Gastric regulates gastric secretion (Coleman NS et al

Gastric secretion is also influenced by the levels of serotonin, an important neurotransmitter of the gastrointestinal tissue. It is widely distributed in the enterochromaffin cells of the gastric mucosa and enteric neurons of the gastrointestinal tract (Beattie DT and Smith JA 2008). It regulates gastric secretion (Coleman NS et al 2003), gastric mucus (Guha and Ghosh 1995), and motility and blood flow to the mucosa (Lepard KJ, et al 1996). The severity of gastric ulceration is also associated with the gastric serotonin levels. The levels of serotonin in the gastrointestinal tissue  decrease in ulcerated conditions as observed in our earlier study (Al Asmari et al 2014) and by others in different models of gastric ulcers (Guha and Ghosh 1995; Debnath S. et. al 2011), while increased gastric serotonin levels reduce gastric secretion in rat stomach (Penissi et al 1998; Debnath and Guha 2007). The inhibitory action of topiramate on gastric secretion in our study may also be assigned to its potential to increase the serotonin levels (Gross S, et al 2008). It has been reported that 5-HT simulates prostaglandin (PG) synthesis by enhanced activity of the cyclooxygenase pathway (Guha and Ghosh 1995), which in turn stimulates mucosal blood flow and helps in the secretion of mucus along with bicarbonate. We also observed an increase in the gastric mucus levels upon topiramate treatment (Fig   ). Since compounds that reduce the increased gastric secretion and acidity are helpful in the attenuation of gastric ulcers. Zhao XIN et al 2017; Tayeby F et al 2017 the gastro protective action of topiramate may also be due to its anti-gastric acid secretory property. 

Ethanol induced gastric ulceration also involves a reduction in gastric mucus and its permeability, leading to increased leakage of hydrogen ions from the lumen ( Kauffman G.L. Jr 1985). Mucus is one of the major components of the mucosal barrier that acts as a defensive shield against noxious substances in the gastric tissue and facilitates the normal functioning of the stomach. Mucus gel adhering to the mucus surface entraps the bicarbonate secreted by the gastric epithelium facilitating neutralization of the luminal acid that may diffuse towards the epithelium (Allen and Flemström 2005; Wallace and Grangers 1996). In addition, the mucus acts as a barrier to diffusion of low molecular weight solutes, microorganisms, and toxins (Seno et al 1995). Furthermore, mucus may also act as an antioxidant, and thus can prevent oxygen free radical-mediated damage to the gastric mucosa (Wallace and Grangers 1996; Seno et al 1995).

The results of this study wherein topiramate treatment significantly attenuated/reversed the ethanol-induced depletion of mucus levels (Fig 4), suggest that TPM protects against ethanol-induced gastric ulceration probably by enhancing the increased secretion of mucus or by stimulation of mucus production. Other recent studies also suggest that an increase in mucus secretion stimulated by different compounds attenuates experimental gastric lesions in rats (Tayeby F. et al 2017; Al Asmari et al 2016).  p53 is an important transcription factor and tumor suppressor that plays a key role in coordinating the many cellular signaling pathways that mediate cellular response to stress (Lazo 2017). P53 is expressed in the Helicobacter pylori infected human gastric mucosa as well as H. pylori associated chronic gastritis (Kodama et al 2007) and is activated upon cellular stress (Lazo 2017).  Our observation of an increased expression of p53 in ethanol treated rats (Fig —) may be the result of an immediate response of the gastric mucosa to the stimulation by exposure to ethanol. The expression of p53 increases in gastric ulcers and carcinoma (Li JH 2005; Bellini et al 2012; Patne SCU et al 2017).  A recent study reported a ten times higher expression of p53 in stomach of rats administered a single dose of ethanol as compared to normal animals (Hamad and Mohamed 2018). Earlier studies have also shown an association between hemorrhagic lesions and gastric ulceration and increased expression of p53 and caspase 3 activities in different models of gastric ulcers (Arab et al 2015; Liu et al 2012). One of the important functions of p53 is to activate the process of apoptosis. Induction of p53 has been observed to alter the REDOX metabolism resulting in an increase in reactive oxygen species and oxidative stress before the onset of apoptotic cell death (Polyak et al 1997). On the other hand, p53 mediated apoptosis and cell death are suppressed in the presence of antioxidant (Hamad and Mohamed 2017).  Our observation of a substantial decrease in the expression of p53 in TPM pre-treated rats may be assigned to its strong antioxidant activity and antiapoptotic effects  (Cardinas-Rodriguez et al 2013; Motaghinejad et al 2017;) and also to a decrease in the gastric mucosal damage induced by ethanol in the presence of TPM. Therefore it may be suggested that TPM treatment ameliorates the damaging effect of ethanol by reducing the expression and accumulation of p53.