Granulocyte-colony stimulating factor, a potential candidate for the treatment of Parkinson's disease.

BACKGROUND: Granulocyte colony-stimulating factor (G-CSF) activates the PI3K/Akt pathway to exert neuroprotective effects. The current study aimed to determine if G-CSF reverses behavioral deficits, even after motor malfunction occurs in Paraquat (PQ)-treated mice. METHODS: Male C57BL/6 mice (8 weeks old) were divided into 3 groups: PQ + G-CSF-treated group (n=8); PQ + saline-treated group (n=8); and saline-treated control group (n=8). Spontaneous locomotor activity was evaluated together with the pole test. The DA, 3, 4-dihydroxyphenyl acetic acid (DOPAC), and homovanillic acid (HVA) levels in the bilateral striatum were determined by HPLC. The number of substantia nigra pars compacta tyrosine hydroxylase (TH)-immunoreactive neurons was calculated using an unbiased cell counting stereology method, the activities of total GSH-PX and SOD, and the malondialdehyde (MDA) content were assessed. RESULTS: After G-CSF treatment, spontaneous motor activity and the Tturn and TLA times in the CSF group were significantly lower than the control group, and the striatal dopamine level in the striatum and the number of TH-positive neurons in the substantia nigra (SN) were significantly increased compared to the control group (5478 ± 654 vs. 3647±488 DA neurons, P < 0.05). Compared to the control group, the GSH-PX and SOD activities were increased, while the MDA level was significantly decreased in the SN (P<0.05). CONCLUSIONS: The data strongly suggest that G-CSF reverses behavioral deficits in PQ-treated mice with movement disorders. Thus, G-CSF may be utilized as a prospective drug candidate for the treatment of Parkinson's disease.

Acteoside Binds to Caspase-3 and Exerts Neuroprotection in the Rotenone Rat Model of Parkinson's Disease.

Parkinson's disease (PD) is characterized by the progressive degeneration of the dopaminergic neurons in the substantia nigra (SN) region. Acteoside has displayed multiple biological functions. Its potential role against PD and the underlying signaling mechanisms are largely unknown. Here, we showed that oral administration of acteoside significantly attenuated parkinsonism symptoms in rotenone-induced PD rats. Further, acteoside inhibited rotenone-induced α-synuclein, caspase-3 upregulation and microtubule-associated protein 2 (MAP2) downregulation in PD rats. The molecular docking and molecular dynamics (MD) simulation results indicated that acteoside may directly bind to and inhibit caspase-3. Acteoside formed hydrogen bonds with at least six residues of caspase-3: ThrA177, SerA178, GlyA238, SerB339, ArgB341 and TrpB348. In addition, a pi-pi interaction was formed between acteoside and caspase-3's HisA237, which might further stabilize the complex. MD simulation results demonstrated that the binding affinity of the caspase-3-acteoside complex was higher than that of caspase-3 and its native ligand inhibitor. Together, we show that acteoside binds to caspase-3 and exerts neuroprotection in the rotenone rat model of PD.

Effects of streptozotocin-induced diabetes on tau phosphorylation in the rat brain.

Brain protein kinase B (Akt) and glycogen synthase kinase-3 (GSK-3) activities are adaptable to changes of peripheral blood glucose level in vivo. GSK-3 phosphorylates microtube-associated protein tau at multiple sites, which can be antagonized by protein phosphatase-2A (PP-2A). The imbalance among these enzymes might have potential connections with diabetes mellitus (DM) and Alzheimer's disease (AD). In this study hyperglycemia rat DM model was achieved by streptozotocin (STZ) treatment. The phosphorylation of tau in the rat hippocampus was detected with specific antibodies. Insulin and Li(2)CO(3) administration were also employed to find out the regulatory efforts of the kinases. We observed that rat hippocampus tau was hyperphosphorylated at Ser(396)/Ser(404) (PHF-1 sites) in STZ-induced DM model, accompanied by lowered phosphorylation levels of Akt, GSK-3 and PP-2A. Lithium, a specific GSK-3 inhibitor, nearly reversed all phosphorylation of tau at above sites in 30days. Insulin administration restored the blood glucose level in DM rats but suppressed PP-2A activity, resulting in the PHF-1 sites of tau not being dephosphorylated. These findings strongly suggest that STZ-induced hyperglycemia may cause disorder of Akt/GSK-3/PP-2A regulations in rat brain and further lead to abnormal phosphorylation of hippocampus tau.

Toxic influence of chronic oral administration of paraquat on nigrostriatal dopaminergic neurons in C57BL/6 mice.

BACKGROUND: Paraquat (PQ; 1,1'-dimethyl-4,4'-bipyridinium), a widely used herbicide, has been repeatedly suggested as a potential etiologic factor for the development of Parkinson's disease (PD), owing to its structural similarity to the known dopaminergic neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). This study aimed to observe the influence of paraquat on nigrostriatal dopaminergic neurons in C57BL/6 mice. METHODS: A total of 24 male C57BL/6 mice were assigned randomly to 3 groups: control group (treated by saline), PQ treated group, and MPTP treated group. Mice in PQ treated group were taken orally with PQ (10 mg/kg) daily for four months. Locomotor activity was measured. Level of dopamine (DA) and its metabolites levels in the striatum were measured by high-performance liquid chromatography with an electrochemical detector (HPLC-ECD), and tyrosine hydroxylase (TH) positive neurons were detected by using immunohistochemistry. At the same time, the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX), and the content of malondialdehyde (MDA) in substantia nigra were measured by spectrophotometry. mRNA expression of dopamine transporter (DAT) in dopaminergic neurons of substantia nigra was also determined by reverse transcription (RT)-PCR technique. RESULTS: Locomotor activities were significantly impaired in the PQ treated group. Level of DA and its metabolites levels in the striatum were declined. The activities of SOD and GSH-PX were decreased, and the content of MDA was increased in PQ treated mice compared with that in control group. Numbers of TH positive neurons and the mRNA expression of DAT in substantia nigra of mice were also decreased after PQ taken orally for four months. CONCLUSIONS: The present study suggests that chronic oral administration of PQ could trigger dopaminergic neuron degeneration. Oxidative stress could be involved in the pathogenic mechanism of PD induced by PQ.