Parkinson's disease is characterised by a slow and progressive degeneration of dopaminergic neurons in the substantia nigra. Despite intensive research, the cause of the neuronal loss in Parkinson's disease is poorly understood. Neuroinflammatory mechanisms might contribute to the cascade of events leading to neuronal degeneration. In this Review, we describe the evidence for neuroinflammatory processes from post-mortem and in vivo studies in Parkinson's disease. We further identify the cellular and molecular events associated with neuroinflammation that are involved in the degeneration of dopaminergic neurons in animal models of the disease. Overall, available data support the importance of non-cell-autonomous pathological mechanisms in Parkinson's disease, which are mostly mediated by activated glial and peripheral immune cells. This cellular response to neurodegeneration triggers deleterious events (eg, oxidative stress and cytokine-receptor-mediated apoptosis), which might eventually lead to dopaminergic cell death and hence disease progression. Finally, we highlight possible therapeutic strategies (including immunomodulatory drugs and therapeutic immunisation) aimed at downregulating these inflammatory processes that might be important to slow the progression of Parkinson's disease.

https://www.thelancet.com/pdfs/journals/laneur/PIIS1474442209700626.pdf

Neuroinflammation in Parkinson's disease: a target for neuroprotection?

Cytokines and chemokines: At the crossroads of cell signalling and inflammatory disease.

Neuroinflammation in Parkinson's disease: its role in neuronal death and implications for therapeutic intervention.

Biochemical and neuropathological studies of brains from individuals with Alzheimer disease (AD) provide clear evidence for an activation of inflammatory pathways, and long-term use of anti-inflammatory drugs is linked with reduced risk to develop the disease. As cause and effect relationships between inflammation and AD are being worked out, there is a realization that some components of this complex molecular and cellular machinery are most likely promoting pathological processes leading to AD, whereas other components serve to do the opposite. The challenge will be to find ways of fine tuning inflammation to delay, prevent, or treat AD.

/pdf/inflammation-in-alzheimer-disease-a-brief-review-of-the-4mnlk1vy66.pdf

Inflammation in Alzheimer Disease—A Brief Review of the Basic Science and Clinical Literature

TNF is a pleiotropic cytokine with important functions in homeostasis and disease pathogenesis. Recent discoveries have provided insights into TNF biology that introduce new concepts for the development of therapeutics for TNF-mediated diseases. The model of TNF receptor signalling has been extended to include linear ubiquitination and the formation of distinct signalling complexes that are linked with different functional outcomes, such as inflammation, apoptosis and necroptosis. Our understanding of TNF-induced gene expression has been enriched by the discovery of epigenetic mechanisms and concepts related to cellular priming, tolerization and induction of 'short-term transcriptional memory'. Identification of distinct homeostatic or pathogenic TNF-induced signalling pathways has introduced the concept of selectively inhibiting the deleterious effects of TNF while preserving its homeostatic bioactivities for therapeutic purposes. In this Review, we present molecular mechanisms underlying the roles of TNF in homeostasis and inflammatory disease pathogenesis, and discuss novel strategies to advance therapeutic paradigms for the treatment of TNF-mediated diseases.

/pdf/tnf-biology-pathogenic-mechanisms-and-emerging-therapeutic-2uzdvwlov2.pdf

TNF biology, pathogenic mechanisms and emerging therapeutic strategies

The mechanisms that trigger or contribute to loss of dopaminergic (DA) neurons in Parkinson's disease (PD) remain unclear and controversial. Elevated levels of tumor necrosis factor (TNF) in CSF and postmortem brains of PD patients and animal models of PD implicate this proinflammatory cytokine in the pathophysiology of the disease; but a role for TNF in mediating loss of DA neurons in PD has not been clearly demonstrated. Here, we report that neutralization of soluble TNF (solTNF) in vivo with the engineered dominant-negative TNF compound XENP345 (a PEGylated version of the TNF variant A145R/I97T) reduced by 50% the retrograde nigral degeneration induced by a striatal injection of the oxidative neurotoxin 6-hydroxydopamine (6-OHDA). XENP345 was neuroprotective only when infused into the nigra, not the striatum. XENP345/6-OHDA rats displayed attenuated amphetamine-induced rotational behavior, indicating preservation of striatal dopamine levels. Similar protective effects were observed with chronic in vivo coinfusion of XENP345 with bacterial lipopolysaccharide (LPS) into the substantia nigra, confirming a role for solTNF-dependent neuroinflammation in nigral degeneration. In embryonic rat midbrain neuron/glia cell cultures exposed to LPS, even delayed administration of XENP345 prevented selective degeneration of DA neurons despite sustained microglia activation and secretion of solTNF. XENP345 also attenuated 6-OHDA-induced DA neuron toxicity in vitro. Collectively, our data demonstrate a role for TNF in vitro and in vivo in two models of PD, and raise the possibility that delaying the progressive degeneration of the nigrostriatal pathway in humans is therapeutically feasible with agents capable of blocking solTNF in early stages of PD.

https://www.jneurosci.org/content/jneuro/26/37/9365.full.pdf

Blocking soluble tumor necrosis factor signaling with dominant-negative tumor necrosis factor inhibitor attenuates loss of dopaminergic neurons in models of Parkinson's disease.

Christine G. Smith

Papers

Blocking soluble tumor necrosis factor signaling with dominant-negative tumor necrosis factor inhibitor attenuates loss of dopaminergic neurons in models of Parkinson's disease.