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Evaluation of the Effects of Donepezil in Psychotic Disorders Using Swiss Albino Mice

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Evaluation of the Effects of Donepezil in Psychotic Disorders Using Swiss Albino Mice International Journal of Basic & Clinical Pharmacology Tanwani H et al. Int J Basic Clin Pharmacol. 2020 Apr;9(4):533-537 http:// www.ijbcp.com pISSN 2319-2003 | eISSN 2279-0780 DOI: http://dx.doi.org/10.18203/2319-2003.ijbcp20201051 Original Research Article Evaluation of the effects of donepezil in psychotic disorders using Swiss albino mice Hemant Tanwani1, Ritesh Churihar2*, Sameer Pandit1 1Department of Pharmacology, MGM Medical College, Indore, Madhya Pradesh, India 2Department of Pharmacology, Govt. Medical College, Ratlam , Madhya Pradesh, India Received: 27 January 2020 Accepted: 10 February 2020 *Correspondence: Dr. Ritesh Churihar, Email: [email protected] Copyright: © the author(s), publisher and licensee Medip Academy. This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. ABSTRACT Background: Schizophrenia as a psychotic disorder is currently treated by various antipsychotic drugs. A large group of patients still remain resistant to the treatment and present in the form of residual cognitive deficits. Donepezil has been advocated at various conferences and seminars for using it in schizophrenia patients. Donepezil is currently approved drug for Alzheimer's disease to improve cognition. Hence, we have tried to assess its role for psychotic models induced by methylphenidate in mice. Methods: Methylphenidate 5 mg/kg was given by intraperitoneal (i.p) route to induce psychosis in Swiss albino mice (n=6). Donepezil was given alone in a dose of 1 mg/kg and in combination with low dose haloperidol 0.1 mg/kg and groups were compared with haloperidol 0.2 mg/kg. Activity of donepezil was also assessed on the haloperidol induced catalepsy test. Statistical analysis was done with ANOVA followed by Bonferroni’s test. Results: Methylphenidate successfully induced characteristic stereotypy behaviour in mice similar to amphetamine. Both donepezil 1 mg/kg and haloperidol 0.2 mg/kg showed significant reduction in stereotypy behaviour and there was no statistically significant difference between the two (p<0.05). Effects with donepezil were only slightly inferior to standard while it’s combination (1 mg/kg with haloperidol 0.1 mg/kg) showed comparable results with the standard haloperidol. Donepezil had only marginally enhanced potential to induce catatonia which was statistically insignificant (p>0.05). Conclusions: Methylphenidate can be used successfully to induce psychosis in animals and donepezil may be a promising and potentially useful drug as add on therapy to routine antipsychotics. Keywords: Donepezil, Methylphenidate, Haloperidol, Stereotypy, Albino mice INTRODUCTION Schizophrenia has a prevalence of 1% in the world and is considered the prototype disorder for understanding the Psychosis is classified as a symptom complex of mental phenomenon of psychosis and the impact of antipsychotic illnesses which is mainly characterized by a loss of touch treatment.1 with the reality. Common psychotic disorders include mood disorders (major depression or mania) with Schizophrenia is characterized by disorganized thoughts psychotic features, substance induced psychosis, (cognition), actions (conation) and behaviour (effect). It dementia or delirium with psychotic features, delusional mainly presents with positive, negative and cognitive disorders, schizo-affective disorders and schizophrenia. symptoms. Positive symptoms-patients may have International Journal of Basic & Clinical Pharmacology | April 2020 | Vol 9 | Issue 4 Page 533 Tanwani H et al. Int J Basic Clin Pharmacol. 2020 Apr;9(4):533-537 delusions, hallucinations (generally auditory), India). The drugs were purchased from the companies combativeness (aggression) or suspicion. Negative ones through their authorized representatives. include- anhedonia, avolition, ambitendency, affect flattening and slowness of activity while lastly cognitive Animals defects like disorganized thinking, reasoning and memory. Adult Swiss albino mice (25-30 g) of either sex were procured from the central animal house, M.G.M. medical Current therapy for psychotic disorders is either by the college, Indore and acclimatized for a period of 7 days, use of typical antipsychotic drugs (e.g. haloperidol, 12 hours cycles of light and dark, at room temperature of chlorpromazine and thioridazine etc) or atypical ones (25±20C) and (50±15%) relative humidity. They were (e.g. olanzapine, risperidone and clozapine etc.). Besides housed in a standard cage and maintained on standard the various adverse effects seen with typical ones, many pellets and water at Librium. The animals