Abstract
The impact of systemic inflammation in nigral dopaminergic cell loss remains unclear. Here, we have investigated the role of peripheral inflammation induced by systemic lipopolysaccharide (LPS) administration in the MPTP-based model of Parkinson’s disease. Brain inflammation, microglia and astroglia activation, disruption of the blood–brain barrier (BBB) and integrity of the nigrostriatal dopaminergic system were evaluated in response to i.p. injection of LPS, MPTP or the combination of both. Our results showed that combinative treatment exacerbates microglia activation and enhances (i) the appearance of galectin-3-positive microglia, recently identified as microglial disease-associated phenotypic marker, (ii) the up-regulation of pro-inflammatory cytokines, (iii) the occurrence of A1 neurotoxic astrocytes, (iv) the breakdown of the BBB, and (v) the loss of dopaminergic neurons in the substantia nigra. Microglia activation was triggered earlier than other degenerative events, suggesting that over-activation of microglia (including different polarization states) may induce dopaminergic neuron loss by itself, initiating the endless cycle of inflammation/degeneration. Our study revitalizes the importance of peripheral inflammation as a potential risk factor for Parkinson’s disease and raises the possibility of using new anti-inflammatory therapies to improve the course of neurodegenerative diseases, including those directly aimed at modulating the deleterious activity of disease-associated microglia.
Highlights
Parkinson’s disease (PD) is the second most prevalent neurodegenerative disorder after Alzheimer’s disease (AD), which is characterized by a permanent and selective loss of dopaminergic neurons in the substantia nigra (SN) pars compacta (Obeso et al, 2000), with the subsequent loss of dopamine (DA) in the striatum
We show for the first time that LPS-induced peripheral inflammation and MPTP act synergistically to enhance (a) the appearance of galectin3 expressing microglia, recently identified as a phenotypic marker of disease-associated microglia (Keren-Shaul et al, 2017; Krasemann et al, 2017; Mathys et al, 2017), (b) central inflammatory response, and (c) the disruption of the blood–brain barrier (BBB)
Iba-1 is a protein associated with major histocompatibility complex II, which is expressed in all microglial phenotypes but overexpressed in reactive microglia
Summary
Parkinson’s disease (PD) is the second most prevalent neurodegenerative disorder after Alzheimer’s disease (AD), which is characterized by a permanent and selective loss of dopaminergic neurons in the substantia nigra (SN) pars compacta (Obeso et al, 2000), with the subsequent loss of dopamine (DA) in the striatum This loss of DA accounts for many of the symptoms that accompany the disease, including motor dysfunction, mood alterations and cognitive impairment (Olanow et al, 2003). Mitochondrial dysfunction, oxidative stress, excitotoxicity, alterations in the ubiquitinproteasome system and neuroinflammatory mechanisms have been shown to cooperate in the Systemic LPS Increases MPTP-Induced Death progressive death of the dopaminergic neurons (Dexter and Jenner, 2013) In this regard, clinical and experimental evidence suggests that PD is associated with neuroinflammatory processes such as microglia activation, T-leukocyte infiltration, and blood–brain barrier (BBB) dysfunction (McGeer and McGeer, 2004; Hirsch and Hunot, 2009; Tiwari and Pal, 2017). Epidemiological studies have demonstrated that regular users of non-steroidal anti-inflammatory drugs or cyclo-oxygenase inhibitors have about 50% lower PD and AD risk than non-users (Chen et al, 2003, 2005; Esposito et al, 2007; Subramaniam and Federoff, 2017)
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