group; cp≤0.05 as compared
to Halo (1) + Cand (3) group; dp≤0.05 as compared to Halo (1) + Lisino (10) group.
Halo: haloperidol; Cand: candesartan; Lisino: lisinopril.
Figure 7. Effect of candesartan and lisinopril on rota-rod activity in haloperidol-treated rats.
Data are expressed as mean ± SEM. ap≤0.05 as compared to control group; bp≤0.05 as compared to haloperidol-treated group; cp≤0.05 as compared
to Halo (1) + Cand (3) group; dp≤0.05 as compared to Halo (1) + Lisino (10) group.
Halo: haloperidol; Cand: candesartan; Lisino: lisinopril.
Table 1. Effects of candesartan and lisinopril on memory performance in elevated plus maze paradigm in haloperidol-treated rats.
Treatment (mg/Kg)
Day 13 (ITL)
Day 14 (1st RTL)
Day 21 (2nd RTL)
Normal control
Halo (1)
Cand (5) Per se
Halo (1) + Cand (3)
Halo (1) + Cand (5)
Lisino (15) Per se
Halo (1) + Lisino (10)
Halo (1) + Lisino (15)
Halo (1) + Cand (3) + Lisino (10)
60.43 ± 3.70
71.32 ± 4.21
68.08 ± 4.1
65.05 ± 3.9
60.04 ± 3.6
70.04 ± 4.2
66.09 ± 3.4
62.68 ± 3.1
58.08 ± 2.9
30.76 ± 3.60
72.45 ± 4.37a
34.04 ± 3.8
58.78 ± 3.8b
46.37 ± 3.1b,c
33.09 ± 3.9
59.05 ± 4.1b
47.04 ± 3.6b,d
42.05 ± 3.1b,c,d
22.32 ± 3.21
80.24 ± 4.50a
25.05 ± 3.4
40.76 ± 3.2b
29.26 ± 2.9b,c
21.09 ± 3.2
43.32 ± 3.7b
31.23 ± 2.9b,d
42.05 ± 2.7b,c,d
Data are expressed as mean ± SEM. ap≤0.05 as compared to control group; bp≤0.05 as compared to haloperidol-treated group; cp≤0.05 as compared
to Halo (1) + Cand (3) group; dp≤0.05 as compared to Halo (1) + Lisino (10) group.
Halo: haloperidol; Cand: candesartan; Lisino: lisinopril.
924
Journal of the Renin-Angiotensin-Aldosterone System16(4)
Figure 8. Effect of candesartan and lisinopril on grip strength in haloperidol-treated rats.
Data are expressed as mean ± SEM. ap≤0.05 as compared to control group; bp≤0.05 as compared to haloperidol-treated group; dp≤0.05 as compared
to Halo (1) + Cand (3) + Lisino (10) group.
Halo: haloperidol; Cand: candesartan; Lisino: lisinopril.
kg) significantly increased the grip strength of haloperidol-treated rats (P<0.05). Further, combination of subtherapeutic doses of candesartan and lisinopril (3 and 10 mg/
kg) significantly potentiated the therapeutic effect as compared to treatment with one drug alone. Candesartan (5
mg/kg) and lisinopril (15 mg/kg) per se did not produce
any significant change in grip strength as compared to control (Figure 8).
Effect of candesartan and lisinopril on MDA
levels and nitrite concentration in haloperidoltreated rats
Rats given chronic treatment with haloperidol showed a
significant increase of lipid peroxidation and nitrite concentration in the cortex and striatum region of the brain as
compared to control animals. However, co-administration
of candesartan (3 and 5 mg/kg) and lisinopril (10 and 15
mg/kg) alone significantly attenuated the rise level of the
lipid peroxidation and nitrite concentration of haloperidoltreated rats (P<0.05). Further, combination of subtherapeutic doses of candesartan and lisinopril (3 and 10 mg/kg)
significantly potentiated their protective effect as compared to their effect alone per se respectively. Candesartan
(5 mg/kg) and lisinopril (15 mg/kg) per se did not produce
any significant change in lipid peroxidation and nitrite levels as compared to control (Table 2).
