Keywords : Paracetamol, Chronic Treatment, Oxidative Stress, Synaptic Ultrastructure, Synaptophysin, Postsynaptic Density-95

Backgrounds: Several studies have recently revealed that cognitive function can be affected by paracetamol (APAP) treatment. However, the exact impact of this drug treatment on learning and memory has not been clarified. This study aimed to investigate the effect of APAP treatment on the alteration of synapses and oxidative stress in the rat frontal cortex and hippocampus.

Methods:  APAP at a dose of 200 mg/kg bw was fed to adult male Wistar rats through either acute (0 days, n = 10), sub-chronic (15 days, n = 10) or chronic (30 days, n = 10) treatment regimens. The synaptic ultrastructure and proteins, synaptophysin (SYP) and postsynaptic density-95 (PSD-95), were monitored. The amount of protein carbonyl oxidation (PCO) and glutathione (GSH) levels were examined. Our results demonstrated that acute treatment with APAP had no effect on the synapses and oxidative stress. However, the synapses obtained from rats with subchronic APAP treatment showed a marked shortening of active zones and widening of the synaptic cleft. Decrement of SYP and PSD-95 proteins were demonstrated in these rats as well. With 30-day APAP treatment, the alteration of the synaptic ultrastructure and proteins was more evident. Moreover, the depletion of GSH and the elevation of PCO levels were demonstrated in the rats treated chronically with APAP.

Conclusions: These results suggest that chronic APAP treatment can induce synaptic degeneration in the hippocampus and frontal cortex. The increase in oxidative stress in these brain areas may be due to the deleterious effect of this drug.