Efeito da indução autofágica em um modelo animal de disfunção cognitiva induzida pela sobrecarga de ferro no período neonatal

Abstract

The aim of the present study was to determine whether rapamycin, an autophagic inducer acting through the inhibition of the mTOR pathway, exerts neuroprotective activity in the cognitive dysfunction model induced by neonatal iron overload, and is able to improve memory. There are studies demonstrating that rapamycin is able to ameliorate the accumulation of toxic protein aggregates observed in neurodegenerative diseases, decrease cell death and cognitive symptoms related to these disorders. Autophagy is an event of cellular autodigestion and removal of components under physiological and pathological conditions. In the context of neurodegeneration, it is important for cell a high and refined control of autophagic regulation, so that the removal of protein deposits can be performed correctly. Moreover, it is already well understood that neonatal iron overload is related to several cognitive deficits, and the deposition of this metal occurs selectively and progressively with age, and may represent an important risk factor for the development of neurodegeneration in humans. Male Wistar rats received a single daily oral dose of vehicle or iron carbonyl (30 mg/kg) at postnatal days 12–14. At the age of 4 months, they received daily intraperitoneal injections of vehicle or rapamycin (0.25 mg/kg) for 14 days. The results showed that iron given in the neonatal period impaired inhibitory avoidance memory and induced a decrease in proteins critically involved in the autophagy pathway, Beclin 1 and LC3, in the hippocampus. Rapamycin in the adulthood reversed iron-induced memory deficits and recovered LC3 levels in iron treated rats. Our results suggest that iron accumulation, as observed in neurodegenerative disorders hinders autophagy, which might play a role in iron-induced neurotoxicity. Rapamycin, by inducing authophagy, was able to ameliorate iron-induced cognitive impairments. These findings support the use of rapamycin as a potential neuroprotective treatment of cognitive decline associated to neurodegenerative disorders.