Effect of candesartan and lisinopril on endogenous
antioxidant (reduced glutathione, SOD and
catalase levels) in haloperidol-treated rats
Chronic administration of haloperidol to rats significantly
decreased reduced glutathione, SOD and catalase activity
in the cortex and striatum region of the rat’s brain as
compared to control animals. However, co-administration
of candesartan (3 and 5 mg/kg) and lisinopril (10 and 15
mg/kg) alone significantly restored the decreased activities
of reduced glutathione, SOD and catalase in the cortex and
striatum region of brain of haloperidol-treated rats
(P<0.05). Further, combination of subtherapeutic doses of
candesartan and lisinopril (3 and 10 mg/kg) significantly
potentiated their antioxidant effect per se due to their synergistic effect. Candesartan (5 mg/kg) and lisinopril (15
mg/kg) per se did not produce any significant change in
antioxidant enzyme activities as compared to control
(Table 2).
Estimation of TNF-α and IL-1β levels
Chronic treatment of rats with haloperidol resulted in significant increases in the levels of TNF-α and IL-1β in the
cortex and striatum region of the rat brains as compared
to control animals. However, co-administration of candesartan (3 and 5 mg/kg) and lisinopril (10 and 15 mg/kg)
significantly attenuated the increased levels of TNF-α
and IL-1β in cortical and striatum region of the rat brains
(P<0.05). Further, combination of subtheraputic doses of
candesartan and lisinopril (3 and 10 mg/kg) significantly
potentiated the therapeutic effect as compare to treatment
with one drug alone. Candesartan (5 mg/kg) and lisinopril (15 mg/kg) per se did not produce any significant
change in TNF-α and IL-1β levels as compared to control
(Figure 9).
Discussion
Haloperidol has a multireceptor effect in the brain. Chronic
administration of haloperidol for 21 days in animals has
been found to produce VCMs and related behavioral disorders. These have been hypothesized as the symptoms of
925
Thakur et al.
Table 2. Effects of candesartan and lisinopril against haloperidol-induced oxidative stress parameters in the striatum and cortex of
rat brain.
Group
Brain
region
LPO (nmol MDA/
mg protein) (% of
control)
Nitrite (µmol/
mg protein) (%
of control)
Reduced
glutathione
(nmol/mg
protein) (% of
control)
SOD nmol/mg
protein (% of
control)
Catalase
µmol of H2O2
decomposed/min/
mg protein) (% of
control)
Normal control
Halo (1)
Cand (5) Per se
Halo (1) + Cand
(3)
Halo (1) + Cand
(5)
Lisino (15)
Per se
Halo (1) + Lisino
(10)
Halo (1) + Lisino
(15)
Halo (1) + Cand
(3) + Lisino (10) Striatum
Cortex
Striatum
Cortex
Striatum
Cortex
Striatum
Cortex
Striatum
Cortex
Striatum
Cortex
Striatum
Cortex
Striatum
Cortex
Striatum
Cortex
100 ± 6.35
100 ± 5.75
225.2 ± 9.45a
202.3 ± 9.32a
97.93 ± 5.35
96.45 ± 5.65
171.32 ± 7.85b
161.76 ± 7.65b
139.45 ± 6.34b,c
134.23 ± 6.21b,c
98.32 ± 5.76
96.89 ± 5.98
174.35 ± 8.12b
168 ± 7.93b
141.34 ± 6.89b,d
136.23 ± 6.53b,d
132.65 ± 5.65b,c,d
129.36 ± 5.45b,c,d
100 ± 5.95
100 ± 6.57
240.78 ± 10.1a
215.53 ± 9.98a
96.78 ± 5.98
97.79 ± 5.87
190.24 ± 7.84b
180.23 ± 7.65b
146.35 ±7.23b,c
140.46 ± 6.96b,c
98.21 ± 5.97
97.27 ± 5.90
193.38 ± 8.25b
187.76 ± 7.96b
145.76 ± 7.12b,d
141.29 ± 7.23b,d
137.45 ±6.34b,c,d
134.38 ±6.23b,c,d
100 ± 6.28
100 ± 6.32
48.78 ± 5.23a
45.76 ± 5.87a
97.35 ± 6.12
96.65 ± 5.97
60.32 ± 5.32b
58.32 ± 5.65b
72.45 ± 5.65b,c
69.36 ± 5.98b,c
95.45 ± 6.21
97.32 ± 5.99
59.65 ± 5.65b
57.98 ± 5.97b
70.35 ±5.98b,d
68.34 ± 6.21b,d
75.35 ± 6.56b,c,d
73.54 ± 6.78b,c,d
100 ± 6.45
100 ± 6.79
37.45 ± 5.12a
40.25 ± 4.65a
96.34 ± 5.63
95.45 ± 5.87
53.25 ± 5.32b
56.76 ± 5.21b
65.53 ± 5.75b,c
67.42 ± 5.23b,c
95.38 ± 5.95
96.32 ± 5.46
52.45 ± 5.76b
55.65 ± 5.86b
64.37 ± 6.12b,d
66.34 ± 5.97b,d
68.65 ± 5.98b,c,d
70.45 ± 5.75b,c,d
100 ± 5.89
100 ± 5.98
42.56 ± 5.72a
46.36 ± 5.65a
95.45 ± 6.32
97.45 ± 6.21
53.45 ± 5.79b
58.78 ± 5.97b
66.46 ± 5.98b,c
69.79 ± 5.67b,c
97.58 ± 6.12
96.26 ± 5.98
53.23 ± 5.97b
57.98 ± 5.65b
65.85 ± 5.97b,d
67.89 ± 5.45b,d
69.45 ± 5.75b,c,d
71.23 ± 5.79b,c,d
Data are expressed as mean ± SEM. ap≤0.05 as compared to control group; bp≤0.05 as compared to haloperidol-treated group; cp≤0.05 as compared
to Halo (1) + Cand (3) group; dp≤0.05 as compared to Halo (1) + Lisino (10) group.
