Parkinson's Disease and Systemic Inflammation

Abstract

Peripheral inflammation triggers exacerbation in the central brain's ongoing damage in several neurodegenerative diseases. Systemic inflammatory stimulus induce a general response known as sickness behaviour, indicating that a peripheral stimulus can induce the synthesis of cytokines in the brain. In Parkinson's disease (PD), inflammation was mainly associated with microglia activation that can underlie the neurodegeneration of neurons in the substantia nigra (SN). Peripheral inflammation can transform the “primed” microglia into an “active” state, which can trigger stronger responses dealing with neurodegenerative processes. Numerous evidences show that systemic inflammatory processes exacerbate ongoing neurodegeneration in PD patient and animal models. Anti-inflammatory treatment in PD patients exerts a neuroprotective effect. In the present paper, we analyse the effect of peripheral infections in the etiology and progression in PD patients and animal models, suggesting that these peripheral immune challenges can exacerbate the symptoms in the disease.

Inflammation in Parkinson’s Disease: Causes and Consequences

“…Increased levels of CD4 + have been reported in the serum of patients with PD, suggesting peripheral activation of lymphocytes (Bas et al, 2001;Fiszer et al, 1994;). Infiltrating cytotoxic CD4 + and CD8 + T cells, but not B cells, have been observed in the inflamed SNpc of post-mortem PD human specimens and in the MPTP-induced mouse model of PD during the course of neurodegeneration (Brochard et al, 2009;Ferrari & Tarelli, 2011;Stone et al, 2009). In support of a role for systemic immune cells in the degeneration of nigral DA neurons, CD4 -/-mice have been shown to be resistant to MPTP-induced neurotoxicity in the SN (Brochard et al, 2009).…”

“…In this instance, microglia in the aged or diseased brain are said to be "primed" and can evoke an exaggerated response contributing to disease progression (Perry et al, 2007). Clinical and epidemiological reports suggest a correlation between systemic inflammatory events, chronic neuroinflammation and the aetiology and progressive nature of PD (Ferrari & Tarelli, 2011;Long-Smith et al, 2009;Perry, 2010). Postulated risk factors implicated in idiopathic PD include age, genetic predisposition, bacterial or viral infections, neuronal injury such as traumatic brain injury or stroke, and environmental toxins (Koprich et al, 2008;Tansey & Goldberg, 2010).…”

“…Through autocrine signalling these cytokines induce self-synthesis and the synthesis of further cytokines (Dantzer, 2009) inducing general inflammation. Compromise of the blood-brain barrier (BBB) which is observed in neurological disorders, stimulates peripheral leucocytes and systemic inflammatory mediators such as cytokines, to migrate into the brain parenchyma where they induce the activation of microglia and the subsequent release of more cytokines (Ferrari & Tarelli, 2011). For example, peripheral TNF can stimulate microglia to secrete chronically elevated pro-inflammatory mediators, which in turn can induce chronic self-perpetuating neuroinflammation, resulting in a slow and progressive loss of DA neurons in the SNpc (Qin et al, 2007).…”

“…A systemic response includes the liver acute phase response and the behavioural and metabolic components that induce sickness behaviour (Ferrari & Tarelli, 2011;Perry et al, 2007). Specifically, peripheral monocytes, macrophages and Kupffer cells express TLRs and PPRs, which innately recognise specific pathogen-associated molecular patterns (PAMPs) associated with invading pathogens (Dantzer, 2009).…”

Neuroinflammation: Peripheral and Neurogenic Underlying Processes

“…A protein aggregation of α-sinuclein has been described, leading to Lewy bodies and Lewy neuritis with extensive gliosis, particularly in substantia nigra (Hirsch and Hunot, 2009 Activated microglia and astrocytes have been found in postmortem brain examination of PD patients. Infiltrating cytotoxic CD4+ and CD8+ T cells in the substantia nigra of PD patients have been observed in a postmortem study (Ferrari and Tarelli, 2011).…”