Autophagy and neuroprotection in astrocytes exposed to 6-hydroxydopamine is negatively regulated by NQO2: relevance to Parkinson's disease.

Dopaminergic degeneration is a central feature of Parkinson's disease (PD), but glial dysfunction may accelerate or trigger neuronal death. In fact, astrocytes play a key role in the maintenance of the blood-brain barrier and detoxification. 6-hydroxydopamine (6OHDA) is used to induce PD in rodent models due to its specific toxicity to dopaminergic neurons, but its effect on astrocytes has been poorly investigated. Here, we show that 6OHDA dose-dependently impairs autophagy in human U373 cells and primary murine astrocytes in the absence of cell death. LC3II downregulation was observed 6 to 48 h after treatment. Interestingly, 6OHDA enhanced NRH:quinone oxidoreductase 2 (NQO2) expression and activity in U373 cells, even if 6OHDA turned out not to be its substrate. Autophagic flux was restored by inhibition of NQO2 with S29434, which correlated with a partial reduction in oxidative stress in response to 6OHDA in human and murine astrocytes. NQO2 inhibition also increased the neuroprotective capability of U373 cells, since S29434 protected dopaminergic SHSY5Y cells from 6OHDA-induced cell death when cocultured with astrocytes. The toxic effects of 6OHDA on autophagy were attenuated by silencing NQO2 in human cells and primary astrocytes from NQO2-/- mice. Finally, the analysis of Gene Expression Omnibus datasets showed elevated NQO2 gene expression in the blood cells of early-stage PD patients. These data support a toxifying function of NQO2 in dopaminergic degeneration via negative regulation of autophagy and neuroprotection in astrocytes, suggesting a potential pharmacological target in PD.

Intensive exercise ameliorates motor and cognitive symptoms in experimental Parkinson's disease restoring striatal synaptic plasticity.

Intensive physical activity improves motor functions in patients with Parkinson's disease (PD) at early stages. However, the mechanisms underlying the beneficial effects of exercise on PD-associated neuronal alterations have not been fully clarified yet. Here, we tested the hypothesis that an intensive treadmill training program rescues alterations in striatal plasticity and early motor and cognitive deficits in rats receiving an intrastriatal injection of alpha-synuclein (α-syn) preformed fibrils. Improved motor control and visuospatial learning in active animals were associated with a recovery of dendritic spine density alterations and a lasting rescue of a physiological corticostriatal long-term potentiation (LTP). Pharmacological analyses of LTP show that modulations of N-methyl-d-aspartate receptors bearing GluN2B subunits and tropomyosin receptor kinase B, the main brain-derived neurotrophic factor receptor, are involved in these beneficial effects. We demonstrate that intensive exercise training has effects on the early plastic alterations induced by α-syn aggregates and reduces the spread of toxic α-syn species to other vulnerable brain areas.

Evaluation of paraoxonase activity and association with serum advanced glycation end products as reliable markers of oxidative stress in Hashimoto's thyroiditis.

BACKGROUND: Oxidative stress has been implicated in the pathogenesis of autoimmune thyroiditis, also referred to as Hashimoto's thyroiditis (HT), and several biomarkers have been measured to evaluate the impact and clinical relevance of oxidative stress in this setting. Recently, advanced glycation end products (AGEs) have been proposed as reliable markers of oxidative stress in HT. In the present study, we investigated the relationship of AGEs with antioxidant paraoxonase (PON-1) activity as potential combined markers of oxidative stress. MATERIALS AND METHODS: We measured the levels of AGEs, and advanced oxidation protein products (AOPPs) and PON-1 activity by spectrophotometric methods, in the serum of 40 HT patients (36 F; mean age 35.4 ± 11.5 yr) and 38 age-, sex- and BMI-matched healthy controls. All subjects were euthyroid at recruitment and none was on LT-4 therapy. RESULTS: Serum levels of AGEs were significantly higher (median 378 vs 290 AU/g protein; P<0.001), while PON1 activity was significantly lower (median 165 vs 201 U/L; P<0.05) in HT patients compared to controls: the two parameters were inversely correlated (P<0.01), clearly indicating a pro-oxidant imbalance in HT patients. At stepwise regression analysis, TPOAb positivity was an independent predictor of both PON-1 activity (P = 0.002) and AGEs levels (P = 0.000). CONCLUSIONS: Increased formation and accumulation of AGEs contribute to enhanced oxidative stress, along with a decrease in PON-1 activity in HT. As a consequence, AGEs levels and alteration in PON 1 may serve as useful markers for monitoring the levels of oxidative stress in this disorder.