Effect of chronic paracetamol treatment on the alteration of learning and memory in rats

Abstract

Paracetamol (acetaminophen: APAP) is widely used for treatment of pain and fever. Although APAP is well accepted as a safe drug, several studies have recently demonstrated that treatment with this drug can lead to an alteration of several neurobehaviors. However, the exact impact of the APAP treatment and the mechanisms underlying those effects are still largely unknown. The present study aimed to investigate the effect of APAP treatment on the alteration of learning and memory and the possible mechanism underlying deleterious effects induced by APAP treatment. In this study, APAP at the dose of 200 mg/kg bw was orally fed to adult male Wistar rats through either acute (0 days), sub-chronic (15 days) or chronic (30 days) treatment regimens. The recognition and spatial memory in all experimental groups were assessed by using the novel object recognition (NOR) and Morris water maze (MWM) test, respectively. The changing of synaptic ultrastructure and proteins, synaptophysin (SYP) and postsynaptic density-95 (PSD-95), related with learning and memory were as well monitored in both the frontal cortex and hippocampus. Moreover, the expression of brain-derived neurotrophic factor (BDNF) was examined in all experimental groups. To investigate the involvement of oxidative stress on the alteration of learning and memory following APAP treatment, the oxidative stress markers including protein carbonyl oxidation (PCO), glutathione (GSH) level and nuclear factor erythroid-2-related factor 2 (Nrf2) were evaluated in the frontal cortex and hippocampus obtained from all experimental groups. The results demonstrated that, as compared with control, acute treatment with APAP had no any effect on learning and memory abilities. The alteration of synapses, BDNF protein expression and oxidative stress markers were not observed in the rats with 0-day APAP treatment. However, the results obtained from the rats treated with APAP for longer periods (sub and chronic treatments) demonstrated a reduction of NOR and MWM performance. The results obtained from the experiment with sub-chronic treatment showed an abnormality of synaptic interfaces (shortening in the active zone and widening of the synaptic cleft) as well as decrements of both SYP and PSD-95 in the hippocampus of the rats with APAP treatment. These alterations were observed in parallel with a down-regulation of hippocampal BDNF protein in those rats. Interestingly, an abnormality of the synapses was clearly demonstrated in the rats with chronic APAP treatment. In addition to the changing of synaptic interfaces (shortening of the active zone and widening of the synaptic cleft), the numbers of synapses in both the frontal cortex and hippocampus were decreased in rats with chronic APAP treatment. The reduction of both frontal cortical and hippocampal BDNF levels were also detected in these rats. Moreover, the alteration of oxidative stress markers indicating an increase of oxidative stress formation (up-regulation of Nrf2 protein, increment of PCO level, and depletion of GSH) were clearly demonstrated in the hippocampus obtained from chronic APAP treated group. Based on the results obtained from this study, we suggest that treatment with APAP for long period can induce an impairment of learning and memory. An increase of oxidative stress in the brain following chronic APAP treatment is possibly participated in the alteration of BDNF protein and synaptic integrity in the frontal cortex and hippocampus which can finally lead to an abnormality of learning and memory performance.