Beneficial effect of candesartan and lisinopril against haloperidol-induced tardive dyskinesia in...

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published online 24 January 2014Journal of Renin-Angiotensin-Aldosterone SystemKuldeep Singh Thakur, Atish Prakash, Rohit Bisht and Puneet Kumar Bansal

Beneficial effect of candesartan and lisinopril against haloperidol-induced tardive dyskinesia in rat

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Introduction

Tardive dyskinesia (TD) is a disabling and potentially irre-versible motor complication encompassing all persistent, abnormal, involuntary hyperkinetic movements occurring in the setting of chronic therapy with dopamine receptor-blocking agents, such as antipsychotic drugs.1,2 Various theories have been put forward to understand the neuropa-thology of TD. Some of these include dopaminergic hyper-sensitivity, 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 fre-quently 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 sugges-tion that late-onset dyskinesia was a reflection of dopa-mine receptor supersensitivity.6 However, several observations indicate that D2 receptor upregulation alone is not sufficient to account for TD. Therefore the patho-physiological mechanism of haloperidol-induced TD is still not clear.

Oxidative stress has also been involved in the patho-physiology of TD.3,7 Oxidative stress increases the release of inflammatory mediators like TNF-α and interleukin-1-beta (IL-1β), IL-6 which initiate the apoptotic pathway, a central mechanism of neuronal cell death.2,8 It has been

Beneficial effect of candesartan and lisinopril against haloperidol-induced tardive dyskinesia in rat

Kuldeep Singh Thakur, Atish Prakash, Rohit Bisht and Puneet Kumar Bansal

AbstractIntroduction: 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.

KeywordsHaloperidol, tardive dyskinesia, oxidative damage, candesartan, lisinopril

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]

515038 JRA0010.1177/1470320313515038Journal of the Renin-Angiotensin-Aldosterone SystemThakur et al.research-article2014

Original Article

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2 Journal of the Renin-Angiotensin-Aldosterone System

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 prostaglan-dins 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 antago-nists 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 dis-orders.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 inhibi-tion 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 haloperidol-induced 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

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 haloperi-dol 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 per-formed in multiple phases as shown in the experimental protocol (Scheme 1). The animals were segregated into the following groups:

Scheme No. Group1 Control2 Haloperidol (1)3 Candesartan (5) Per Se4 Haloperidol (1) + Candesartan (3)5 Haloperidol (1) + Candesartan (5)6 Lisinopril (15) Per Se7 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 when-ever 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


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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). Ani-mals 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 reten-tion 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, Har-yana, India), which operates on photoelectric cells con-nected in a circuit with a counter. Before subjecting the animals to a cognitive task, all the animals were individu-ally 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 rotat-ing 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 inter-face 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 indi-vidually in a 1000 ml beaker and various behaviors (rear-ing, sniffing and grooming) were scored for the time period

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, fore-brain 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 assess-ing 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 stand-ard curve.

Estimation of reduced glutathione. Reduced glutathione was estimated according to the method described by Ell-man.34 Supernatant (1 ml) was precipitated with 4% sul-phosalicylic 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



were calculated using molar extinction co-efficient of the chromophore (1.36 × 104 (mol/l)-1cm-1).

Estimation of antioxidant enzyme activity

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 absorb-ance at 560 nm using a Perkin Elmer Lambda 20 spectrophotometer.

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 superna-tant 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 Biu-ret 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 instruc-tions 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. Fol-lowing 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 within-subjects factors. The biochemical estimations were sepa-rately analyzed by one-way ANOVA. Post hoc comparisons

between groups were made using Tukey’s test. P<0.05 was considered significant.

Results

Effect of candesartan and lisinopril on orofacial dyskinesia in haloperidol-treated rats

Chronic administration of haloperidol resulted in time-dependent increases in VCMs, tongue protrusion and facial jerking in rats. However, concomitant administra-tion of candesartan (3 and 5 mg/kg) and lisinopril (10 and 15 mg/kg) alone significantly improved the haloperidol-induced 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 orofa-cial dyskinesia as compared to control (Figures 1, 2 and 3).