LPO: Lipid per-oxidation; MDA: Malondialdehyde; SDO: superoxide dismutase; Halo: haloperidol; Cand: candesartan; Lisino: lisinopril.
Figure 9. Effect of candesartan and lisinopril on TNF-α and
IL-1β in haloperidol-treated rats.
Data are expressed as mean ± SEM. ap≤0.05 as compared to control
group; bp≤0.05 as compared to haloperidol-treated group; cp≤0.05 as
compared to Halo (1) + Cand (3) group; dp≤0.05 as compared to Halo
(1) + Lisino (10) group.
Halo: haloperidol; Cand: candesartan; Lisino: lisinopril.
orofacial dyskinetic movements, which are generally
observed in patients who are on chronic treatment with
typical neuroleptics.38 Some earlier studies have demonstrated that chronic administration of haloperidol for 21
days is associated with the initiation of orofacial dyskinetic movements (VCMs, facial jerking and tongue
protrusion).2,3,39,40 Administration of haloperidol may lead
to dopamine receptor supersensitivity, enhanced dopamine
metabolism, free radical generation and enhanced prostaglandin production, and these effects may finally result in
TD-like symptoms.4 It has been reported that haloperidol
is able to block the dopamine D2 inhibitory receptor
located in the glutamatergic terminals in the striatum leading to the enhanced release of glutamate, which damages
the striatal neurons resulting in orofacial dyskinetic movements and oxidative damage, which in turn leads to the
symptoms of TD. It has been reported that reduced
GABAergic tone in substantia nigra is responsible for the
production of stereotypic behavior following antipsychotic
treatment in rats.41 Clinical studies have also demonstrated
decreased concentration of GABA in the cerebrospinal
fluid of patients with dyskinetic problems.42 In the present
study, chronic administration of haloperidol showed
increased frequencies of orofacial dyskinetic movements
(VCMs, tongue protrusions, facial jerking, sniffing and
grooming) when compared with the vehicle treated control
animals. Besides these behavioral disorders the chronic
administration of haloperidol also resulted in a decrease in
locomotor, rota-rod and grip strength activity and also a
decrease in the body weight of rats. Recent literature suggests that the chronic use of antipsychotics results in the
imbalanced production and detoxification of free radicals
926
which may be associated with the initiation of orofacial
movements.43 The present study showed memory deficits
in elevated plus maze after chronic treatment with haloperidol in animals. It has been reported that chronic administration of haloperidol significantly produced learning
and memory impairment in animal models with orofacial
dyskinesia.44 Our study indicated that chronic administration of haloperidol also resulted in an increase in oxidative
stress shown by increased levels of lipid per-oxidation
(LPO) and nitrite concentration and decreased levels of
reduced glutathione, catalase and SOD as compared to
vehicle-treated animals in the cortex as well as in the striatal region. The increased oxidative metabolism in these
regions after chronic haloperidol administration may be
associated with a decrease in antioxidant brain defensive
system. It has been suggested that dopamine blockers
block the dopamine receptors and increase metabolism of
dopamine. An increased concentration of dopamine
metabolism may lead to the generation of free radicals and
cause oxidative stress. Generation of excessive free radicals and oxidative stress by chronic haloperidol administration may damage different neurons such as GABAergic
or dopaminergic systems and produce TD-like symptoms
in animals. Chronic administration of haloperidol may
lead to enhanced production of neuro-inflammatory mediators and astrocytes which cause the oxidative damage in
the brain and exaggerate TD-like symptoms.4 Chronic
administration also resulted in a marked increase of neuroinflammatory markers like TNF-α and IL-1β in the striatum and cortex of the haloperidol-induced rat brain. Many
cellular studies indicated that haloperidol has been associated with an increased expression of inflammatory markers such as TNF-α and NF-kB against oxidative damage
induced by haloperidol that may lead to neurotoxicity.11,12
Generally, the RAS has been well established in the
pathogenesis of hypertension and related cardiovascular
