Comparison of effects of high and low dose paracetamol treatment and toxicity on brain and liver in rats

Abstract

P aracetamol is one of the most widely used drugs in the world as analgesics and antipyretics. Although it has been classified as non-steroidal anti-inflammatory drugs (NSAIDs) for many years, it has been classified as "other" analgesic and antipyretic drugs in recent years due to lack of anti-inflammatory properties. Although it acts by inhibiting the cyclooxygenase (COX) enzyme and prostaglandin synthesis, such as NSAIDs, several studies have shown that the potential for inhibition of COX enzymes in peripheral tissues is quite low [1]. Therefore, ABSTRACT OBJECTIVE: Paracetamol is thought that it acts by inhibiting the central cyclooxygenase (COX) enzyme; its mechanism of action is still not fully explained. Although its most important side effect is hepatoxicity, it is thought to cause toxicity on the brain in recent years. The present study aims to investigate the treatment and toxic effects of low and high doses of paracetamol on the liver and brain. METHODS: Wistar-albino rats were used in this study. At doses of 20-500 mg/kg, paracetamol was administered intraperitoneally once a day for one and three days. The brain and liver were used for immunohistochemical evaluation using COX-3, prostaglandin E 2 (PGE 2) and caspase 3 antibodies and for total antioxidant (TAS), total oxidant (TOS) and oxidative stress index (OSI) measurements. Results were evaluated using the Kruskal Wallis test (SPSS ver.24). RESULTS: The liver COX-3 levels were significantly lower in both groups with higher doses (p<0.05). In the brain, there was no statistically significant difference in COX-3 levels between the groups. There was no statistically significant difference in PGE 2 levels in the liver and brain between the groups (p>0.05). The caspase 3 level in the liver was statistically significantly higher in the low dose group compared to the other groups (p<0.05). In both liver and brain, OSI values were significantly higher in the 3-day high-dose group compared to others (p<0.05). There was no statistically significant difference between the groups in ALT and AST values (p>0.05). CONCLUSION: The results of our study show that paracetamol inhibits the COX-3 enzyme in the liver but has no effect in the brain, and COX-3 does not have an effect on PGE 2. Paracetamol causes apoptosis in the liver only in low doses; higher doses may cause toxicity by increasing oxidative stress, especially in the brain.

Clinical and pharmacological approaches to the choice of a drug for a tension-type headache relief

“…Комбинирование с парацетамолом дает возможность усилить анальгетический эффект в результате аддитивного действия за счет центральных механизмов. В то же время в комбинированном препарате применяются более низкие дозировки парацетамола, что снижает вероятность возникновения нежелательных эффектов, связанных с приемом данного препарата, включая гепатотоксичность, окислительный стресс, в том числе в тканях мозга [35].…”

The protective effect of Thai rice bran on N-acetyl-ρ-aminophen-induced hepatotoxicity in mice

“…At therapeutic concentrations, it is safe; an adult’s typical dose is 10-15 mg/kg, and a maximum daily intake of 3-4 g is recommended ( 1 2 ). Despite being classified APAP as a non-steroidal anti-inflammatory drug (NSAID), it has very modest anti-inflammatory activities due to its ability to block the cyclooxygenase enzyme and prostaglandin synthesis ( 3 ). For treating fever and both acute and chronic pain, because of its many benefits including its affordable price, easy accessibility, and few side effects, APAP is often chosen as the first medication of choice ( 4 ).…”

“…Conversely, when ingested in excess, hepatocyte glutathione depots decrease and NAPQI levels rise. Glutathione reserves that fall below 30% of the typical level are the first indications of hepatic damage ( 3 6 ). Moreover, NAPQI, which is not metabolized, combines with lipids, proteins, and DNA in the cells to induce necrosis.…”