Effect of candesartan and lisinopril on stereotypic rearing behavior in haloperidol-treated rats

Chronic administration of haloperidol showed a time-dependent decrease in stereotypic rearing behavior up to the 7th day which there after increased time dependently up to the last behavioral quantification. However, concomi-tant 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, combina-tion 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 rear-ing 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 halo-peridol-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 halo-peridol-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).


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Effect of candesartan and lisinopril on locomotor and rota-rod activity in haloperidol-treated 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 activ-ity and motor (rota-rod) activity of haloperidol-treated rats dose dependently (P<0.05). Further, combination of sub-theraputic 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

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.



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).

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/

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.

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.


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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 60.43 ± 3.70 30.76 ± 3.60 22.32 ± 3.21Halo (1) 71.32 ± 4.21 72.45 ± 4.37a 80.24 ± 4.50a

Cand (5) Per se 68.08 ± 4.1 34.04 ± 3.8 25.05 ± 3.4Halo (1) + Cand (3) 65.05 ± 3.9 58.78 ± 3.8b 40.76 ± 3.2b

Halo (1) + Cand (5) 60.04 ± 3.6 46.37 ± 3.1b,c 29.26 ± 2.9b,c

Lisino (15) Per se 70.04 ± 4.2 33.09 ± 3.9 21.09 ± 3.2Halo (1) + Lisino (10) 66.09 ± 3.4 59.05 ± 4.1b 43.32 ± 3.7b

Halo (1) + Lisino (15) 62.68 ± 3.1 47.04 ± 3.6b,d 31.23 ± 2.9b,d

Halo (1) + Cand (3) + Lisino (10) 58.08 ± 2.9 42.05 ± 3.1b,c,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.



kg) significantly increased the grip strength of haloperi-dol-treated rats (P<0.05). Further, combination of subther-apeutic doses of candesartan and lisinopril (3 and 10 mg/kg) significantly potentiated the therapeutic effect as com-pared 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 con-trol (Figure 8).

Effect of candesartan and lisinopril on MDA levels and nitrite concentration in haloperidol-treated rats

Rats given chronic treatment with haloperidol showed a significant increase of lipid peroxidation and nitrite con-centration 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 haloperidol-treated rats (P<0.05). Further, combination of subthera-peutic doses of candesartan and lisinopril (3 and 10 mg/kg) significantly potentiated their protective effect as com-pared 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 lev-els 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 syn-ergistic 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 sig-nificant 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 cande-sartan (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 lisino-pril (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 disor-ders. These have been hypothesized as the symptoms of

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.


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orofacial dyskinetic movements, which are generally observed in patients who are on chronic treatment with typical neuroleptics.38 Some earlier studies have demon-strated that chronic administration of haloperidol for 21 days is associated with the initiation of orofacial dyski-netic 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 prosta-glandin 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 lead-ing to the enhanced release of glutamate, which damages the striatal neurons resulting in orofacial dyskinetic move-ments 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 sug-gests that the chronic use of antipsychotics results in the imbalanced production and detoxification of free radicals

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 Striatum 100 ± 6.35 100 ± 5.95 100 ± 6.28 100 ± 6.45 100 ± 5.89 Cortex 100 ± 5.75 100 ± 6.57 100 ± 6.32 100 ± 6.79 100 ± 5.98Halo (1) Striatum 225.2 ± 9.45a 240.78 ± 10.1a 48.78 ± 5.23a 37.45 ± 5.12a 42.56 ± 5.72a

Cortex 202.3 ± 9.32a 215.53 ± 9.98a 45.76 ± 5.87a 40.25 ± 4.65a 46.36 ± 5.65a

Cand (5) Per se Striatum 97.93 ± 5.35 96.78 ± 5.98 97.35 ± 6.12 96.34 ± 5.63 95.45 ± 6.32 Cortex 96.45 ± 5.65 97.79 ± 5.87 96.65 ± 5.97 95.45 ± 5.87 97.45 ± 6.21Halo (1) + Cand (3)

Striatum 171.32 ± 7.85b 190.24 ± 7.84b 60.32 ± 5.32b 53.25 ± 5.32b 53.45 ± 5.79b

Cortex 161.76 ± 7.65b 180.23 ± 7.65b 58.32 ± 5.65b 56.76 ± 5.21b 58.78 ± 5.97b

Halo (1) + Cand (5)

