Efeitos da azitromicina no sistema nervoso central em modelo de kindling induzido por pentilenotetrazol em camundongos

Abstract

Epilepsy is characterized by neuronal hyperexcitability and is associated with redox imbalance, which supports the investigation of drugs capable of modulating seizure outcomes and oxidative-nitrosative biomarkers. The effect of azithromycin (AZT) on the seizure phenotype and redox axis was evaluated in pentylenetetrazole (PTZ)-induced models in mice. An experimental, controlled, in vivo study was conducted, comprising an acute and a chronic model. In the acute model, AZT was administered intraperitoneally at doses of 100 or 200 mg/kg, followed by a challenge with 85 mg/kg PTZ to record the latencies to the first seizure and death. In the chronic model, PTZ-kindling (35 mg/kg on alternate days for 21 days) was used, with behavioral assessment using the Racine Scale. At the end of the protocols, reduced glutathione (GSH), nitrite, and thiobarbituric acid reactive substances (TBARS) were quantified in the prefrontal cortex, hippocampus, and striatum. A dual effect, dependent on dose and exposure time, was observed. In the acute model, AZT 100 mg/kg reduced the latency to the first seizure (median of 36 s vs. 49 s in the control), while AZT 200 mg/kg prolonged the time to death (median of 200 s vs. 173 s in the control). Biochemically, the acute phase was marked by a nitrosative peak, with a significant increase in nitrite across the three regions evaluated at the 200 mg/kg dose (p < 0.01). In the chronic model, the 200 mg/kg dose transiently attenuated seizure severity (median score 3.0 vs. 4.0 in the control; p = 0.0407 on day 13), whereas the 100 mg/kg dose was associated with high mortality and the maintenance of high scores (median between 4.0 and 5.0). In contrast to the acute phase, no statistically significant changes were detected in the redox panel (p > 0.05 for GSH, nitrite, and MDA) at the end of the kindling protocol, suggesting late biochemical adaptation or buffering. It was concluded that AZT acted as a complex and non-linear modulator in the central nervous system, with manifestations ranging from excitatory facilitation and transient behavioral attenuation to acute nitrosative induction, diverging from the profile of a classic and uniform neuroprotective agent.