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Study of CNS Depressant and Behavioral Effects of Cyclopyrrolone Compound Zopiclone in Different Animal Models

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Study of CNS Depressant and Behavioral Effects of Cyclopyrrolone Compound Zopiclone in Different Animal Models id10341328 pdfMachine by Broadgun Software - a great PDF writer! - a great PDF creator! - http://www.pdfmachine.com http://www.broadgun.com ISSN : 0974 - 7532 Volume 4 Issue 4 Research & Reviews in Trade Science Inc. BBiiooSScciieenncceess Regular Paper RRBS, 4(4), 2010 [173-176] Study of CNS depressant and behavioral effects of cyclopyrrolone compound zopiclone in different animal models Uma A.Bhosale*1, Anand A.Bhosale2 1Dept. of Pharmacology SKNMC, Narhe (Ambegaon) Pune-41, (INDIA) 2Dept. of Pathology SKNMC, Narhe (Ambegaon) Pune-41, (INDIA) E-mail : [email protected] Received: 10th September, 2010 ; Accepted: 20th September, 2010 ABSTRACT KEYWORDS Objectives: To evaluate CNS depressant and behavioral effects of zopiclone Incline plane; in comparison with BZD (lorazepam) by using different animal models. Pentobarbitone Methods: Pharmacological assays used for evaluating CNS Depressant sleeping time; activity are righting reflex test, pentobarbitone sleeping time potentiation, Rota rod apparatus; Rota rod apparatus and Incline plane performance test in albino mice. Open Zopiclone. field apparatus (OFT) was used to study behavioral effects. Data analyzed ’s unpaired-‘t’ test and p<0.05 considered significant. by student Results: Zopiclone (7.5mg/kg p.o.) did not inhibit the Righting reflex however sig- nificant (p<0.001) potentiation of Pentobarbitone sleeping time and de- creased fall off time in Rota rod as well as inclined plane test (P<0.05, P<0.02 respectively) were observed. In OFT increased in exploration (P<0.001) suggestive of anxiolysis was observed. Conclusions: Zopiclone (7.5mg/kg p.o.) has weak CNS Depressant activity and more selective behavioral activity compared to BZDs. 2010 Trade Science Inc. - INDIA INTRODUCTION cognitive function, physical dependence and tolerance. Besides addiction liabilities, benzodiazepines adversely Advance in science and technology has contrib- affect the respiratory, digestive and immune system of uted to an enormous improvement in the quality of life body and the chronic treatment with benzodiazepines of humankind. However, modern life stress, associated often prove more harmful in the longer run[1]. In this trials and tribulation are responsible for the surge in in- context, a resurgence of interest in medicine is seen so cidence of variety of psychiatric disorders. Path break- as to discover newer drugs with significantly lesser side ing research in psychopharmacology has flooded the effects than that observed with conventional drugs while market place with drugs for specification. For instance, having comparable efficacy. benzodiazepines (diazepam, nitrazipam lorazepam and Cyclopyrrolones are a new class of psychothera- alprazolam etc) are the most frequently prescribed syn- peutic agents possessing a pharmacological profile of thetic drugs for variety of condition particularly anxiety, high efficacy and low toxicity. Zopiclone is the first of depression, epilepsy and insomnia. But these the Cyclopyrrolones, chemical structure of which is com- psychoneural drugs have very serious side effects like pletely different from BZDs. Qualitatively it possesses chronic use of benzodiazepines causes deterioration of similar pharmacological profile as BZDs. It acts at 174 Zopiclone (Cyclopyrrolone): CNS. depressant and behavioral study RRBS, 4(4) 2010 Regular Paper GABA-BZD-Cl- -ionophore-receptor even then rela- experiment. All experiments were carried out in day- tively more specific in action i.e. more potent light. Hypnosedative and weak anticonvulsant-muscle relax- Drugs and doses ant. This specificity is due to its distinctive binding mechanism at the site close to rather than identical to Doses were selected from earlier studies. the site occupied by BZDs[2-4]. Lorazepam (Ativan 2mg tablet obtained from Wyeth Earlier in vitro and animal studies have demon- Lederle Ltd.) dissolved in DW given orally (p.o.) in the strated that Zopiclone causes minimal impairment of dose of 5mg/kg. Zopiclone (Zopicon 7.5mg tablet; psychomotor skills and mental acuity in the morning af- obtained from Intas Pharmaceuticals Ltd.) suspended ter a bedtime dose, which is thought to be due to its in 0.25% CMC, given orally (p.o.) in the dose of 7.5mg/ short half-life of about 5 hours and no long acting me- kg, Pentobarbitone sodium given intraperitoneal (i.p.) tabolites. Zopiclone has a low dependence liability. Thus, in the dose of 40mg/kg. with its short duration of action and good tolerability Test methods profile, Zopiclone could be a good alternative to the Animals were divided into various groups in such [4,5] benzodiazepine hypnotics . way that 6 animals were there in each group. Group-A Present study was therefore designed to confirm received 0.1ml NS orally served as control for all ex- the findings of earlier studies and to evaluate CNS de- periments except righting reflex test where animals