Striatum 139.45 ± 6.34b,c 146.35 ±7.23b,c 72.45 ± 5.65b,c 65.53 ± 5.75b,c 66.46 ± 5.98b,c

Cortex 134.23 ± 6.21b,c 140.46 ± 6.96b,c 69.36 ± 5.98b,c 67.42 ± 5.23b,c 69.79 ± 5.67b,c

Lisino (15) Per se

Striatum 98.32 ± 5.76 98.21 ± 5.97 95.45 ± 6.21 95.38 ± 5.95 97.58 ± 6.12Cortex 96.89 ± 5.98 97.27 ± 5.90 97.32 ± 5.99 96.32 ± 5.46 96.26 ± 5.98

Halo (1) + Lisino (10)

Striatum 174.35 ± 8.12b 193.38 ± 8.25b 59.65 ± 5.65b 52.45 ± 5.76b 53.23 ± 5.97b

Cortex 168 ± 7.93b 187.76 ± 7.96b 57.98 ± 5.97b 55.65 ± 5.86b 57.98 ± 5.65b

Halo (1) + Lisino (15)

Striatum 141.34 ± 6.89b,d 145.76 ± 7.12b,d 70.35 ±5.98b,d 64.37 ± 6.12b,d 65.85 ± 5.97b,d

Cortex 136.23 ± 6.53b,d 141.29 ± 7.23b,d 68.34 ± 6.21b,d 66.34 ± 5.97b,d 67.89 ± 5.45b,d

Halo (1) + Cand (3) + Lisino (10)

Striatum 132.65 ± 5.65b,c,d 137.45 ±6.34b,c,d 75.35 ± 6.56b,c,d 68.65 ± 5.98b,c,d 69.45 ± 5.75b,c,d

Cortex 129.36 ± 5.45b,c,d 134.38 ±6.23b,c,d 73.54 ± 6.78b,c,d 70.45 ± 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.



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 halop-eridol in animals. It has been reported that chronic admin-istration of haloperidol significantly produced learning and memory impairment in animal models with orofacial dyskinesia.44 Our study indicated that chronic administra-tion 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 stri-atal 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 radi-cals and oxidative stress by chronic haloperidol adminis-tration 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 medi-ators 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 neuro-inflammatory markers like TNF-α and IL-1β in the stria-tum and cortex of the haloperidol-induced rat brain. Many cellular studies indicated that haloperidol has been associ-ated with an increased expression of inflammatory mark-ers 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 distrib-uted 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 lisin-opril (10 and 15 mg/kg) individually or in combination sig-nificantly 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

the administration of olmesartan (another AT1 blocker) and Compound 21 (AT2 receptor agonist) ameliorate the cogni-tive 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 antip-sychotics like haloperidol.

A number of recent studies suggest that neuro-inflam-mation 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 acti-vation 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 neu-roprotective 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 cardiovascu-lar patients.58 In our study, candesartan and lisinopril atten-uated 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 angioten-sin type 1 receptor antagonists telmisartan significantly protects the oxidative stress in the retina of streptozotocin-induced diabetic rats due to its antioxidant and anti-apop-tosis properties.59 Additionally, it has been recently reported that AT1 blocker (losartan) and AT2 blocker (PD-123177) 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, cande-sartan and lisinopril significantly improved the rota-rod and grip strength activity in haloperidol-induced TD sug-gesting 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 sug-gests that brain endogenous AII increases the neurotoxin


Thakur et al. 11

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 pharmaco-logical action of the RAS in TD is still not clear, but regu-latory 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 neu-roprotective effect in animal models of Parkinson’s dis-ease by regulating key proteins of PD pathology such as α-synuclein (SYN) and neurotrophic factors (BDNF and GDNF), dopamine transporter (DAT), tyrosine hydroxy-lase (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 inhibi-tor) either individually or in combination along with neu-roleptics in the treatment of schizophrenia, prevent or delay the symptoms of TD by involving antioxidant and anti-inflammatory like effects. However, the exact molec-ular 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.

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