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Reversal of Reserpine-Induced Orofacial Dyskinesia
And Catalepsy by Sida Cordifolia
Navneet Khurana, Pushpendra Kumar Jain, Yogesh Pounikar, Shailendra Patil & Asmita Gajbhiye
Department of Pharmaceutical Sciences, Dr. Hari Singh Gour Central University, Sagar, Madhya Pradesh, India E-mail : [email protected] Abstract - Reserpine-induced catalepsy is an animal model used to mimic the behavioural symptoms of Parkinson's disease (PD) in
experimental animals. The present study was designed to investigate the effect of aqueous and hydro-ethanolic extracts of Sida
cordifolia (AESC and EESC respectively), in reserpine-induced orofacial dyskinesia and catalepsy along with lipid peroxidation
evaluated by the levels of thiobarbituric acid like reactive substances (TBARS) in rat forebrain. Sida cordifolia is a well know
Ayurvedic plant which has been administered anciently for nervous disorders such as hemiplegia, facial paralysis and PD. It also
possesses significant in vitro and ex vivo antioxidant activity. Repeated administration of reserpine (1 mg/kg; s.c.) on alternate days
(day 1, 3 and 5) for a period of 5 days significantly increased the vacuous chewing movements (VCM), tongue protrusions (TP),
orofacial bursts (OB) and catalepsy along with increased forebrain TBARS levels in rats which was dose-dependently reversed by
AESC (50, 100 and 250 mg/kg; p.o.) treatment. No significant effect on these behavioural parameters was observed following
varying dose (50, 100 and 250 mg/kg; p.o.) treatment of EESC in reserpine treated rats. These findings suggest the involvement of
antioxidant activity along with other underlying mechanisms for the ameliorative effect of AESC in reserpine-induced orofacial
dyskinesia and catalepsy. It predicts the scope of AESC in the possible treatment of neuroleptic-induced orofacial dyskinesia and
PD.
Key words - Reserpine; Parkinson's disease; Sida cordifolia; oxidative stress; orofacial dyskinesia; catalepsy.
tremor, bradykinesia, hypokinesia, balance and gait disturbances. The pathologic hallmark of the disease, Increased oxidative stress and free radical damage which is well known to contribute to these disabling is a well-known feature of the age related brain symptoms in PD, is the progressive degeneration of disorders [1]. The free radical byproducts from dopaminergic neurons in the Substantia Nigra pars catecholamine metabolism in the basal ganglia may compacta and consequent loss of their projecting nerve cause neurotoxic effect seen in tardive dyskinesia and fibers in the striatum that results in the profound deficit other motor related disorders [2]. The neuroleptic drugs in striatal dopamine content [6]. The parkinsonian cause secondary increase in turnover and metabolism of symptoms can be mimicked in the experimental animals dopamine by blocking dopamine receptors, which may by agents that block striatal dopamine D lead to increased formation of dopamine quinones as 2 receptors like haloperidol or cause dopamine deficiency like reserpine well as of hydrogen peroxide through the activity of monoamine oxidase [2]. Previous studies have shown that neuroleptic drugs induce oxidative stress and cell Reserpine is known to be associated with the death which support this "free radical hypothesis" for development of tardive dyskinesia [8] and behavioural generation of these dysfunctional motor symptoms symptoms of PD because of depletion of catecholamines [3]. According to some clinical studies, levels of lipid [9]. Rats treated with this monoamine-depleting agent peroxidation byproducts in blood or cerebrospinal fluid develop orofacial dyskinesia characterized by tongue of tardive dyskinesia patients are increased as compared protrusion (TP), orofacial bursts (OB), vacuous chewing to normal patients [4]. The increased lipid peroxidation movements (VCM) and cataleptic behaviour [10, in substantia nigra has also been reported in Parkinson's 11]. This reserpine-induced animal model also showed disease (PD) [5]. the contributory role of increased levels of lipid peroxidation PD is a progressive neurodegenerative disorder that dysfunctional motor activities resembling PD features primarily affects individuals between ages of 50 and 60. [12, 13]. Different experimental paradigms have It currently affects nearly 1% of the population over 55 confirmed the protective action of different