Abstract
Systemic inflammation is a crucial factor for microglial activation and neuroinflammation in neurodegeneration. This work is aimed at assessing whether previous exposure to systemic inflammation potentiates neurotoxic damage by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and how chronic systemic inflammation participates in the physiopathological mechanisms of Parkinson's disease. Two different models of systemic inflammation were employed to explore this hypothesis: a single administration of lipopolysaccharide (sLPS; 5 mg/kg) and chronic exposure to low doses (mLPS; 100 μg/kg twice a week for three months). After three months, both groups were challenged with MPTP. With the sLPS administration, Iba1 staining increased in the striatum and substantia nigra, and the cell viability lowered in the striatum of these mice. mLPS alone had more impact on the proinflammatory profile of the brain, steadily increasing TNFα levels, activating microglia, reducing BDNF, cell viability, and dopamine levels, leading to a damage profile similar to the MPTP model per se. Interestingly, mLPS increased MAO-B activity possibly conferring susceptibility to MPTP damage. mLPS, along with MPTP administration, exacerbated the neurotoxic effect. This effect seemed to be coordinated by microglia since minocycline administration prevented brain TNFα increase. Coadministration of sLPS with MPTP only facilitated damage induced by MPTP without significant change in the inflammatory profile. These results indicate that chronic systemic inflammation increased susceptibility to MPTP toxic effect and is an adequate model for studying the impact of systemic inflammation in Parkinson's disease.
Highlights
Parkinson’s disease (PD) is the second most common neurodegenerative disease and is characterized by a chronic progressive neuronal loss mainly in the substantia nigra, which causes a decrease in the production and availability of dopamine and manifests as a loss of movement control [1]
Neurodegenerative diseases are chronic inflammatory and oxidative processes associated with aging that lead to neuronal death
The single administration of lipopolysaccharide (sLPS) administration scheme induces a well-known neuroinflammatory process [15]; we found that Multiple low dose LPS treatment (mLPS) is a more complete neuroinflammatory model that per se resembles the MPTP model with higher brain TNFα levels, increased Iba1 staining in the substantia nigra and striatum, and diminished brain brain-derived neurotrophic factor (BDNF) and dopamine levels, as well reduced cell viability and striatal dopamine
Summary
Parkinson’s disease (PD) is the second most common neurodegenerative disease and is characterized by a chronic progressive neuronal loss mainly in the substantia nigra, which causes a decrease in the production and availability of dopamine and manifests as a loss of movement control [1]. Despite the amount of research on this neurodegenerative disease, its origin remains unclear. 5-10% of cases have a genetic background [2,3,4,5], while the rest are of idiopathic origin [6], some risk factors have been identified, such as age, environmental toxins, and infections [7, 8]. The inflammatory process, oxidative stress, and microglia activation are essential components in the pathogenesis of many neurodegenerative disorders such as PD [9]. During aging, microglia are activated, secrete inflammatory cytokines, and promote the release of secondary inflammatory mediators such as prostaglandins and nitric oxide
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