[Curcumin alleviates the manganese-induced neurotoxicity by promoting autophagy in rat models of manganism].

OBJECTIVE

To investigate the protective effects of curcumin(CUR) and its mechanism on a rat model of neurotoxicity induced by manganese chloride (MnCl), which mimics mangnism.

METHODS

Sixty male SD rats were randomly divided into 5 groups, with 12 rats in each group. Control group received 0.9% saline solution intraperitoneally (ip) plus double distilled water (dd) HO intragastrically (ig), MnCl group received 15 mg/kg MnCl(Mn 6.48 mg/kg) intraperitoneally plus dd HO intragastrically, CUR group received 0.9% saline solution intraperitoneally plus 300 mg/kg CUR intragastrically, MnCl+ CUR1 group received 15 mg/kg MnCl intraperitoneally plus 100 mg/kg curcumin intragastrically, MnCl+ CUR2 group received 15 mg/kg MnCl intraperitoneally plus 300 mg/kg CUR intragastrically, 5 days/week, 4 weeks. Open-field and rotarod tests were used to detect animals' exploratory behavior, anxiety, depression, movement and balance ability. Morris water maze (MWM) experiment was used to detect animals' learning and memory ability. ICP-MS was used to investigate the Mn contents in striata. The rats per group were perfused , their brains striata were removed by brains model and fixed for transmission electron microscope (TEM), histopathological and immunohistochemistry (ICH) analyses. The other 6 rats per group were sacrificed. Their brains striata were removed and protein expression levels of transcription factor EB (TFEB), mammalian target of rapamycin (mTOR), p-mTOR, Beclin, P62, microtubule-associated protein light chain-3 (LC3) were detected by Western blotting. Terminal deoxynucleotidyl transterase-mediated dUTP nick end labeling (TUNEL) staining was used to determine neurocyte apoptosis of rat striatum.

RESULTS

After exposure to MnCl for four weeks, MnCl-treated rats showed depressive-like behavior in open-field test, the impairments of movement coordination and balance in rotarod test and the diminishment of spatial learning and memory in MWM ( < 0.05). The striatal TH neurocyte significantly decreased, eosinophilic cells, aggregative α-Syn level and TUNEL-positive neurocyte significantly increased in the striatum of MnCl group compared with control group ( < 0.05). Chromatin condensation, mitochondria tumefaction and autophagosomes were observed in rat striatal neurocytes of MnCl group by TEM. TFEB nuclear translocation and autophagy occurred in the striatum of MnCl group. Further, the depressive behavior, movement and balance ability, spatial learning and memory ability of MnCl+ CUR2 group were significantly improved compared with MnCl group ( < 0.05). TH+ neurocyte significantly increased, the eosinophilic cells, aggregative α-Syn level significantly decreased in the striatum of MnCl+ CUR2 group compared with MnCl group. Further, compared with MnCl group, chromatin condensation, mitochondria tumefaction was alleviated and autophagosomes increased, TFEB-nuclear translocation, autophagy was enhanced and TUNEL-positive neurocyte reduced significantly in the striatum of MnCl+ CUR2 group ( < 0.05).

CONCLUSION

Curcumin alleviated the MnCl-induced neurotoxicity and α-Syn aggregation probably by promoting TFEB nuclear translocation and enhancing autophagy.