Biomedical Engineering Reference
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infl ammagen bacterial endotoxin lipopolysaccharide (LPS)
(38
,
41-44)
. Third,
addition of some of these factors, often in various combinations, to neuron/glia
cultures has been shown to induce neuronal death
(45-47)
. Fourth, inhibition
of the production of cytokines such as TNF-
, free radicals such as
NO and reactive oxygen intermediates, and eicosanoids such as prostaglandins
affords neuroprotection
(42
,
48-52)
. Interestingly, neurons may not be solely
the innocent victims of infl ammation-mediated degeneration. Interactions
between neurons and glial cells via molecules such as the neural cell adhesion
molecules may actually serve to suppress the immune response of glial cells,
and loss of the “neuronal suppression” may be part of the mechanism of action
underlying reactive gliosis
(53
,
54)
.
and IL-1
5. Microglial Activation: Part of the Etiology of PD?
The hallmark of PD is the progressive degeneration of the nigrostriatal
dopaminergic system involving the loss of dopaminergic neurons in the
substantia nigra and their fi bers in the striatum. Suffi cient damage to the
dopaminergic pathways, over time, eventually leads to disorders in movement
regulation. It has now been recognized that microglial activation is involved in
the neurodegenerative process of PD
(55-58)
. Furthermore, epidemiological
studies appear to suggest that microglial activation, as a consequence of expo-
sure to infectious agents and environmental toxins and occurrence of early-life
traumatic brain injuries, may play a role in the early stage of the pathogenetic
process of PD
(59-64)
. Some of the important clues in favor of the hypothesis
that microglial activation will result in dopaminergic neurodegeneration have
come from experiments with neuron-glia cultures stimulated with the bacterial
endotoxin LPS. Indeed, LPS neurotoxicity requires the presence of glia,
and activation of glia, especially of microglia, leads to the degeneration of
dopaminergic neurons
(65)
. In addition, intranigral injection of LPS activates
microglia and induces the degeneration of nigral dopaminergic neurons
(66-68)
. Microglial activation occurs as early as 6 h after the infusion of LPS
into rat brains, and signifi cant production of cytokines (TNF-
) and
free radicals (NO and superoxide) can be detected 2-12 hr after stimulation of
neuron-glia cultures with LPS
(67
,
69
,
70)
. In contrast, signifi cant degeneration
of dopaminergic neurons in vitro and in vivo was not observed until after
the occurrence of signifi cant microglial activation, indicating that microglial
activation and production of neurotoxic factors precede dopaminergic neuro-
degeneration. These results demonstrate that, at least in rodents, infl ammagen
(LPS)-induced microglial activation is capable of causing the degeneration of
nigral dopaminergic neurons.
, IL-1
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