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Hypoxia-inducible factor-1 alpha (HIF-1 alpha) is a transcription factor that activates the transcription of genes and is responsible for progression of cell survival and proliferation. The synthesis of HIF-1 alpha can be stimulated via oxygen (O(2))-independent mechanisms; whereas, the degradation of HIF-1 alpha is regulated via Fe(2+) and/or O(2)-dependent enzyme prolyl hydroxylase (PHD). Aberrant iron accumulation, mitochondrial dysfunction and impairment of protein degradation system, such as autophagy, have been implicated in the pathogenesis of Parkinson's disease, among which, iron and mitochondrial dysfunction may enhance the enzyme activity of prolyl hydroxylase and cause the decrease of HIF-1 alpha. Recent reports have indicated that HIF-1 alpha may induce autophagy under hypoxic condition. Considering the metabolic characteristics of HIF-1 alpha under the pathogenesis of Parkinson's disease, we speculated that compounds that might stabilize HIF-1 alpha could prevent neuronal injury caused by excessive iron or mitochondrial injury under normoxic condition. Deferoxamine is one of iron chelators that may accumulate HIF-1 alpha due to the decreased degradation of HIF-1 alpha via inhibition of prolyl hydroxylase activity. In this study, we showed that the protein level of HIF-1 alpha was decreased in rotenone or MPP(+)-treated SH-SY5Y cell models of Parkinson's disease. We demonstrated that deferoxamine caused accumulation of HIF-1 alpha accompanied by the enhancement of autophagy in SH-SY5Y cells. When HIF-1 alpha gene was inhibited, deferoxamine-induced autophagy was suppressed accordingly, indicating that deferoxamine-induced autophagy was dependent on the expression of HIF-1 alpha. Our results also showed that deferoxamine attenuated rotenone-induced apoptosis, which was blocked when HIF-1 alpha or autophagy related gene Beclin 1 was suppressed. In summary, the present study indicated that the level of HIF-1 alpha was decreased under the situation when mitochondrial complex I was inhibited, and the neuroprotective role of deferoxamine in rotenone-induced apoptosis could be partially explained by its effects on the accumulation of HIF-1 alpha and HIF-1 alpha-mediated induction of autophagy., ((c) 2010 Elsevier Ltd. All rights reserved.)

Oxidative stress has been implicated in the etiology of Parkinson's disease (PD). The important biochemical features of PD, being profound deficit in dopamine (DA) content, reduced glutathione (GSH), and enhanced lipid peroxidation (LPO) in dopaminergic (DA-ergic) neurons resulting in oxidative stress, mitochondrial dysfunction and apoptosis. Rotenone-induced neurotoxicity is a well acknowledged preclinical model for studying PD in rodents as it produces selective DA-ergic neuronal degeneration. In our previous study, we have shown that chronic administration of rotenone to rats is able to produce motor dysfunction, which increases progressively with rotenone treatment and centrophenoxine (CPH) co-treatment is able to attenuate these motor defects. The present study was carried out to evaluate the antioxidant potential of CPH against rotenone-induced oxidative stress. Chronic administration of rotenone to SD rats resulted in marked oxidative damage in the midbrain region compared to other regions of the brain and CPH co-treatment successfully attenuated most of these changes. CPH significantly attenuated rotenone-induced depletion in DA, GSH and increase in LPO levels. In addition, the drug prevented the increase in nitric oxide (NO) and citrulline levels and also enhanced the activity of catalase and superoxide dismutase (SOD). Histological analysis carried out using hematoxylin and eosin staining has indicated severe damage to mid brain in comparison to cortex and cerebellum and this damage is attenuated by CPH co-treatment. Our results strongly indicate the possible therapeutic potential of centrophenoxine as an antioxidant in Parkinson's disease and other movement disorders where oxidative stress is a key player in the disease process.

Catalpol has been shown to rescue neurons from kinds of damage in vitro and in vivo in previous reports. However, the effect of catalpol on the nitric oxide (NO) system via MAPKs signaling pathway of mesencephalic neurons largely remains to be verified. The current study examined that whether catalpol modulated NO and iNOS increase by rotenone in primary mesencephalic neurons and investigated its underlying signaling pathways. Present results indicated that catalpol inhibited primary mesencephalic neurons from apoptosis by morphological assay, immunocytochemistry and flow cytometric evaluation. Moreover, the ERK signaling pathway plays an important role in NO-mediated degeneration of neuron. The current results suggest that catalpol is a potential agent for the prevention of neurons apoptosis by regulating NO and iNOS increase in ERK-mediated neurodegenerative disorders.

The present study investigated oxidative damage and neuroprotective effect of the antiparkinsonian drug, L-deprenyl in neuronal death produced by intranigral infusion of a potent mitochondrial complex-I inhibitor, rotenone in rats. Unilateral stereotaxic intranigral infusion of rotenone caused significant decrease of striatal dopamine levels as measured employing HPLC-electrochemistry, and loss of tyrosine hydroxylase immunoreactivity in the perikarya of ipsilateral substantia nigra (SN) neurons and their terminals in the striatum. Rotenone-induced increases in the salicylate hydroxylation products, 2,3- and 2,5-dihydroxybenzoic acid indicators of hydroxyl radials in mitochondrial P2 fraction were dose-dependently attenuated by L-deprenyl. L-deprenyl (0.1-10mg/kg; i.p.) treatment dose-dependently attenuated rotenone-induced reductions in complex-I activity and glutathione (GSH) levels in the SN, tyrosine hydroxylase immunoreactivity in the striatum or SN as well as striatal dopamine. Amphetamine-induced stereotypic rotations in these rats were also significantly inhibited by deprenyl administration. The rotenone-induced elevated activities of cytosolic antioxidant enzymes superoxide dismutase and catalase showed further significant increase following L-deprenyl. Our findings suggest that unilateral intranigral infusion of rotenone reproduces neurochemical, neuropathological and behavioral features of PD in rats and L-deprenyl can rescue the dopaminergic neurons from rotenone-mediated neurodegeneration in them. These results not only establish oxidative stress as one of the major causative factors underlying dopaminergic neurodegeneration as observed in Parkinson's disease, but also support the view that deprenyl is a potent free radical scavenger and an antioxidant.