Polaprezinc (Zinc L-Carnosine) Is a Potent Inducer of Anti-oxidative Stress Enzyme, Heme Oxygenase (HO)-1 — a New Mechanism of Gastric Mucosal Protection

Abstract

Abstract. Heme oxygenase (HO)-1 is implicated in cytoprotection in various organs. We tested a possibility that polaprezinc (PZ), an anti-ulcer drug, could induce HO-1 in the gastric mucosa. Male 6-week-old Wistar rats were intragastrically administered PZ. Gastric expression of HO-1 was assessed by real time RT-PCR and western blotting, and localization of HO-1 was observed by in situ hybridization and immunohistochemistry. The levels of HO-1 mRNA were increased in a dose-dependent manner. The levels of HO-1 mRNA were increased 4-fold by PZ at the dose of 200 mg/ kg at 3 h as compared with control levels. The levels of immunoreactive HO-1 were increased 3-fold at 6 h. Signals for HO-1 mRNA and immunoreactivity were detected strongly in the surface gastric mucosal cells and moderately in the gastric macrophages. Treatment with an HO-1 inhibitor, stannous mesoporphyrin (SnMP) significantly worsened the HCl-induced acute gastric mucosal lesions and increased the apoptosis of mucosal cells. Mucosal lesions were decreased by pretreatment with PZ, while they were increased by co-administration with SnMP. These data indicate for the first time that PZ is an effective inducer of HO-1 in the stomach. PZinduced HO-1 functions as a part of the mucosal protective effects of PZ.

Gastroprotective Oligopeptides

“…Oligopeptides were shown to be involved in the regulation of intracellular communication processes, nociception, vessel permeability, neoangiogenesis, nervous impulse transduction as well as affect the activity of hormones and enzymes and exhibit neuro-and immunomodulatory effects [13][14][15][16][17][18][19][20][21]. It is also hypothesized that biological activity of short peptides is mainly associated with their prominent antioxidant properties, although this data is a little bit contradictory as some compounds were reported to have an opposite effect, increasing the processes of oxidation [2,8,16,[24][25][26].…”

“…For example, it is known that dipeptide L-carnosine, that for about two decades is used in Japan as antiulcer remedy, exerts its gastroprotective effect through the stimulation of protective mucous production and increases the activity of antioxidant defense enzymes and heat shock proteins expression in stomach, dose dependently preventing gastric ulceration [26].…”

“…In 1979, the team of Y. Taché and coauthors reported for the first time that peptides act in the brain to protect against the development of gastric erosions induced by cold restraint stress in rats [11,26,41]. They injected the 14-amino acid neuropeptide bombesin into the cisterna magna and noted the changes in the autonomic nervous system activity, resulting in the simultaneous inhibition of gastric acid and pepsin secretion and motility [42].…”

“…Oligopeptides were shown to be involved in the regulation of intracellular communication processes, nociception, vessel permeability, neoangiogenesis, nervous impulse transduction as well as affect the activity of hormones and enzymes and exhibit neuro-and immunomodulatory effects [13][14][15][16][17][18][19][20][21]. It is also hypothesized that biological activity of short peptides is mainly associated with their prominent antioxidant properties, although this data is a little bit contradictory as some compounds were reported to have an opposite effect, increasing the processes of oxidation [2,8,16,[24][25][26].Due to the recent literary data, the most explored representatives of oligopeptides with gastroprotective properties are met-enkephaline (His-D-Trp-Ala-Trp-D-Phe-Lys-NH2) [27,28] and leu-enkephaline (Tyr-Gly-Gly-Phe-Leu) [27][28][29], demorphine (Н-Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH 2 ) and sedatine (H-ArgTyr-D-Ala-Phe-Gly-OH) [5,30], pentadecapeptide BPC 157 (GlyGlu-Pro-Pro-Pro-Gly-Lys-Pro-Ala-Asp-Asp-Ala-Gly-Leu-Val) [10,[31][32][33]; proline-and hydroxyproline-containing products …”

P2‐452: Effects of dietary supplementation of carnosine on mitochondrial dysfunction, amyloid pathology, and cognitive deficits in 3xTg‐AD mice

“…Thus, in such scenario, a decreased Zn 2+ bioavailability induced by carnosine supplementation may in part exert negative effects on the neurotransmission and neurotrophic signalling that modulate cognitive functions, and in doing so, counteracts the positive activity on amyloid deposition and mitochondrial functioning. In that respect, it could be interesting to verify the possibility that more effective synergistic activity can be achieved when carnosine and Zn 2+ are administered together in a combined form similarly to what has been described for the compound named Polaprezinc, a preparation that combines Zn 2+ and Lcarnosine [48,49]. In theory, this compound, given the different K d for Zn 2+ of carnosine and Ab can act as an homeostatic molecule that sequesters Zn 2+ from Ab but then releases a sufficient amount of the cation in the synaptic cleft to exert neurotrophic actions.…”