disorders. However, several components of the RAS,
namely angiotensinogen, angiotensin converting enzyme,
angiotensin II and their receptors have been widely distributed in the central nervous system (CNS) suggesting the
role of the RAS in the brain. The RAS in the CNS may
contribute to the disease process of different CNS disorders
probably through neuronal death.45–47 In the present study
the administration of candesartan (3 and 5 mg/kg) and lisinopril (10 and 15 mg/kg) individually or in combination significantly improved the behavior alterations in
haloperidol-induced rats. Many reports demonstrated that
ACE inhibitors were found to be neuroprotective through
mediating the mitochondrial oxidative pathways. Our study
also indicated that both the drugs improved the memory
performance in elevated plus maze in haloperidol-induced
TD in rats. It has been demonstrated that the administration
of telmisartan, an AT1 receptor blocker, significantly
improved learning and memory in the water maze task in
hypertension-induced rats.48 Also it was recently found that
Journal of the Renin-Angiotensin-Aldosterone System16(4)
the administration of olmesartan (another AT1 blocker) and
Compound 21 (AT2 receptor agonist) ameliorate the cognitive alterations observed in a shuttle-box avoidance task
observed in a specific type 2 diabetes mellitus model in
mice.49 This neuroprotective effect of ACE inhibitors could
be perhaps explained by improving cerebral blood flow and
protects against neuronal damage induced by chronic antipsychotics like haloperidol.
A number of recent studies suggest that neuro-inflammation and oxidative stress play a pivotal role at least in
the progression of TD, and the RAS plays a key role in the
initiation and perpetuation of inflammation and oxidative
damage in several tissues. High levels of angiotensin II are
reported to contribute to oxidative stress and inflammation
which produce deleterious effects in the CNS.50,51 It has
been demonstrated that stimulation of the RAS causes activation of inflammatory cytokines that may play a vital role
in neurodegenerative disorders.52,53 ACEI (lisinopril) and
ARB (telmisartan) have been reported in recent studies to
possess anti-inflammatory actions.54,55 Our study reported
that candesartan and lisinopril attenuated the increased
expression of inflammatory markers such as TNF-α and
IL-1β in haloperidol-treated rats. Clinical exposure to
ACEIs that cross the BBB have been found to have a neuroprotective effect as compared to those ACEIs which do
not cross the blood brain barrier (BBB).56,57 A recent report
suggests that lisinopril is associated with reductions in the
incidence and progression of AD dementia in cardiovascular patients.58 In our study, candesartan and lisinopril attenuated the increased levels of TBARS and nitrite and
restored the decreased levels of antioxidant enzymes
(reduced glutathione, catalase and SOD) in the rat striatum
as compared to the vehicle-treated group. Another recent
study also suggested that chronic treatment with angiotensin type 1 receptor antagonists telmisartan significantly
protects the oxidative stress in the retina of streptozotocininduced diabetic rats due to its antioxidant and anti-apoptosis properties.59 Additionally, it has been recently
reported that AT1 blocker (losartan) and AT2 blocker (PD123177) and ACE inhibitor (captopril) reduces oxidative
stress status in rat hippocampus due to inhibition of central
angiotensin II.60 Advanced genetic and cellular studies
also demonstrated that blocking the AT1 receptors with
olmesartan results in decreased oxidative stress levels in
transgenic mice for renin and angiotensinogen.49 This
could be the possible mechanism. In present study, candesartan and lisinopril significantly improved the rota-rod
and grip strength activity in haloperidol-induced TD suggesting the anti-parkinsonism effect which improved the
rigidity of muscle. It has been demonstrated that chronic
treatment with the ARB, such as candesartan and losartan,
protects dopaminergic neuronal cell death against the
(1-methyl-4phenyl-1, 2, 3, 6-tetrahydropyridine) (MPTP)induced Parkinson’s Disease (PD) in rats.61,62 This suggests that brain endogenous AII increases the neurotoxin
Thakur et al.
