In the present study, we investigated the mechanisms underlying the mediation of iron transport by Ltype Ca 2? channels (LTCCs) in primary cultured ventral mesencephalon (VM) neurons from rats. We found that cotreatment with 100 lmol/L FeSO 4 and MPP ? (1-methyl-4phenylpyridinium) significantly increased the production of intracellular reactive oxygen species, decreased the mitochondrial transmembrane potential and increased the caspase-3 activation compared to MPP ? treatment alone. Co-treatment with 500 lmol/L CaCl 2 further aggravated the FeSO 4 -induced neurotoxicity in MPP ? -treated VM neurons. Co-treatment with 10 lmol/L isradipine, an LTCC blocker, alleviated the neurotoxicity induced by co-application of FeSO 4 and FeSO 4 /CaCl 2 . Further studies indicated that MPP ? treatment accelerated the iron influx into VM neurons. In addition, FeSO 4 treatment significantly increased the intracellular Ca 2? concentration. These effects were blocked by isradipine. These results suggest that elevated extracellular Ca 2? aggravates ironinduced neurotoxicity. LTCCs mediate iron transport in dopaminergic neurons and this, in turn, results in elevated intracellular Ca 2? and further aggravates iron-induced neurotoxicity.

Growing evidence suggests, as Parkinson's disease (PD) progresses, that its non-motor symptoms appear prior to or in parallel with its motor deficits. Alpha-synuclein A53T transgenic mouse (A53T) is an essential tool to investigate the onsets and the extents of PD non-motor symptoms. Our aim is to investigate spatial learning and memory ability in A53T mice. In our rotarod tests, no motor coordination impairments were detected in mice of 3, 6, 9, and 12 months old. We then investigated their spatial learning and memory ability through Morris water maze in 3- and 9-month-old mice. No significant difference in escape latency was detected among the A53T mice and the control mice. However, an unexpected improvement in spatial learning and memory ability was observed in the probe session among the A53T mice. Reversal learning by Morris water maze also indicated that 3- and 9-month-old A53T mice exhibited a better cognitive flexibility compared to their littermate controls. Further studies by western blots showed that alpha-synuclein expressions in hippocampus of the A53T mice were noticeably up-regulated. The immunofluorescence staining of 5-bromo-2-deoxyuridine (Brdu) and doublecortin (DCX) demonstrated that neither the Brdu-positive neurons nor the Brdu/DCX positive neurons in hippocampus were significantly altered between the two groups. These results suggest that our A53T mice exhibit improved spatial learning and memory ability prior to their motor coordination deficits. These results are not induced by neurogenesis in the hippocampus.

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Previous research demonstrated that the progressive accumulation of iron in the substantia nigra pars compacta (SNpc) may contribute to dopaminergic (DA) neurons selective degeneration in Parkinson's disease (PD). However, the etiology and mechanism underlying iron-induced neurotoxicity processes are as yet unresolved. It has been reported that L-type calcium channels (LTCCs) may mediate iron influx into neuronal cells and can compete with calcium for common routes to enter primary neurons. The present study, we found that isradipine can alleviate iron-induced toxicity caused by raising intracellular calcium in MES23.5 cells. Analysis of experimental results revealed that an increase in extracellular free CaCl 2 (500 µmol/L) is sufficient to promote FeSO 4 (100 µmol/L) entry by activating L-type Ca 2+ channels (LTCCs) significantly. The enhancement of calcium and/or iron influx was accompanied by a corresponding decrease of cell viability and higher susceptibility of toxicity, such as decrease of mitochondrial membrane potential (ΔΨm) and increase of nucleus pyknosis ratio and cleaved caspase-3 protein expression in MPP + (5 µmol/L) treatment MES23.5 cells. Pre-treatment with isradipine (10 µmol/L), a LTCCs blocker, for 15 min, can antagonize calcium and/or iron-induced neurotoxicity. These results suggest that application of isradipine may be a potential method for the treatment of the neurodegenerative disease induced by calcium and/or iron dysmetabolism.