In this research, liver damage caused by experimentally induced ischemia-reperfusion was compared to the biochemical and histological effects of molnupiravir. In a study identical to this one, Tanrikulu et al. temporarily occluded the hepatic pedicle to cause ischemia (12). Then, reperfusion was achieved. In their research, Gundogdu et al. also used the ischemia-reperfusion paradigm (13). Following the excision, the tissues were histopathologically and biochemically examined. In our research, a clamp was set on the hepatic artery for one hour to create complete hepatic ischemia, followed by six hours of reperfusion.
The evidence leads us to believe that elevated free oxygen radicals cause injury from ischemia-reperfusion in any system or organ (14). Superoxide, hydroxyl radicals, hydrogen peroxide are traditionally cited as the main culprits in reperfusion injury (15). First, in the LIR and MIR groups of our experiment, we determined an increase in MDA levels and a decrease in tGSH levels. The increase in MDA and decrease in tGSH were greater in the MIR group. When the equilibrium among oxidants and antioxidants is thrown off, oxidative damage occurs. Notwithstanding the fact that MDA is an oxidative final product, our findings show that free oxygen radicals are responsible for the harm caused by ischemia and subsequent reperfusion. This is true even if MDA is an oxidant end product. Our results are in line with earlier studies that claim free oxygen radicals may injure the liver (16). On the other hand, research has revealed that ischemia-reperfusion formation activation boosts the production of proinflammatory cytokines such IL-1β, TNF-α, and NF-κB (17, 18). Numerous proinflammatory mediators are produced when NF-κB is activated, which results in organ damage (19). Inflammatory mediators that start inflammation include TNF-α and IL-1β. In our investigation, IL-1β, TNF- α, and NF-κB levels were also greater in the LIR and MIR groups. Although the increase in IL-1β, TNF-α, and NF-kB was not statistically significant, it was greater in the MIR group. Thus, we draw the conclusion that these abnormalities may be brought on by inflammatory reactions brought on by liver damage. Although the MIR group's liver damage was not statistically significant, we may say that molnupiravir enhances ischemia/reperfusion injury because IL-1β, TNF-α, and NF-kB were higher than in the LIR group.
The LIR group's histopathological findings revealed extensive hepatocyte degeneration and necrosis and moreover cells of inflammation in the parenchyma and portal region, which showed that the tissue of liver had been harmed by oxidation and inflammation processes. After ischemia-reperfusion, it was also shown that hepatocytes resembled one another in the liver parenchyma, according to Gundogdu et al. (13). In our study, histopathological examination revealed that congestion/hemorrhage, hepatosteatosis, and cytoplasmic fading were statistically substantially higher in the LIR group than in the SG group and in the MIR group compared to the LIR group. When the abnormalities in the nuclei were examined, it was shown that apoptotic nuclei were much greater in the LIR and MIR groups compared to the SG group, but there was no significant difference between the MIR and LIR groups. The LIR group had much more necrotic/pycnotic nuclei than the SG group, and the MIR group had significantly more than the LIR group. Based on these findings, it can be said that molnupiravir contributes negatively to the pathology of reperfusion injury after ischemia.
According to our hypothesis, elevation in ALT and AST levels, increased levels of MDA, IL-1β, TNF-α and NF-kB, and histopathological changes may be caused by oxidative and inflammatory processes. These results show that variations in oxidative and inflammatory balance may be responsible for the observed anomalies in ALT and AST levels as well as the overall histopathological changes. The ALT and AST levels in the LIR and MIR groups in our study were found to be relatively high when compared to the SG group, however even though they were greater in the MIR group than the LIR group, this difference was not statistically significant.
The ribonucleoside analog N-hydroxycytidine (NHC), which is the basis of the oral prodrug molnupiravir, has demonstrated in vitro activity against a number of coronaviruses, including SARS-CoV-1 and SARS-CoV-2. At dosages of 400 to 1600 mg twice daily, it has been determined to be safe, with no obvious dose-related toxicity and no increased incidence of adverse events compared to placebo. Molnupiravir was administered to more than 900 participants in pre-licensing studies for 5 days; no clinically significant liver damage cases were reported (8). In our research, it was found that those who received molnupiravir treatment for five days had higher ischemia/reperfusion harm than those who only received ischemia/reperfusion. The amount of the damage was greater, even though this difference in the biochemical tests was not statistically significant. This finding shows that molnupiravir can worsen liver injury in stressful situations like ischemia/reperfusion, in contrast to earlier research demonstrating no negative effects on normal liver tissue.
This study has several limitations that need to be made clear. Considering the reality that we use a small number of rats; we made an effort to respect animal rights by using as few as possible. Second, a future study may compare the effects of molnupiravir against those of other antioxidants, which would be fascinating to do. Finally, because this is an experimental investigation, direct dose and pharmacokinetic comparisons between species may create modifications to administration and metabolism.