re- pressant and behavioral effects of Zopiclone in com- ceived Pentobarbitone (40mg/kg) IP as control, Group parison with BZDs (Lorazepam) with reference to its –B received Lorazepam (5mg/kg) served as standard –C received Zopiclone (7.5mg/kg). Each ani- selectivity and efficacy. & Group Aim and objectives mal was treated with respective drug 30 min before Present study is a single dose pharmacodynamic experimentation. Following are the details of experi- study designed to evaluate CNS depressant and be- ments performed. havioral effects of zopiclone by using different animal Righting reflex test models. Drugs like barbiturates induce hypnosis by CNS To compare these actions with conventional depression easily determined by loss of righting reflex. Hypnosedative i.e. BZD (Lorazepam). In righting reflex test animal is are kept gently on its back over an undulated surface, normally it corrects MATERIALS AND METHODS immediately; if retained on back for 30secs or more it is recorded as loss of righting reflex. Loss of righting Present study has been conducted at Government reflex is taken as index of CNS depression[6]. Medical College, Miraj. The experimental protocol was approved by Institutional Animal Ethics Committee Pentobarbitone sleeping time potentiation (IAEC). Pentobarbitone (barbiturate) produces quick on- Experimental animals set of sleep as indicated by loss of righting reflex and recovery is also easily detected as the animal regain Albino mice weighing 20-25gms of either sex, bred righting reflex. Animals in all three groups received the in Central Animal House (CAH) facility of the Govern- respective drugs and 30 min later treated with Pento- ment Medical College, Miraj were used for the study. barbitone (40mg/kg) IP. The time interval between loss The animals were housed under standard laboratory of righting reflex and reappearance of righting reflex is conditions, maintained on natural light and dark cycle recorded as duration of sleep. The animal that corrects and had free access to food and water. They were ac- itself 3 times in 1 min is considered to have recovered climatized to laboratory conditions before the experi- from drug effect[7]. ment. Pre-experiment screening for righting reflex was done 1 day prior to rule out CNS disco-ordination. Open field apparatus behavior (OFT) The animals that show positive righting reflex were se- Open field apparatus (OFA) is designed as de- lected for study. Each animal was used once in every scribed by Gray and Lalji (1971) with little modifica- RRBS, 4(4) 2010 Uma A.Bhosale and Anand A.Bhosale 175 Regular Paper TABLE 1 : Observations in Righting reflex & Pentobarbi- TABLE 2 : Observations in Rota-rod apparatus and inclined tone sleeping time potentiation test plane performance Duration of ± SEM) Groups Righting Fall off time in secs(Mean Treatment Treatment sleep(min) Groups (n=6) reflex ± SEM) Treatment (Mean (n=6) Rota-rod Inclined plane Control ±1.2 apparatus performance A Control (pentobarbitone 40mg/kg) Absent 63.3 ± 13.4 ± 20.3 NS(0.1ml) A Control (0.1 ml NS) 210 243.3 Lorazepam ± 2.2* B Lorazepam (5 mg/Kg) Present 85.8 ± 4.2*** ± 13.3*** (5 mg/Kg) B Lorazepam (5 mg/Kg) 156.7 133.3 Zopiclone a ± 4.8* ± 6* ± 3.1** C Zopiclone (7.5 mg/Kg) Present 98.5 C Zopiclone (7.5 mg/Kg) 170.2 180.5 (7.5mg/Kg) ± SEM, data ± SEM, data Each group consists of 6 animals. Values are Mean Each group consists of 6 animals. Values are Mean ’s ‘t’ test. ’s ‘t’ test. analyzed by student unpaired- (*P<0.001 compared to analyzed by student unpaired- (*P<0.05, **P<0.02, control; a P<0.05 compared to Lorazepam) ***P<0.01 compared to control) tions. Dimensions are 100cm x 100cm x 40cm made experimentation fall off time in secs was recorded for up of themacol open from top and bottom kept on white each animal and decreased fall off time was taken as table top; surface is divided into 25 equal squares i.e. 9 criteria for CNS depression[10,11]. central and 16 peripheral. The animals were pretreated Statistical analysis with the samples (Zopiclone7.5mg/kg and reference ’s unpaired-’t’ test. All Data analyzed by Student drugs) 30min before. During 5 min session of observa- ±SEM). tion, each animal is placed in the corner of open field the results were expressed as mean ( apparatus & behavior of animal as determined by P <0.05 was considered significant. ambulation (number of squares entered with both fore- limbs) and, exploration (number of central squares en- RESULTS tered) was recorded[8]. Righting reflex test Rota rod apparatus test Zopiclone did not inhibit righting reflex at dose of The Rota rod apparatus described by Dunham and 7.5 mg/kg like Pentobarbitone (TABLE 1). Miya (1957) was used for the test. Albino mice under- went a pretest on the apparatus. Only those animals, Pentobarbitone sleeping time potentiation which had demonstrated their ability to remain on the In the potentiation of Pentobarbitone sleep test, revolving rod (5 rpm) for 3 min, were used for the test. Zopiclone significantly increased the sleeping time in mice The animals were treated in the same way as mentioned at dose of 7.5 mg/kg compared to controls (P<0.001) under test methods.
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