effect of MPTP on the DA system and that the AT1 blocker,
candesartan, inhibits the enhancing effect of AII on
Dopamine (DA) cell death. This neuroprotective effect
may be expected since candesartan has been shown to be a
potent AT1 blocker and to penetrate the BBB to inhibit
centrally mediated effects of AII.63,64 The exact pharmacological action of the RAS in TD is still not clear, but regulatory interactions between the dopaminergic and
renin-angiotensin systems have been well-established in
the substantia nigra and striatum. Recently, it has been
suggested that telmisartan has been reported to exert a neuroprotective effect in animal models of Parkinson’s disease by regulating key proteins of PD pathology such as
α-synuclein (SYN) and neurotrophic factors (BDNF and
GDNF), dopamine transporter (DAT), tyrosine hydroxylase (TH), vesicular monoamine transporter 2 (VMAT2)
and Glial fibrillary acidic proteins (GFAP).65 These above
proteins contribute to the progression of dopaminergic
degeneration in several neurodegenerative disorders.
Therefore, this could be the additional possible mechanism
of dopamine receptors modulation in TD pathology.
Our present study concluded that administration of
candesartan (AT1 antagonist) and lisinopril (ACE inhibitor) either individually or in combination along with neuroleptics in the treatment of schizophrenia, prevent or
delay the symptoms of TD by involving antioxidant and
anti-inflammatory like effects. However, the exact molecular and cellular mechanisms need to be further explored.
Acknowledgements
We express our sincere thanks to Management and Mr. Parveen
Garg, Honorable Chairman, ISF College of Pharmacy, Moga,
(INDIA), for providing necessary facilities and infrastructure for
this study.
Conflict of interest
None declared.
Funding
This research received no specific grant from any funding agency
in the public, commercial or not-for-profit sectors.
References
1. Blanchet PJ. Antipsychotic drug-induced movement disorders. Can J Neurol Sci 2003; 30: 101–107.
2. Bishnoi M, Chopra K and Kulkarni SK. Activation of striatal inflammatory mediators and caspase-3 is central to
haloperidol-induced orofacial dyskinesia. Eur J Pharmacol
2008; 590: 241–245.
3. Kulkarni SK and Naidu PS. Pathophysiology and drug
therapy of tardive dyskinesia: Current concepts and future
perspectives. Drugs Today (Barc) 2003; 39: 19–49.
4. Bishnoi M and Boparai RK. An animal model to study the
molecular basis of tardive dyskinesia. Methods Mol Biol
2012; 829: 193–201.
927
5. De Leon J. The effect of atypical versus typical antipsychotics on tardive dyskinesia: A naturalistic study. Eur Arch
Psychiatry Clin Neurosci 2007; 257: 169–172.
6. Klawans HL Jr and Rubovits R. An experimental model of
tardive dyskinesia. J Neural Transm 1972; 33: 235–246.
7. Zhu M, Gu F, Shi J, et al. Increased oxidative stress and
astrogliosis responses in conditional double-knockout mice
of Alzheimer-like presenilin-1 and presenilin-2. Free Radic
Biol Med 2008; 45: 1493–1499.
8. Bishnoi M, Chopra K and Kulkarni SK. Theophylline,
adenosine receptor antagonist prevents behavioral, biochemical and neurochemical changes associated with an
animal model of tardive dyskinesia. Pharmacol Rep 2007;
59: 181–191.
