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Tanaka. Neuroimmunol Neuroinflammation 2020;7:73-91 I http://dx.doi.org/10.20517/2347-8659.2020.04 Page 77

undergo degeneration, and microglia then become activated in response to damage-associated molecular
[49]
patterns (DAMPs), such as high mobility group box-1 protein (HMGB1) released from damaged neurons .
The activated microglia may exacerbate the degenerative processes of DA neurons. Another rat PD model
[48]
is prepared via injection of lipopolysaccharide (LPS) either direct into the SNc or in its vicinity . In this
model, microglial activation is primarily induced followed by DA neuron degeneration, suggesting that
activated microglia could be a key cause of neuronal degeneration.

The hematopoietic cytokines interleukin-3 (IL-3) and granulocyte/macrophage colony-stimulating
factor (GM-CSF) have been shown to modulate the phenotype of microglia in the SNc while suppressing
proinflammatory nature and increasing secretion of neurotrophic factors, insulin-like growth factor
[44]
1 (IGF-1), and hepatocyte growth factor (HGF) . Following this, DA neurons increase the expression
of anti-apoptotic factor Bcl-xL, and the symptoms of PD are ameliorated. This suggests that further
investigation of microglial phenotypes would lead to a potential intervention for neurological disorders.

Microglia in the SNc have been the sole focus of studies investigating microglia in PD pathology. However,
upon immunostaining sections of the mesencephalon of PD model rats with antibodies to microglia
markers, activation of microglia in the substantia nigra pars reticulata (SNr) was more apparent than that
[47]
+
of those in the SNc . The activated microglia in the SNr bore large CD68 phagosomes in their cytoplasm,
in which synaptic proteins were included. In the PD pathology, glutamatergic neurons in the subthalamic
nuclei (STN) become hyperactivated and release excess amounts of glutamate in the basal ganglia outputs
that are the SNr and the internal segment of the globus pallidus (GPi). The change causes bradykinesia,
rigidity, and other PD symptoms. Activated microglia with large phagosomes are present not only in
the SNr but also in the GPi. They internalize the glutamatergic synapses from the hyperactive STN. As
the neurological deficits do not manifest until most DA neurons are lost, it is likely that there are some
[50]
significant compensatory mechanisms that prevent the symptoms from appearing . Microglia should
contribute to this compensation by eliminating hyperactive glutamatergic synapses. Administration of a
single high dose of a synthetic glucocorticoid dexamethasone (Dex) to the PD model rats aggravated their
motor deficits. Dex suppresses CD68 expression in the SNr and GPi, suggesting suppression of microglial
phagocytosis.

Conversely, chronic administration of glucocorticoid [51,52] and other anti-inflammatory agents, such as
bromovalerylurea (BU) , has been shown in laboratory settings to ameliorate the outcome of the motor
[43]
deficits, likely because of suppression of proinflammatory activation of microglia in the SNc. These
findings reveal that microglia play both ameliorative and detrimental roles. There appear to be two forms
of microglia activation: one is characterized by the production of proinflammatory mediators found in the
[47]
SNc [43,44] , and the other is characterized by enhanced phagocytic ability in the SNr and GPi . The dual role
of microglia in the PD pathophysiology is summarized in a schematic diagram [Figure 1].

Despite significant evidence showing the involvement of microglia in the DA neuron loss in animal PD
models, it is not clear whether microglia actually affect the pathology of human PD cases. A few clinical
[53]
trials have shown the positive effects of antiinflammatory drugs , and activated microglia are found in PD
patients’ brains by in vivo imaging with positron emission tomography . However, there is still no firm
[54]
evidence demonstrating that microglia actually induce DA neuron death in human PD cases. Most anti-
inflammatory interventions are not ameliorative [55,56] . This contrasts with animal model cases, in which
anti-inflammatory interventions markedly suppress DA neuron death. The discrepancy between animal
PD models and human cases may be partially attributable to the speed of the pathological processes.
The animal model is acutely prepared, whereas human PD is a chronic disease. Furthermore, when PD
is diagnosed based on motor symptoms, more than 60 % of DA neurons in the SNc are degenerated. In
animal models, anti-inflammatory drugs are often given simultaneously with or even before administration