Chemico-Biological Interactions 190 (2011) 155–164 Contents lists available at ScienceDirect Chemico-Biological Interactions journal homepage: www.elsevier.com/locate/chembioint Gastroprotective potential of risperidone, an atypical antipsychotic, against stress and pyloric ligation induced gastric lesions Bhagawati Saxena, Sairam Krishnamurthy, Sanjay Singh ∗ Department of Pharmaceutics, Institute of Technology, Banaras Hindu University, Varanasi, Uttar Pradesh 221005, India article info Article history: Received 19 July 2010 Received in revised form 1 February 2011 Accepted 4 February 2011 Available online 18 February 2011 Keywords: Risperidone Gastroprotective Cold restraint stress Prostaglandin K ATP channel Nitric oxide Sulpiride Ketanserin abstract Risperidone has been used in some stress disorders and may be potentially protective against stress- induced gastric lesions. Thus, the aim of the present study is to investigate, whether risperidone, a D 2 receptor and 5-HT 2A receptor antagonist, would be able to result in gastroprotective effect in stress- induced lesions and also explore the possible mechanism of action behind its gastroprotective activity. Gastroprotective activity of risperidone was evaluated both by single treatment and 21 days repeated (0.03, 0.1, 0.3 and 1 mg/kg, p.o.) treatment in the cold restraint stress (CRS) model and 21 days repeated treatment in the pyloric ligation (PL) model and compared with that of sulpiride (D 2 receptor antagonist) and ketanserin (5-HT 2 receptor antagonist) as standard. Histopathological assessment was done to evalu- ate the gastroprotective activity of risperidone in CRS model. The roles of nitric oxide (NO), sulfhydryl (SH) group, ATP-sensitive K + channels (K ATP channels) and prostaglandins (PGs) in the gastroprotective effect of risperidone against CRS were also investigated. PGE 2 , hexosamine as a marker of mucus barrier and microvascular permeability were also estimated. Results show that repeated treatment of risperidone, sulpiride and ketanserin exhibited a gastroprotective effect against CRS-induced lesions while single administration of risperidone was found to be ineffective. Moreover, repeated treatment of risperidone and ketanserin was found to be ineffective in case of PL in contrast to sulpiride. Risperidone pretreatment reverses the stress induced alteration in hexosamine, PGE 2 and microvascular permeability. Pretreatment with l-NAME, NEM, glibenclamide and indomethacin reversed the gastroprotective effect of risperidone. The results suggest that risperidone has significant gastroprotective effects in CRS-induced gastric lesions models, which appears to be mediated by endogenous NO, SH, PGs and K ATP channel opening. © 2011 Elsevier Ireland Ltd. All rights reserved. 1. Introduction Gastric ulcer, a multi-etiologic disease, is one of the most com- mon chronic illnesses among adults. Despite great research, its etiology has not been completely elucidated. Various factors, such as imbalance between aggressive (increased acid and pepsin secre- tions) and protective factors (mucous and bicarbonates), stress, trauma, sepsis, hemorrhagic shock, burns, pulmonary and liver dis- eases, helicobacter pylori, use of cigarettes and alcohol, steroidal and non-steroidal drugs, have been shown to play a role in gastric ulcerogenesis [1,2]. Stress is one of the important factors for gastric lesions. Stress- related mucosal disease (SRMD) remains significant concern in critically ill patients and places them at a high risk of death. Clinical studies indicate that 75–100% of patients in the intensive care unit (ICU) suffer from SRMD [3]. SRMD not only increases the mortality due to excessive GI bleeding and multiple organ failure [4] but also ∗ Corresponding author at: Tel.: +91 542 6702707; fax: +91 542 2368314. E-mail address: drsanjaysingh@rediffmail.com (S. Singh). increases total cost of treatment by increasing the stay of patient at hospital [3]. Thus, due to the above facts stress ulcer prophylaxis has become an established routine practice in ICU [3]. Apart from this, depression with psychotic and somatic symp- toms has been seen in patients with gastrointestinal tract (GIT) diseases [5]. Further, one report shows that stress and psychosis shares common neuro-physiological pathways [6]. Both preclini- cal and clinical evidences suggest that atypical antipsychotics may modulate the stress response [7]. Glavin and Hall [8] reported cloza- pine, an atypical antipsychotic is beneficial in stress-induced gastric lesions. Another known atypical antipsychotic drug is risperidone, known for antagonistic activities toward both dopamine (D 2 ) and 5-hydroxytryptamine (5-HT 2A ) receptors [9]. However, as of now risperidone has not been explored for its gastroprotective activity against stress-induced gastric lesions. Risperidone has been shown to be effective in the treatment of post-traumatic stress disorder (PTSD) [10]. As stress is common denominator between stress related mucosal disorder and post- traumatic stress disorder, risperidone may be beneficial for the treatment of stress-induced gastric lesions. Further, it has been reported that risperidone has anxiolytic activity [11] and certain 0009-2797/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.cbi.2011.02.002