9. Goff DC and Coyle JT. The emerging role of glutamate in
the pathophysiology and treatment of schizophrenia. Am J
Psychiatry 2001; 158: 1367–1377.
10.Lieberman JA, Bymaster FP, Meltzer HY, et al.
Antipsychotic drugs: Comparison in animal models of
efficacy, neurotransmitter regulation, and neuroprotection.
Pharmacol Rev 2008; 60: 358–403.
11. Post A, Holsboer F and Behl C. Induction of NF-kappaB
activity during haloperidol induced oxidative toxicity in
clonal hippocampal cells: suppression of NFkappaB and
neuroprotection by antioxidants. J Neurosci 1998; 18:
8236–8246.
12. Post A, Rücker M, Ohl F, et al. Mechanisms underlying the protective potential of alpha-tocopherol (vitamin E) against haloperidol-associated neurotoxicity. Neuropsychopharmacology
2002; 26: 397–407.
13. Leung JG and Breden EL. Tetrabenazine for the treatment of
tardive dyskinesia. Ann Pharmacother 2011; 45: 525–531.
14. Singh B, Sharma B, Jaggi AS, et al. Attenuating effect of
lisinopril and telmisartan in intracerebroventricular streptozotocin induced experimental dementia of Alzheimer’s
disease type: Possible involvement of PPAR- g agonistic
property. J Renin Angiotensin Aldosterone Syst 2013; 14:
124–136.
15. Wright JW and Harding JW. The brain RAS and Alzheimer’s
disease. Exp Neurol 2010; 223: 326–333.
16. Yamada K, Uchida S, Takahashi S, et al. Effect of a centrally active angiotensin-converting enzyme inhibitor perindopril on cognitive performance in a mouse model of
Alzheimer’s disease. Brain Res 2010; 1352: 176–186.
17. Horiuchi M and Mogi M. Role of activation of angiotensin
II receptor subtypes in ischemic brain damage and cognitive
function. Br J Pharmacol 2011; 163: 1122–1130.
18. Labandeira-Garcia JL, Rodriguez-Pallares J, Rodríguez
Perez AI, et al. Brain angiotensin and dopaminergic degeneration: relevance to Parkinson’s disease. Am J Neurodegener
Dis 2012; 1: 226–244.
19. Lu Q, Zhu YZ and Wong PT. Neuroprotective effects of
candesartan against cerebral ischemia in spontaneously
hypertensive rats. Neuroreport 2005; 16: 2269–2272.
20. Thoene-Reineke C, Rumschüssel K, Schmerbach K, et al.
Prevention and intervention studies with telmisartan, ramipril and their combination in different rat stroke models.
PLoS One 2011; 6: e23646.
21. Garrido-Gilet al. Involvement of PPAR-gin the neuroprotective and anti-inflammatory effects of angiotensin type
928
1 receptor inhibition: effects of the receptor antagonist
telmisartan and receptor deletion in a mouse MPTP model
of Parkinson’s disease. Journal of Neuroinflammation
2012; 9: 38.
22. Bhateja DK, Dhull DK, Gill A, et al. Peroxisome proliferator-activated receptor-α activation attenuates 3-nitropropionicacid induced behavioral and biochemical alterations in
rats: Possible neuroprotective mechanisms. Eur J Pharmacol
2012; 674: 33–43
23. Pathan AR, Viswanad B, Sonkusare SK, et al. Chronic
administration of pioglitazone attenuates intracerebroventricular streptozotocin induced-memory impairment in rats.
Life Sci 2006; 79: 2209–2216.
24. Naidu PS, Singh A and Kulkarni SK. Effect of Withania
somnifera root extract on reserpine-induced orofacial dyskinesia and cognitive dysfunction. Phytother Res 2006; 20:
140–146.
25. Sharma A and Kulkarni SK. Evaluation of learning and
memory mechanisms employing plus maze in rats and
mice. Prog Neuropsychopharmacol Biol Psychiatry 1992;
16: 117–125.
26. Kumar P, Kalonia H and Kumar A. Novel protective mechanisms of antidepressants against 3-nitropropionic acid
induced Huntington’s-like symptoms: A comparative study.
J Psychopharmacol 2011; 25: 1399–1411.
