Curcumin alleviates the manganese-induced neurotoxicity by promoting autophagy in rat models of manganism / 北京大学学报(医学版)

OBJECTIVE@#To investigate the protective effects of curcumin(CUR) and its mechanism on a rat model of neurotoxicity induced by manganese chloride (MnCl2), 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) H2O intragastrically (ig), MnCl2 group received 15 mg/kg MnCl2(Mn2+ 6.48 mg/kg) intraperitoneally plus dd H2O intragastrically, CUR group received 0.9% saline solution intraperitoneally plus 300 mg/kg CUR intragastrically, MnCl2+ CUR1 group received 15 mg/kg MnCl2 intraperitoneally plus 100 mg/kg curcumin intragastrically, MnCl2+ CUR2 group received 15 mg/kg MnCl2 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 in situ, 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 MnCl2 for four weeks, MnCl2-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 (P < 0.05). The striatal TH+ neurocyte significantly decreased, eosinophilic cells, aggregative α-Syn level and TUNEL-positive neurocyte significantly increased in the striatum of MnCl2 group compared with control group (P < 0.05). Chromatin condensation, mitochondria tumefaction and autophagosomes were observed in rat striatal neurocytes of MnCl2 group by TEM. TFEB nuclear translocation and autophagy occurred in the striatum of MnCl2 group. Further, the depressive behavior, movement and balance ability, spatial learning and memory ability of MnCl2+ CUR2 group were significantly improved compared with MnCl2 group (P < 0.05). TH+ neurocyte significantly increased, the eosinophilic cells, aggregative α-Syn level significantly decreased in the striatum of MnCl2+ CUR2 group compared with MnCl2 group. Further, compared with MnCl2 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 MnCl2+ CUR2 group (P < 0.05).@*CONCLUSION@#Curcumin alleviated the MnCl2-induced neurotoxicity and α-Syn aggregation probably by promoting TFEB nuclear translocation and enhancing autophagy.

Effects of Chronic Manganism on Hearing and Cochlear Cells in Rats / 听力学及言语疾病杂志

Objective To study the effects of chronic manganism on hearing and cochlear cells in rats by using animal model of chronic manganism .Methods Sixty adult SD rats were randomly divided into Mn - exposed and controlgroups.RatsweretreatedwithMnCl24H2O(100mg·kg -1·d-1)ordeionizedwaterbygastricperfusion, lasted for 12 weeks .The Mn concentration in peripheral blood was measured respectively at 4 weeks ,8 weeks and 12 weeks after treatment .At 12 weeks after treatment ,the auditory brainstem response was recorded ,the hair cells morphology and counting were examined by stretched preparation of basilar membrane stained with FITC -phalloi-din ,and the spiral ganglion cells morphology and counting were studied by HE staining ,the ultrastructure changes of hair cells and spiral ganglion cells were detected by transmission electron microscopy .Results The blood Mn concentration increased gradually with time after treatment .ABR thresholds at 4 ,8 ,16 ,24 and 32 kHz were sig-nificantly increased at 12 weeks after treatment ,especially in the high-frequency range .Morphological study at 12 weeks after treatment showed loss of outer hair cells ,mainly in the basal turn of the cochlea ,and decreased number of spiral ganglion cells .The ultrastructure changes of outer hair cells and spiral ganglion cells included the break -ups ,disappearance or vacuolar change of mitochondria cristas .Conclusion Our data demonstrate that chronic man-ganism can cause loss of outer hair cells and spiral ganglion cells in cochlear in rats ,leading to hearing loss .

Neurobehavioral Deficits and Parkinsonism in Occupations with Manganese Exposure: A Review of Methodological Issues in the Epidemiological Literature

Exposure to manganese (Mn) is associated with neurobehavioral effects. There is disagreement on whether commonly occurring exposures in welding, ferroalloy, and other industrial processes produce neurologically significant neurobehavioral changes representing parkinsonism. A review of methodological issues in the human epidemiological literature on Mn identified: (1) studies focused on idiopathic Parkinson disease without considering manganism, a parkinsonian syndrome; (2) studies with healthy worker effect bias; (3) studies with problematic statistical modeling; and (4) studies arising from case series derived from litigation. Investigations with adequate study design and exposure assessment revealed consistent neurobehavioral effects and attributable subclinical and clinical signs and symptoms of impairment. Twenty-eight studies show an exposure-response relationship between Mn and neurobehavioral effects, including 11 with continuous exposure metrics and six with three or four levels of contrasted exposure. The effects of sustained low-concentration exposures to Mn are consistent with the manifestations of early manganism, i.e., consistent with parkinsonism. This is compelling evidence that Mn is a neurotoxic chemical and there is good evidence that Mn exposures far below the current US standard of 5.0 mg/m3 are causing impairment.

Research Progress on Biomarkers of Manganism / 环境与健康杂志

Manganese(Mn) is one of the essential trace elements in biologic metabolism.With proper quantity,Mn acts as some enzymes’active groups,reactivators,and participates in the physiological functions of central nervous system.Overdose exposure to Mn in industry may result in occurrence of occupational manganism,which can cause damage of many aspects of the body such as nerve,immunity and reproduction.The aim of present essay is to review the current studies on nerval behavior function and biomarkers of manganism both in China and other countries.