Abstract
Oxidative stress and neuroinflammation are common bases for disease onset and progression in many neurodegenerative diseases. In Parkinson disease, which is characterized by the degeneration of dopaminergic neurons resulting in dopamine depletion, the pathogenesis differs between hereditary and solitary disease forms and is often unclear. In addition to the pathogenicity of alpha-synuclein as a pathological disease marker, the involvement of dopamine itself and its interactions with glial cells (astrocyte or microglia) have attracted attention. Pacemaking activity, which is a hallmark of dopaminergic neurons, is essential for the homeostatic maintenance of adequate dopamine concentrations in the synaptic cleft, but it imposes a burden on mitochondrial oxidative glucose metabolism, leading to reactive oxygen species production. Astrocytes provide endogenous neuroprotection to the brain by producing and releasing antioxidants in response to oxidative stress. Additionally, the protective function of astrocytes can be modified by microglia. Some types of microglia themselves are thought to exacerbate Parkinson disease by releasing pro-inflammatory factors (M1 microglia). Although these inflammatory microglia may further trigger the inflammatory conversion of astrocytes, microglia may induce astrocytic neuroprotective effects (A2 astrocytes) simultaneously. Interestingly, both astrocytes and microglia express dopamine receptors, which are upregulated in the presence of neuroinflammation. The anti-inflammatory effects of dopamine receptor stimulation are also attracting attention because the functions of astrocytes and microglia are greatly affected by both dopamine depletion and therapeutic dopamine replacement in Parkinson disease. In this review article, we will focus on the antioxidative and anti-inflammatory effects of astrocytes and their synergism with microglia and dopamine.
Highlights
The pathophysiology and pathogenesis of Parkinson disease involves the depletion of dopamine following the degeneration and loss of dopaminergic neurons by undetermined causes in the substantia nigra [1,2,3]
The glycolytic system is dominant in astrocytes, and the lactate produced in astrocytes is Whether the astrocyte–neuron lactate shuttle (ANLS) model can be adapted to understand the activities of dopaminergic supplied to neurons, which produce adenosine triphosphate (ATP) as an energy substrate; this concept is known as neurons in healthy people and patients with Parkinson disease is an important question
We examined glucose utilization in rat cultured therapeutic strategy for neurodegenerative diseases.astroglia the in vitro before and dopamine application usingand the
Summary
The pathophysiology and pathogenesis of Parkinson disease involves the depletion of dopamine following the degeneration and loss of dopaminergic neurons by undetermined causes in the substantia nigra [1,2,3]. In brain regions that require continuous neuronal activity, including the pacemaking activity of dopaminergic neurons, the ROS generated in neurons can cause secondary damage to their own mitochondria, resulting in local dysfunction and regional neurological symptoms [13,14] The possibility that such excessive neuronal activity may trigger the degeneration of various neurons has long been recognized, and hyperexcitability may contribute to disease exacerbation by inducing the degeneration of both motor neurons and dopaminergic neurons. Glutamate released into the synaptic cleft is immediately recovered by glutamate transporters expressed in the end-feet of astrocytes surrounding the synapse, and the elevated extracellular concentration is transient, meaning that postsynaptic neuronal damage is unlikely to occur during normal neural activity [28,29,30,31] In this situation, metabolic mechanisms within astrocytes process glutamate metabolism rapidly. This difference is thought to be relevant to the pathogenesis of Parkinson disease, especially in association with alpha-synuclein toxicity [13,14,29,30,31,32,33,34,35]
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