NEEM FOR GASTRIC HYPERACIDITY AND ULCER 747 Copyright © 2009 John Wiley & Sons, Ltd. Phytother. Res. 23, 747–755 (2009) DOI: 10.1002/ptr Copyright © 2009 John Wiley & Sons, Ltd. PHYTOTHERAPY RESEARCH Phytother. Res. 23, 747–755 (2009) Published online 12 January 2009 in Wiley InterScience (www.interscience.wiley.com) DOI: 10.1002/ptr.2721 REVIEW ARTICLE The Use of Neem for Controlling Gastric Hyperacidity and Ulcer Pallab Maity 1 , Kaushik Biswas 2 , Ishita Chattopadhyay 2 , Ranajit K. Banerjee 2 and Uday Bandyopadhyay 1 * 1 Division of Infectious Disease and Immunology, Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Jadavpur, Kolkata-700032, West Bengal, India 2 Division of Physiology, Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Jadavpur, Kolkata-700032, West Bengal, India H 2 -receptor blockers and proton pump inhibitors are now used extensively to control gastric and duodenal ulcer, inflammation and pain, but these drugs have limitations and are not always affordable. The development of novel nontoxic antiulcer drugs, including from medicinal plants, is therefore desirable, and Azadirachta indica A. Juss, commonly known as Neem, is known to have potent gastroprotective and antiulcer effects. This review deals with the pharmacological and biochemical studies carried out regarding the antiulcer activities of Neem extracts and their mechanism of action, including the inhibition of acid secretion. A comparison with ranitidine and omeprazole in some animal models has been included and clinical studies, where available, have also been incorporated, along with a safety evaluation. Neem bark extract has the potential for the development of novel medicines for the therapeutic control of gastric hyperacidity and ulcer. Copyright © 2009 John Wiley & Sons, Ltd. Keywords: Neem; antiulcer activity; hyperacidity; oxidative stress; gastric mucosal apoptosis. Received 26 August 2008 Accepted 15 September 2008 * Correspondence to: Uday Bandyopadhyay, Division of Infectious Disease and Immunology, Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Jadavpur, Kolkata-700032, West Bengal, India. E-mail: ubandyo_1964@yahoo.com Contract/grant sponsor: Council of Scientific and Industrial Research (CSIR), New Delhi; contract/grant number: Suprainstitutional Project (SIP 0007). INTRODUCTION The gastric mucosa is under constant attack by both endogenous and exogenous factors which induce gastric damage, but these are counterbalanced by endogenous gastroprotective factors which maintain the integrity of the mucosa (Holzer, 2000; Wallace and Granger, 1996). Endogenous damaging factors mainly include histamine, acid, pepsin, reflux bile, leukotrienes, pro-inflammatory cytokines, ischaemia, activated neutrophils, reactive oxygen species (O 2 •- , H 2 O 2 , • OH) and proapoptotic pro- teins. Exogenous damaging factors include stress (Cho et al., 1992; Miller, 1987), non-steroidal antiinflammatory drugs (NSAIDs) such as indomethacin, aspirin and phenylbutazone etc. (Hawkey, 2000; Ivey, 1988), alco- hol (Liu and Cho, 2000) and Helicobacter pylori, a gram- negative bacteria (Konturek et al., 1999a; Marshall and Warren, 1984). The main gastroprotective factors are prostaglandins, the mucus–bicarbonate barrier, surface- active phospholipids, mucosal blood flow, angiogenic factors, nitric oxide, antioxidants and antioxidant enzymes, cell proliferating/growth factors and antiapoptotic pro- teins. Gastric ulcer develops when the balance between damaging and protective factors is lost, and is exacerbated by the secretion of acid-peptic juice, which although a physiological event, aggravates the ulcer by cell dam- age and capillary destruction thereby preventing wound healing (Tarnawski and Halter, 1995). Although anti- ulcer therapy employing proton pump inhibitors (such as omeprazole, lansoprazole, pantoprazole) and H 2 receptor blockers (such as ranitidine, famotidine) is effective (Howden and Hunt, 1994; Langtry and Wilde, 1998), recent interest has been directed towards the development of novel non-toxic antiulcer drugs, includ- ing from medicinal plants used traditionally. In this re- gard, extracts from Neem (Azadirachta indica indica A. Juss) have been shown to possess potent antisecretory and antiulcer activities (Bandyopadhyay et al., 2002; Chattopadhyay et al., 2004; Dorababu et al., 2004; Garg et al., 1993). This review presents the pharmacological, biochemical and clinical evidence for the therapeutic potential of Neem extracts and their mechanism of action, for the prevention and treatment of gastric ulcer and related conditions. CELLULAR AND MOLECULAR BASIS OF GASTRIC ULCERATION The pathogenesis of gastric ulceration is a multifactorial process which is associated with inflammation, acid- induced necrosis, oxidative damage, apoptosis and loss of gastroprotection. The following are considered to be major causative factors for the gastric lesions: oxidative injury induced by reactive oxygen species (ROS) (Guslandi, 1999; Phull et al., 1995), which develop due to neutrophil infiltration (Wallace et al., 1990), a disturbed antioxidant system (Bhattacharjee et al., 2002; Das and Banerjee, 1993) and ischaemia (Perry et al., 1986) caused by mucosal microvascular damage and decreased blood flow (Konturek et al., 1999b; Kwiecien et al., 2002).