27. Kumar P and Kumar A. Effect of lycopene and epigallocatechin-3-gallate against 3-nitropropionic acid induced
cognitive dysfunction and glutathione depletion in rat: A
novel nitric oxide mechanism. Food Chem Toxicol 2009;
47: 2522–2530.
28. Butchbach ME, Edwards JD and Burghes AH. Abnormal
motor phenotype in the SMNDelta7 mouse model of spinal
muscular atrophy. Neurobiol Dis 2007; 27: 207–219.
29. Brooks SP and Dunnett SB. Tests to assess motor phenotype
in mice: A user’s guide. Nat Rev Neurosci 2009; 10: 519–529.
30. Corti S, Nizzardo M, Nardini M, et al. Neural stem cell
transplantation can ameliorate the phenotype of a mouse
model of spinal muscular atrophy. J Clin Invest 2008; 118:
3316–3330.
31. Passini MA, Bu J, Roskelley EM, et al. CNS-targeted gene
therapy improves survival and motor function in a mouse
model of spinal muscular atrophy. J Clin Invest 2010; 120:
1253–1264.
32. Wills ED. Mechanism of lipid peroxide formation in animal
tissues. Biochem J 1966; 99: 667–676.
33. Green LC, Wagner DA, Glagowski J, et al. Analysis of
nitrate, nitrite and (15 N) nitrate in biological fluids. Annal
Biochem 1982; 126: 131–138.
34.Ellman GL. Tissue sulfhydryl groups. Arch Biochem
Biophys 1959; 82: 70–77.
35. Kono Y. Generation of superoxide radical during autooxidation of hydroxylamine and an assay for superoxide
dismutase. Arch Biochem Biophys 1978; 186: 189–195.
36. Luck H. Catalase. In: Bergmeyer HU (ed) Methods of enzymatic analysis. New York: Academic Press, 1971, pp. 885–893.
37. Gornall AG, Bardawill CT and David MM. Determination
of serum proteins by means of Biuret reaction. J Biol Chem
1949; 177: 751–766.
38. Ishiwari K, Betz A, Weber S, Felsted J, et al. Validation of
the tremulous jaw movement model for assessment of the
Journal of the Renin-Angiotensin-Aldosterone System16(4)
motor effects of typical and atypical antipychotics: Effects
of pimozide (Orap) in rats. Pharmacol Biochem Behav
2005; 80: 351–362.
39. Bishnoi M, Kulkarni SK and Chopra K. In vivo microdialysis studies of striatal level of neurotransmitters after haloperidol and chlorpromazine administration. Indian J Exp Biol
2009; 47: 91–97.
40. Naidu PS, Singh A and Kulkarni SK. Carvedilol attenuates
neuroleptic-inducedorofacial dyskinesia: Possible antioxidant mechanisms. Br J Pharmacol 2002; 136: 193–200.
41. Gittis AH and Kreitzer AC. Striatal microcircuitry and
movement disorders. Trends Neurosci 2012; 35: 557–564.
42. Lujan R and Ciruela F. GABAB receptors-associated proteins potential drug targets in neurological disorders? Curr
Drug Targets 2012; 13: 129–144.
43. Reifsnyder JW and Tettambel MA. Conservative approach
to tardive dyskinesia-induced neck and upper back pain. J
Am Osteopath Assoc 2013; 113: 636–639.
44. Rosengarten H and Quatermain D. The effect of chronic
treatment with typical and atypical antipsychotics on
working memory and jaw movements in three and eighteen month old rats. Prog Neuropsychopharmacol Biol
Psychiatry 2002; 26: 1047–1054.
45. Savaskan E. The role of the brain renin-angiotensin system
in neurodegenerative disorders. Curr Alzheimer Res 2005;
2: 29–35.
46. Kumaran D, Udayabanu M, Kumar M, et al. Involvement
of angiotensin converting enzyme in cerebral hypoperfusion
induced anterograde memory impairment and cholinergic
dysfunction in rats. Neuroscience 2008; 155: 626–639.
47. Ciobica A, Bild W, Hritcu L, et al. Brain renin-angiotensin
system in cognitive function: Pre-clinical findings and implications for prevention and treatment of dementia. Acta Neurol
Belg 2009; 109: 171–180
48. Tota S, Kamat PK, Awasthi H, et al. Candesartan improves
memory decline in mice: Involvement of AT1 receptors
in memory deficit induced by intracerebral streptozotocin.
