Celecoxib-induced gastrointestinal, liver and brain lesions in rats, counteraction by BPC 157 or L-arginine, aggravation by L-NAME

Abstract

AIMTo counteract/reveal celecoxib-induced toxicity and NO system involvement.METHODSCelecoxib (1 g/kg b.w. ip) was combined with therapy with stable gastric pentadecapeptide BPC 157 (known to inhibit these lesions, 10 μg/kg, 10 ng/kg, or 1 ng/kg ip) and L-arginine (100 mg/kg ip), as well as NOS blockade [N(G)-nitro-L-arginine methyl ester (L-NAME)] (5 mg/kg ip) given alone and/or combined immediately after celecoxib. Gastrointestinal, liver, and brain lesions and liver enzyme serum values in rats were assessed at 24 h and 48 h thereafter.RESULTSThis high-dose celecoxib administration, as a result of NO system dysfunction, led to gastric, liver, and brain lesions and increased liver enzyme serum values. The L-NAME-induced aggravation of the lesions was notable for gastric lesions, while in liver and brain lesions the beneficial effect of L-arginine was blunted. L-arginine counteracted gastric, liver and brain lesions. These findings support the NO system mechanism(s), both NO system agonization (L-arginine) and NO system antagonization (L-NAME), that on the whole are behind all of these COX phenomena. An even more complete antagonization was identified with BPC 157 (at both 24 h and 48 h). A beneficial effect was evident on all the increasingly negative effects of celecoxib and L-NAME application and in all the BPC 157 groups (L-arginine + BPC 157; L-NAME + BPC 157; L-NAME + L-arginine + BPC 157). Thus, these findings demonstrated that BPC 157 may equally counteract both COX-2 inhibition (counteracting the noxious effects of celecoxib on all lesions) and additional NOS blockade (equally counteracting the noxious effects of celecoxib + L-NAME).CONCLUSIONBPC 157 and L-arginine alleviate gastrointestinal, liver and brain lesions, redressing NSAIDs’ post-surgery application and NO system involvement.

Lectinocytochemical study of rat stomach mucosa under the conditions of cyclooxygenase-1/-2 blockage and pretreatment witH H-Glu-Asp-Gly-OH

“…Prostaglandins are known to play a crucial role in the processes of gastric mucosa integrity maintenance, including contributing to the decrease of hydrogen chloride production in stomach in response to stimuli, the increase of bicarbonate secretion, production of the protective mucus in the gastrointestinal tract, phospholipid biosynthesis, and enhanced blood flow [1,2]. Gastrointestinal complications are probably the most critical adverse effects of NSAIDs and the indomethacin model of experimental gastric lesion induction is well described in the literature [1,2,5]. In our studies nonselective cyclooxygenase-1/2 blockage with indomethacin also resulted in extensive gastric mucosal damage.…”

“…Nonsteroidal antiinflammatory drugs (NSAIDs), whose therapeutic effect is based on the inhibition of cyclooxygenase (COX) activity, are the most commonly prescribed medications worldwide for the management of pain and inflammation, however adverse effects of NSAIDs, in particular stomach mucosa toxicity, present one of the major health care challenges [1,2,[4][5][6]. Research data from the last decade provide scientific evidence that various short chain peptides may be worth attention as promising gastroprotective agents, especially for chronic NSAIDs users [2][3][4][5][6]. Short derivatives of regulatory peptides are known to be involved in the regulation of acid/base secretion in the gastrointestinal tract, motility, enzymatic activity, production of prostaglandins and nitric oxide and interaction with the neuroendocrine system [2,[4][5][6].…”

“…Research data from the last decade provide scientific evidence that various short chain peptides may be worth attention as promising gastroprotective agents, especially for chronic NSAIDs users [2][3][4][5][6]. Short derivatives of regulatory peptides are known to be involved in the regulation of acid/base secretion in the gastrointestinal tract, motility, enzymatic activity, production of prostaglandins and nitric oxide and interaction with the neuroendocrine system [2,[4][5][6]. Important characteristics of oligopeptides, in contrast to conventionally used proton pump inhibitors or blockers of histamine-2 receptors, are lack of side effects and extremely low effective doses [2,4,5].…”

“…Short derivatives of regulatory peptides are known to be involved in the regulation of acid/base secretion in the gastrointestinal tract, motility, enzymatic activity, production of prostaglandins and nitric oxide and interaction with the neuroendocrine system [2,[4][5][6]. Important characteristics of oligopeptides, in contrast to conventionally used proton pump inhibitors or blockers of histamine-2 receptors, are lack of side effects and extremely low effective doses [2,4,5]. Oligopeptides were also reported to be resistant to the influence of gastric and enteric proteinases, which allows their oral administration to the patient [4].…”

Celecoxib treatment improves muscle function in mdx mice and increases utrophin A expression

“…It did not come as a surprise that a low dose could have a significant effect in mdx mouse muscles, because treatment with a low celecoxib dose has been shown to be sufficient to have beneficial effects in mice with spinal muscular atrophy by activating survival motor neuron expression and in cancer cells by regulating the cell cycle and apoptosis (56,103). It is important to note that at higher doses, celecoxib treatment can have damaging side effects, such as increased likelihood of cardiovascular thrombotic events and liver and gastrointestinal lesions (88,104,105). However, when converting the dose required for the attenuation of the dystrophic pathology in mice to an equivalent human dose by adjusting for differences in body surface area (106), we obtained a dose ;100 times smaller than the recommended oral dose for patients (1-5 mg/kg twice daily).…”