Parkinson Disease: Frank-Cannon TC

Tansey MG, Frank-Cannon TC, McCoy MK, Lee JK, Martinez TN, McAlpine FE, Ruhn KA, Tran TA. · Department of Physiology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390-9040, USA. · Front Biosci. · Pubmed #17981581 No free full text.

Abstract: The inflammatory response in the brain associated with most chronic neurodegenerative diseases is termed neuroinflammation. Neuropathological and neuroradiological studies indicate that in certain neurodegenerative disorders neuroinflammation may be detectable years before significant loss of neurons occurs. In this review, we discuss the evidence from human studies and experimental models that implicate neuroinflammatory processes in the progressive neurodegeneration of the nigrostriatal pathway, the hallmark of Parkinson's Disease (PD). We discuss the neurotoxic role of microglia-derived inflammatory mediators which are suspected to hasten the death of nigral dopaminergic neurons, in particular the pro-inflammatory cytokine Tumor Necrosis Factor (TNF) and its downstream signaling pathways. We also entertain the possibility that chronic microglia activation links proteinopathies to neurodegeneration. The rationale for current and future use of anti-inflammatory approaches to protect vulnerable neuronal populations in PD is also reviewed.

Tansey MG, McCoy MK, Frank-Cannon TC. · Department of Physiology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, USA. · Exp Neurol. · Pubmed #17720159 No free full text.

Abstract: Most acute and chronic neurodegenerative conditions are accompanied by neuroinflammation; yet the exact nature of the inflammatory processes and whether they modify disease progression is not well understood. In this review, we discuss the key epidemiological, clinical, and experimental evidence implicating inflammatory processes in the progressive degeneration of the dopaminergic (DA) nigrostriatal pathway and their potential contribution to the pathophysiology of Parkinson's disease (PD). Given that interplay between genetics and environment are likely to contribute to risk for development of idiopathic PD, recent data showing interactions between products of genes linked to heritable PD that function to protect DA neurons against oxidative or proteolytic stress and inflammation pathways will be discussed. Cellular mechanisms activated or enhanced by inflammatory processes that may contribute to mitochondrial dysfunction, oxidative stress, or apoptosis of dopaminergic (DA) neurons will be reviewed, with special emphasis on tumor necrosis factor (TNF) and interleukin-1-beta (IL-1beta) signaling pathways. Epigenetic factors which have the potential to trigger neuroinflammation, including environmental exposures and age-associated chronic inflammatory conditions, will be discussed as possible 'second-hit' triggers that may affect disease onset or progression of idiopathic PD. If inflammatory processes have an active role in nigrostriatal pathway degeneration, then evidence should exist to indicate that such processes begin in the early stages of disease and that they contribute to neuronal dysfunction and/or hasten neurodegeneration of the nigrostriatal pathway. Therapeutically, if anti-inflammatory interventions can be shown to rescue nigral DA neurons from degeneration and lower PD risk, then timely use of anti-inflammatory therapies should be investigated further in well-designed clinical trials for their ability to prevent or delay the progressive loss of nigral DA neurons in genetically susceptible populations.