Neuroprotective Role of Astroglia in Parkinson Disease by Reducing Oxidative Stress Through Dopamine-Induced Activation of Pentose-Phosphate Pathway

Abstract

Oxidative stress plays an important role in the onset and progression of Parkinson disease. Although released dopamine at the synaptic terminal is mostly reabsorbed by dopaminergic neurons, some dopamine is presumably taken up by astroglia. This study examined the dopamine-induced astroglial protective function through the activation of the pentose-phosphate pathway (PPP) to reduce reactive oxygen species (ROS). In vitro experiments were performed using striatal neurons and cortical or striatal astroglia prepared from Sprague-Dawley rats or C57BL/6 mice. The rates of glucose phosphorylation in astroglia were evaluated using the [14C]deoxyglucose method. PPP activity was measured using [1-14C]glucose and [6-14C]glucose after acute (60 min) or chronic (15 hr) exposure to dopamine. ROS production was measured using 2′,7′-dichlorodihydrofluorescein diacetate. The involvement of the Kelch-like ECH-associated protein 1 (Keap1) or nuclear factor-erythroid-2-related factor 2 (Nrf2) system was evaluated using Nrf2 gene knockout mice, immunohistochemistry, and quantitative reverse transcription polymerase chain reaction analysis for heme oxygenase-1. Acute exposure to dopamine elicited increases in astroglial glucose consumption with lactate release. PPP activity in astroglia was robustly enhanced independently of Na+-dependent monoamine transporters. In contrast, chronic exposure to dopamine induced moderate increases in PPP activity via the Keap1/Nrf2 system. ROS production from dopamine increased gradually over 12 hr. Dopamine induced neuronal cell damage that was prevented by coculturing with astroglia but not with Nrf2-deficient astroglia. Dopamine-enhanced astroglial PPP activity in both acute and chronic manners may possibly reduce neuronal oxidative stress.

Metabolic compartmentalization between astroglia and neurons in physiological and pathophysiological conditions of the neurovascular unit

“…Astroglia releases GSH and reduces dopamine‐induced ROS toxicity in Nrf2‐depenent manners. We have found that astroglia protect neurons against dopamine exposure by reducing ROS, while astroglia prepared from Nrf2‐KO mice are incapable of such activity . An in vivo model supports the notion that Nrf2‐KO mice are susceptible to a Parkinson's disease‐like phenotype and that an Nrf2 activator can modify the progression of Parkinson's disease …”

“…Of note, the functional activation of neurons increases glucose utilization locally, and both neurons and astroglia contribute to glucose consumption. We have focused on the roles of glucose metabolism, especially glycolysis in astroglia, from the perspective of their supportive aspects in the protection of neurons against oxidative stress . Neuronal energy production is dependent on mitochondrial oxidative metabolism, which produces small amounts of reactive oxygen species (ROS).…”

“…Neuronal energy production is dependent on mitochondrial oxidative metabolism, which produces small amounts of reactive oxygen species (ROS). Oxidative stress has been implicated in the pathogenesis of numerous neurological disorders (i.e., stroke, ALS, Parkinson's disease) as well as normal aging of the brain . The glutathione system acts as an intrinsic protective mechanism.…”

“…[21][22][23] Now, the NVU is a tool that can be used to understand normal brain physiology as well as the pathophysiology of numerous neurological disorders. [24][25][26][27][28][29] Conversely, the malfunction of astroglia in the NVU (i.e., "astrogliopathy") [30][31][32][33][34] induces neuronal dysfunction, leading to various neurological disorders including cerebrovascular disease (e.g., stroke and small vessel disease-like Binswanger's disease and cerebral autosomaldominant arteriopathy with subcortical infarct and leukoencephalopathy [CADASIL]/ 35 cerebral autosomal recessive arteriopathy with subcortical infarct and leukoencephalopathy [CARASIL]), 36,37 neurodegenerative disease (e.g., Alzheimer's disease, 38,39 Parkinson's disease, 40,41 and amyotrophic lateral sclerosis [ALS]), [42][43][44] and neuroimmunological disease (e.g., multiple sclerosis [MS], [45][46][47][48] and neuromyelitis optica spectrum disorder [NMOSD]). 49,50 This review will focus on the supportive roles of astroglia in the NVU from the perspective of three major metabolic compartments with neurons: (i) glucose and lactate; (ii) fatty acid and ketone bodies (KBs); and (iii) D-and L-serine.…”

Neuroprotection by glucose‐6‐phosphate dehydrogenase and the pentose phosphate pathway

“…In the context of PD, astroglia plays pivotal roles in disease pathology . A recent report has indeed showed that dopamine‐induced increase in PPP activity in astroglia produced a protective effect on cocultured neurons …”