Chronic Systemic Inflammation Exacerbates Neurotoxicity in a Parkinson’s Disease Model

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.

Experimental Pulmonary Tuberculosis in the Absence of Detectable Brain Infection Induces Neuroinflammation and Behavioural Abnormalities in Male BALB/c Mice

“…Thus, the M. tb -induced neuroinflammation is probably an indirect effect of lung inflammation. Similar results were found in a study that used multiple low doses of LPS administration; it found that systemic inflammation generated by LPS induces a significant rise in the brain levels of TNFα, IL-6, IL-10 and TGFβ [ 40 ]. Similar results were found in murine models infected with Plasmodium falciparum [ 41 ] or coinfected with Toxocara canis and Toxoplasma gondii [ 42 , 43 ] that induced an increase in TNFα, IFNγ, IL10 and IL4 brain production following infection with these parasites.…”

“…Our results showed that after two months of infection, the permeability of BBB increased. Similar results have been found with the administration of LPS, where chronic systemic inflammation by itself affects BBB integrity [ 40 , 53 ]. Furthermore, metabolic syndrome and the resulting insulin and leptin resistance and hyperglycaemia have pro-inflammatory effects with profound consequences on the BBB [ 54 ].…”

Negative Correlation between Serum Brain-derived Neurotrophic Factor Levels and Obesity Predictor Markers and Inflammation Levels in Females with Obesity

“…It has recently been reported that obesity is associated with a low-grade inflammatory state [9], [10], [27]. Such a condition triggers systemic inflammation which is an important factor for microglial activation and neuroinflammation in neurodegeneration [11]. This may happen due to excess macronutrients in adipose tissue that stimulate the release of pro-inflammatory mediators, such as TNF-α and IL-6 and reduce the production of anti-inflammatory agents, such as adiponectin [12].…”

“…Potential mechanisms in these changes include inflammation and vascular and metabolic changes [8]. Recently, obesity has also been associated with a low-grade inflammatory state [9], [10], [11]. This condition triggers systemic inflammation which becomes an important factor for microglial activation and neuroinflammation in neurodegeneration [12].…”

The Neuroimmune Role of Intestinal Microbiota in the Pathogenesis of Cardiovascular Disease

“…It was also shown that the intravenous injection of indol, which is similar to the product of bacterial metabolism of tryptophan, allows overcoming the BBB [ 111 ]. Neuro-inflammatory effects of LPS act through TLR activation in peripheral tissues, causing secondary effects in the nervous system by BBB-positive pro-inflammatory cytokines [ 112 , 113 , 114 ].…”