were used as patients have still persistence of residual symptoms (to per standard animal care guidelines. The study was done the extent of 60% with typical group, even with in the department of pharmacology, M.G.M. Medical worsening of cognition and secondary depression which College, Indore and the study protocol were approved by are only partially improved by atypical ones (cognitive the institutional animals’ ethics committee (IAEC) defects may still remain up to 30%) in addition to registered with CPCSEA (Reg No 709). positive and negative symptoms.2 Hence a constant search is on for newer drugs which can be useful in above Methylphenidate induced psychosis cognitive features too. So, we planned our study by using an anticholinesterase drug like donepezil, which is Animals were kept fasting after midnight and only water currently US FDA approved for Alzheimer’s disease. was allowed in the morning. The psychosis was induced Donepezil is used as an off labelled drug for bipolar in mice by using methylphenidate in dose of 5 mg/kg by disorders too. There is genetic similarity between the suspending in 2% gum acacia. Methylphenidate, by bipolar disorders and schizophrenia. The off springs of stimulating dopaminergic receptors in mesolimbic patients of schizophrenia patients are also found to have a system, can stimulate a stereotype behavior (purposeless, high frequency of bipolar mood disorders.3 Few of the repeated and abnormal facial movements like a gnawing, gene pair defects are associated with higher familial paw leaking and sniffing) in animals.6 This behavior is inheritance of above disorders: 1) a balanced reciprocal presently considered equivalent to psychotic features and translocation between 1q42 and 11q14.3, 2) there is used for evaluating the antipsychotic potential of new associated between 1.5 mega base deletion of 22q11 and drugs.7 Mice of either sex were selected and they were schizophrenia. It is associated with velo cardio facial randomly divided into 6 groups (n=6). syndrome.4,5 Group I animals received gum Acacia 2% 0.2 ml and Amphetamine is classically used as a model to induce considered as control group. Group II animals received psychosis and evaluate the antipsychotic activity in methylphenidate alone (5 mg/kg). Group III mice animals for new potential drugs. It works by stimulating methylphenidate (5 mg/kg) and haloperidol (0.2 mg/kg). of postsynaptic striatal fibres and mesolimbic dopamine Animals in group IV received methylphenidate (5 mg/kg) receptors by its release. We have tried to use and haloperidol (0.1 mg/kg). Group V mice received methylphenidate as an alternative to induce psychosis due methylphenidate (5 mg/kg) and donepezil (1 mg/kg) and to its similar CNS stimulant nature and pharmacological mice in group VI received methylphenidate (5 mg/kg), actions.6-9 It has been shown preliminary to induce donepezil (1 mg/kg), and haloperidol (0.1 mg/kg). stereotype in animals. Based on these findings, it was planned to induce psychosis in albino mice and to All the drugs were given by intraperitoneal route (i.p). evaluate the antipsychotic activity of donepezil alone and The drugs donepezil and haloperidol were given half an in combination with low dose haloperidol. The activity of hour before methylphenidate injection (pre-treatment) donepezil was also seen on haloperidol induced catatonia and animals placed in stainless steel cages and number of since enhanced cholinergic activity itself can theoretically stereotype movements were recorded for 10 minutes after aggravate extra-pyramidal potential and currently half an hour of methylphenidate injection. Stereotype centrally acting anticholinergics like biperidin and movements were characterized by continuous sniffing, trihexiphenidyl are used to treat above symptoms. licking or compulsive gnawing. An animal was considered to be protected if stereotype behavior was METHODS significantly reduced or abolished. Drugs and chemicals Haloperidol induced catatonia Injection Serenace (haloperidol 5 mg/ml, RPG LIFE, Principle-phenothiazines (chlorpromazine as prototype) India), Tab addwise (methylphenidate-10 mg-Sun and butyrophenone (e.g. haloperidatol) group of typical pharma, India), Tab Alzil (donepezil 5 mg, Intas pharma, antipsychotic drugs is known to produce extra pyramidal symptoms like akinesia, tremors and rigidity International Journal of Basic & Clinical Pharmacology | April 2020 | Vol 9 | Issue 4 Page 534 Tanwani H et al. Int J Basic Clin Pharmacol. 2020 Apr;9(4):533-537 (parkinsonian features) in humans.1 These symptoms are RESULTS due to blockage of dopamine receptors, causing imbalance of its ratio with acetylcholine at basal Antipsychotic activity ganglion. Therefore, above drugs are used in animals to induce catatonia symptoms and
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