Behav Brain Res 2009; 199: 235–240.
49. Inaba S, Iwai M, Furuno M, et al. Continuous activation
of renin–angiotensin system impairs cognitive function in
renin/angiotensinogen transgenic mice. Hypertension 2009;
53: 356–362.
50.Sukhanov S, Semprun-Prieto L, Yoshida T, et al.
Angiotensin II, oxidative stress and skeletal muscle wasting. Am J Med Sci 2011; 342: 143–147.
51. Kim JM, Uehara Y, Choi YJ, et al. Mechanism of attenuation of pro-inflammatory Ang II-induced NF-κB activation by genistein in the kidneys of male rats during aging.
Biogerontology 2011; 12: 537–550.
52. Yaffe K, Lindquist K, Penninx BW, et al. Inflammatory
markers and cognition in well-functioning AfricanAmerican and white elders. Neurology 2003; 61: 76–80.
53. Tuppo EE and Arias HR. The role of inflammation in
Alzheimer’s disease. Int J Biochem Cell Biol 2005; 37:
289–305.
54. Haraguchi T, Takasaki K, Naito T, et al. Cerebroprotective
action of telmisartan by inhibition of macrophages/microglia expressing HMGB1 via a peroxisome proliferatoractivated receptor gamma-dependent mechanism. Neurosci
Lett 2009; 464: 151–155.
Thakur et al.
55. Ismail H, Mitchell R, McFarlane SI, et al. Pleiotropic effects
of inhibitors of the RAAS in the diabetic population: Above
and beyond blood pressure lowering. Curr Diab Rep 2010;
10: 32–36.
56. Yasar S, Zhou J, Varadhan R, et al. The use of angiotensin converting enzyme inhibitors and diuretics is associated
with a reduced incidence of impairment on cognition in
elderly women. Clin Pharmacol Ther 2008; 84: 119–126.
57. Ohrui T, Matsui T, Yamaya M, et al. Angiotensin-converting
enzyme inhibitors and incidence of Alzheimer’s disease in
Japan. J Am Geriatr Soc 2004; 52: 649–650.
58. Li NC, Lee A, Whitmer RA, et al. Use of angiotensin receptor
blockers and risk of dementia in a predominantly male population: prospective cohort analysis. BMJ 2010; 340: 5465.
59. Ola MS, Ahmed MM, Abuohashish HM, et al. Telmisartan
ameliorates neurotrophic support and oxidative stress in the
retina of streptozotocin-induced diabetic rats. Neurochem
Res 2013; 38: 1572–1579.
60. Bild W, Hritcu L, Stefanescu C, et al. Inhibition of central
angiotensin II enhances memory function and reduces oxidative stress in rat hippocampus. Prog Neuropsychopharmacol
Biol Psychiatry 2013; 43: 79–88.
929
61. Joglar B, Rodriguez-Pallares J, Rodriguez-Perez AI, et al. The
inflammatory response in the MPTP model of Parkinson’s
disease is mediated by brain angiotensin: Relevance to progression of the disease. J Neurochem 2009; 109: 656–669.
62. Dominguez-Mejjide A, Villar-Cheda B, Garrido-Gil P, et al.
Effect of chronic treatment with angiotensin type 1 receptor
antagonists on striatal dopamine levels in normal rats and
in a rat model of Parkinson’s disease treated with l-DOPA.
Neuropharmacology 2014; 76: 156–168.
63. Gohlke P, Weiss S, Jansen A, et al. AT1 receptor antagonist telmisartan administered peripherally inhibits central
responses to angiotensin II in conscious rats. J Pharmacol
Exp Ther 2001; 298: 62–70.
64. Jung KH, Chu K, Lee ST, et al. Blockade of AT1 receptor
reduces apoptosis, inflammation, and oxidative stress in normotensive rats with intracerebral hemorrhage. J Pharmacol
Exp Ther 2007; 322: 1051–1058.
65. Sathiya S, Ranju V, Kalaivani P, et al. Telmisartan attenuates MPTP induced dopaminergic degeneration and motor
dysfunction through regulation of α-synuclein and neurotrophic factors (BDNF and GDNF) expression in C57BL/6J
mice. Neuropharmacology 2013; 73: 98–110.