antioxidant years of age. It is characterized clinically, by resting International Journal of Pharmacology and Pharmaceutical Technology (IJPPT), ISSN: 2277 – 3436, Volume-1, Issue- 2, 2012 Reversal of Reserpine-Induced Orofacial Dyskinesia And Catalepsy by Sida Cordifolia plants in reserpine-induced orofacial dyskinesia and has been deposited in the herbarium of the same catalepsy [12, 14]. department (Voucher Specimen no. Bot./Her./5234). The fresh whole plant was water washed, dried, finely Sida cordifolia, belonging to the family Malvaceae, powdered and sieved (400 µm). Powdered material was is an important Ayurvedic medicinal plant, having divided into two parts and one part was soaked in water significant in vitro and ex vivo antioxidant activity in a ratio of 1:6 w/v at room temperature for 24 hours reported for its aqueous extract [15]. It is also reported and filtered (45 µm) to obtain a clear filtrate. The marc in the ancient Ayurvedic literature that this plant can be was re-extracted and filtrates were reconstituted to get administered for nervous disorders such as hemiplegia, aqueous extract (9.6% w/w) of Sida cordifolia (AESC). facial paralysis [16] and PD [17]. Franco et al. have Another part of powdered material was extracted with reported the CNS pharmacological actions of 70% 70% hydro-ethanol using Soxhlet apparatus at 50 ᵒC hydro-ethanolic extract of plant [18]. Sumanth and temperature for 72 hours followed by filtration to obtain Mustafa have showed the antistress activity of hydro- hydro-ethanolic extract (10.2% w/w) of Sida cordifolia ethanolic extract of this plant [19]. (EESC). Extracts were then freeze dried and stored at So the present study was designed to evaluate the 40C for pharmacological investigations. effect of aqueous and 70% hydro-ethanolic extracts D. Treatment schedule of Sida cordifolia (AESC and EESC respectively) on reserpine-induced orofacial dyskinetic (VCM, TP and The rats were randomly assigned into ten different OB) and cataleptic behaviors along with associated lipid groups (n = 6). Group 1 served as control group and was peroxidation. The lipid peroxidation was evaluated by administered with 0.5% CMC solution (5 ml/kg; p.o.) estimating the levels of thiobarbituric acid like reactive along with a solution (1 ml/kg; s.c.) consisting of small substances (TBARS) in rat forebrain. quantity of glacial acetic acid in water as used in the other reserpine treated groups to dissolve reserpine. II. MATERIALS AND METHODS
Group 2 served as reserpine treated negative control group and was administered with 0.5% CMC solution (5 A. Animals ml/kg; p.o.) along with reserpine (1 mg/kg; s.c.) Male Sprague Dawley rats (5–7 week old) weighing dissolved in small quantity of glacial acetic acid and then 180-220 g, obtained from National Institute of Nutrition, diluted in water. Group 3 and 4 served as per se groups Hyderabad, were used for the present study. The of AESC and EESC respectively and received 100 mg/kg animals were housed in standard cages and maintained p.o. dose of respective treatment along with solution at an ambient temperature with natural day-and-night containing acetic acid in water as mentioned above (1 cycles (12:12 h light and dark cycles). All experiments ml/kg; s.c.). Group 5 to 7 served as AESC (50, 100, 250 were carried out between 09:00 and 16:00 hour. mg/kg; p.o) treated groups and Group 8 to 10 as EESC Animals were allowed a one-week habituation period to (50, 100, 250 mg/kg; p.o) treated groups. Groups 5 to 10 the animal room before testing. All procedures were were co-administered with reserpine (1 mg/kg; s.c.) conducted as per guidelines of the committee for the along with the respective treatment. The reserpine purpose of control and supervision of experimental treatment was followed on alternate days (day 1, 3 and 5) animals. The protocol for the use of animals for this for a period of 5 days in all reserpine treated groups. study was approved by the Institutional Animal Ethics AESC and EESC was suspended in 0.5% CMC solutions committee, Dr. Hari Singh Gour Central University, and administered for 5 consecutive days. The different Sagar, Madhya Pradesh, India. doses of extracts were selected based on acute toxicity studies done as per OECD guidelines in our previous B. Drugs and chemicals unpublished study. Reserpine was provided as gift sample from E. Evaluation of orofacial dyskinesia Chemical Resources (Panchkula, India). Thiobarbituric acid, total protein test kit and all other chemicals were After the injection of reserpine on the last day of procured from local suppliers (Hi-Media Chemicals, treatment (day 5), rats were placed individually in a Span Diagnostics Ltd, Spectrochem Pvt. Ltd. and Sisco small (30×20×30 cm) plexiglas observation cage for a Research Laboratory). initial 10 minutes habituation period. Then all rats were observed for 5 minutes by an observer blinded to the C. Preparation of plant extracts treatment and number of occurrence of orofacial The plant was collected during November, 2009 dyskinetic movements (VCM, TP and OB) were from Sagar, Madhya Pradesh, India. The plant was recorded as described by Naidu et al. [20]. VCM are identified by Prof. T. R. Sahu, Taxonomist, Department referred to as single mouth openings in the vertical plane of Botany, Dr. Hari Singh Gour Central University, not directed toward physical material. Counting was Sagar, Madhya Pradesh, India and a voucher specimen International Journal of Pharmacology and Pharmaceutical Technology (IJPPT), ISSN: 2277 – 3436, Volume-1, Issue- 2, 2012

Reversal of Reserpine-Induced Orofacial Dyskinesia And Catalepsy by Sida Cordifolia stopped whenever the rat began grooming, and restarted tetra methoxy propane. The TBARS value was when grooming stopped. expressed in nM/mg of protein [22]. F. Evaluation of catalepsy H. Protein estimation Catalepsy was measured using the bar test in which, The total protein was determined by the method of the rats were placed in half rearing position with both Lowry et al. with slight modification using Total Protein the front paws on a horizontal bar, 9 cm above and Modified Biuret, End Point Assay Test Kit [23]. parallel to the base. The effect on catalepsy was Statistical analysis observed after 1 hour of reserpine treatment on the last day (day 5). Rats were observed with a stopwatch to All the results were expressed as mean ± SEM. All note the time of removal of one paw from the bar. The the data was analyzed using one-way analysis of maximum cutoff time for observation was fixed at 180 s variance (ANOVA) followed by Tukey test (Sigma Stat Software, 3.5). P-values <0.05 were considered as statistically significant for all comparisons. G. TBARS assay III. RESULTS
sacrificed, brains were removed, and forebrain was A. Assessment of orofacial dyskinesia and catalepsy dissected out and weighted. A 10% (w/v) tissue homogenate was prepared in 0.1 M phosphate buffer Reserpine treatment resulted into significant (pH 7.4). It was subjected to centrifugation at 3000 rpm (P<0.05) increase in VCM, TP, OB and catalepsy as for 15 minutes to obtain the clear supernatant. The compared to control group. Co-treatment with varying supernatant, 0.2 ml, of the homogenate was pipetted out doses of AESC (50, 100 and 250 mg/kg) significantly in a test tube, followed by addition of 0.2 ml of 8.1% (P<0.05) reversed the increase in reserpine-induced sodium dodecyl sulphate, 1.5 ml of 30% acetic acid (pH VCM, TP, OB and catalepsy, showing maximum effect 3.5), 1.5 ml of thiobarbituric acid, and the volume was at 100 mg/kg dose. Co-treatment with varying doses of made up to 4 ml with distilled water. The test tubes were EESC (50, 100 and 250 mg/kg) did not showed any incubated for 1 h at 95 ᵒC, then cooled and added 1 ml significant (P>0.05) difference in VCM, TP, OB and of distilled water followed by addition of 5 ml of n- catalepsy as compared to reserpine treated negative butanol-pyridine mixture (15:1 v/v). The tubes were control group. AESC and EESC (100 mg/kg) per se centrifuged at 4000 g for 10 min. The absorbance of the treatment did not cause any significant (P>0.05) change in VCM, TP, OB and catalepsy as compared to control spectrophotometrically group (Fig. 1A, B, C and D). spectrophotometer 1240) at 532 nm. A standard calibration curve was prepared using 1-10 nM 1, 1, 3, 3- Fig. 1 : Effect of Reserpine (Res), AESC per se (100 mg/kg), AESC (50, 100 and 250 mg/kg) plus Res, AFSC per se (100 mg/kg) and AFSC (50, 100
and 250 mg/kg) plus Res on (A): vacuous chewing movements (VCM), (B): tongue protrusions (TP), (C): orofacial bursts (OB) and (D): Catalepsy in
rats on last day (day 5) of treatment. Data is represented as mean values ± S.E.M. * represents P<0.05 significant as compared to control group, #
represents P<0.05 significant as compared to reserpine treated group.
