Protection of dopaminergic cells by urate requires its accumulation in astrocytes

Abstract

Urate is the end product of purine metabolism and a major antioxidant circulating in humans. Recent data link higher levels of urate with a reduced risk of developing Parkinson’s disease (PD) and with a slower rate of its progression. In this study, we investigated the role of astrocytes in urate-induced protection of dopaminergic cells in a cellular model of PD. In mixed cultures of dopaminergic cells and astrocytes oxidative stress-induced cell death and protein damage were reduced by urate. By contrast, urate was not protective in pure dopaminergic cell cultures. Physical contact between dopaminergic cells and astrocytes was not required for astrocyte-dependent rescue as shown by conditioned medium experiments. Urate accumulation in dopaminergic cells and astrocytes was blocked by pharmacological inhibitors of urate transporters expressed differentially in these cells. The ability of a urate transport blocker to prevent urate accumulation into astroglial (but not dopaminergic) cells predicted its ability to prevent dopaminergic cell death. Transgenic expression of uricase reduced urate accumulation in astrocytes and attenuated the protective influence of urate on dopaminergic cells. These data indicate that urate might act within astrocytes to trigger release of molecule(s) that are protective for dopaminergic cells.

Switching from astrocytic neuroprotection to neurodegeneration by cytokine stimulation

“…Moreover, it will be highly interesting to study mechanisms that might restore, or even boost, the neuroprotective properties of astrocytes, even in a neuroinflammatory environment. A promising approach may be the triggering of the Nrf-2 pathway (Dodla et al 2010;Gupta et al 2012) or utilization of the properties of urate in glia-neuron interactions (Cipriani et al 2012). Moreover, our model might support the quest for specific anti-inflammatory compounds that dampen astrocyte reactions, but not the protective capacity of the peripheral innate immune response.…”

“…Besides a general maintenance of brain homeostasis, astrocytes can protect neurons in multiple ways. For instance, they secrete neurotrophins such as GDNF or CDNF (Lindholm et al 2007), supply antioxidants and other beneficial factors (Cipriani et al 2012;Pizzurro et al 2014;Shih et al 2003), promote synaptogenesis (Dodla et al 2010), foster neuritogenesis (Guizzetti et al 2008), and allow growth under unfavorable conditions (Kuegler et al 2012).…”

Urate as a Marker of Risk and Progression of Neurodegenerative Disease

“…In vitro, in PD models, urate prevents spontaneous degeneration of cultured nigral neurons, as well as dopaminergic cell death induced by oxidative and mitochondrial toxins [34,36]. In vivo, genetic manipulation of urate oxidase and resulting increased concentrations of urate in the CNS led to improved phenotype and histopathologic findings in PD mouse models [35,49].…”

“…At physiologically relevant concentrations, urate was also shown to enhance function and survival of dopaminergic neurons in primary cultures of rat ventral mesencephalon [53]. Interestingly, urate-mediated effects may require its accumulation in astrocytes, suggesting a noncell-autonomous mechanism for urate's neuroprotective activity [36,37]. The mechanisms underlying urate's neuroprotective effects are not completely clear, though recent in vitro studies have begun to shed light on urate's targets.…”

ALSUntangled No. 37: Inosine*

“…Across a range of Parkinson's disease models, urate elevation has prevented in vitro cell death induced by oxidative and mitochondrial toxins (24)(25)(26) and has improved function in vivo (24). Urate was also neuroprotective in various models of neurotoxicity beyond Parkinson's disease, including cultured spinal cord neurons (27) and models of spinal cord injury and stroke (28,29).…”