The endotoxin-induced neuroinflammation model of Parkinson's disease

Abstract

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the progressive loss of dopaminergic (DA) neurons in the substantia nigra. Although the exact cause of the dopaminergic neurodegeneration remains elusive, recent postmortem and experimental studies have revealed an essential role for neuroinflammation that is initiated and driven by activated microglial and infiltrated peripheral immune cells and their neurotoxic products (such as proinflammatory cytokines, reactive oxygen species, and nitric oxide) in the pathogenesis of PD. A bacterial endotoxin-based experimental model of PD has been established, representing a purely inflammation-driven animal model for the induction of nigrostriatal dopaminergic neurodegeneration. This model, by itself or together with genetic and toxin-based animal models, provides an important tool to delineate the precise mechanisms of neuroinflammation-mediated dopaminergic neuron loss. Here, we review the characteristics of this model and the contribution of neuroinflammatory processes, induced by the in vivo administration of bacterial endotoxin, to neurodegeneration. Furthermore, we summarize the recent experimental therapeutic strategies targeting endotoxin-induced neuroinflammation to elicit neuroprotection in the nigrostriatal dopaminergic system. The potential of the endotoxin-based PD model in the development of an early-stage specific diagnostic biomarker is also emphasized.

Figure 1

Simplified schematic representation of the link between LPS-induced microglial activation, inflammatory mediators, and dopaminergic neurodegeneration. Microglia respond to pathogens, proinflammatory cytokines, neuronal dysfunction, and cellular debris after injury or necrosis. These cells are at the forefront of the defence mechanisms that could set the conditions for repair or contribute to neuronal damage. Such equilibrium might depend on the expression and function of specific TLRs and how they are activated by endogenous and exogenous ligands and signals. Recognition of such signals lead to transcriptional activation of innate immune genes. Bacterial endotoxin LPS is a potent stimulator of macrophages, monocytes, microglia, and astrocytes causing release of various immunoregulatory and proinflammatory cytokines and free radicals. Neurons do not express functional TLR-4. Thus, LPS does not appear to have a direct effect on neurons, making it an ideal activator to study indirect neuronal injury mediated by microglial activation [64]. LPS binds to its intermediate receptor CD14 and in concert with TLR4 and accessory adaptor protein MD2 triggers the activation of kinases of various intracellular signaling pathways. The MyD88-dependent cascade initiates NFκB activation through the IKKs and/or the MAPK pathway, leading to the upregulated expression of proinflammatory cytokines (TNFα, IL-1β) and increased production of other inflammatory mediators (NO and PGE2, synthesized by iNOS and COX-2, resp.). These soluble mediators collectively damage nigral dopaminergic neuron. MMP-3 and αSYN released by stressed neurons aggravate microglial activation. Astrocyte, different activation states of microglia, peripheral immune cells, many molecules involved in intracellular signaling pathways, and crosstalk between TLR signaling pathway and NADPH oxidase enzyme system are not shown for the simplicity. Please see text for the abbreviations and the details of TLR signaling pathway.