International Journal of Pharmacology and Pharmaceutical Technology (IJPPT), ISSN: 2277 – 3436, Volume-1, Issue- 2, 2012

Reversal of Reserpine-Induced Orofacial Dyskinesia And Catalepsy by Sida Cordifolia chronic neuroleptic use and it contributes to the B. TBARS assay initiation of catalepsy along with hyperkinetic Reserpine treatment resulted in significant (P<0.05) movements in the orofacial regions [24]. The increased increase in forebrain TBARS levels as compared to oxidative metabolism in forebrain after reserpine control animals. Co-treatment with varying doses of administration may be associated with decrease in AESC and EESC (50, 100 and 250 mg/kg) significantly antioxidant brain defense, as evidenced by increased (P<0.05) prevented the increase in TBARS levels, levels of TBARS. These results are in accordance with showing maximum effect by AESC (100 mg/kg). AESC the data from literature showing increased oxidative and EESC (100 mg/kg) per se treatment did not cause damage to forebrain after the administration of reserpine any significant (P>0.05) change in TBARS levels as compared to control group (Fig. 2). AESC dose-dependently protected reserpine-treated rats against the increase in TBARS levels in the forebrain. AESC might have prevented the oxidative damage caused by reserpine treatment and thus, reversed the behavioural changes due to reserpine. However, varying doses of EESC also protected the reserpine-treated rats against the increase in TBARS levels in the forebrain but failed to reverse the behavioural changes caused by reserpine. These observations suggest the involvement of some other underlying mechanism in addition to antioxidant activity, for the protective effect of AESC in reserpine-induced behavioural changes. The antioxidant activity is common for both the AESC and EESC. So there is possibility for the presence of some important class of phyto-constituents in AESC which are responsible for the reversal of these reserpine-induced behavioural changes, through an additional underlying Fig. 2 : Effect of Reserpine (Res), AESC per se (100 mechanism, along with the antioxidant activity. It may mg/kg), AESC (50, 100 and 250 mg/kg) plus Res, be involved through the reversal of reserpine-induced AFSC per se (100 mg/kg) and AFSC (50, 100 and 250 dopamine depletion by catecholaminergic pathways. mg/kg) plus Res on thiobarbituric acid like reactive Some important classes of phyto-constituents like substances (TBARS) levels in rat forebrain. Data is sympathomimetic alkaloids and phytosterols have been represented as mean values ± S.E.M. * represents P<0.05
reported in this plant which might be responsible for the significant as compared to control group, # represents
above behavioural effects [25]. Further studies should P<0.05 significant as compared to reserpine treated be done for the screening and evaluation of the particular phyto-constituents present in AESC, which have shown the protective effect in this study. IV. DISCUSSION
The present study showed the reversal of reserpine- In the present study, reserpine-treated animals induced orofacial dyskinesia and catalepsy by AESC developed cataleptic behaviour along with orofacial and thus, opens its scope as a possible potential dyskinesia, which was determined by an increase in candidate for the treatment and management of PD. VCM, TP and OB. The administration of varying doses of AESC showed protective effect against reserpine- induced behavioural changes. EESC, at varying doses, failed to reverse these reserpine-induced behavioural The authors are thankful to Council of Scientific and Industrial Research (CSIR), Government of India, for providing the financial assistance (Grant number 09/150/(0108)/2011/EMR-I) to Mr. Navneet Khurana catecholamines in the forebrain, and thus producing for this project. The authors would also like to thank these behavioural features of PD in rats. Previous Chemical Resources, Panchkula, India for providing gift literature indicates that imbalance in production and sample of reserpine. detoxification of free radicals may be associated with International Journal of Pharmacology and Pharmaceutical Technology (IJPPT), ISSN: 2277 – 3436, Volume-1, Issue- 2, 2012 Reversal of Reserpine-Induced Orofacial Dyskinesia And Catalepsy by Sida Cordifolia REFERENCES
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