Evidence for Increased Chronic Inflammation in PD

Studies on chronic inflammation in human and animal PD models: Microglia initiated chronic inflammation responses also play an important role in the mechanism of degeneration of DA neurons in PD [14, 15]. Aggregated or nitrated alpha- synuclein activates microglia which release pro-inflammatory cytokines and other neurotoxic factors that contribute to the degeneration of DA neurons [55, 56]. Activated microglia also release nitric oxide and superoxide that promote inflammation as well as formation of abnormal alpha-synuclein (excessive amount or mutated form) that cause degeneration of DA neurons in transgenic mice model of PD [57].

In the autopsied brain samples of PD brains, the number of activated microglia cells increased in the substantia nigra during the progression of PD. The levels of pro-inflammatory cytokines IL-6 and TNF-alpha increased in both PD and Lewy body disease [58]. The presence of extracellular neuromelanin serves as a source of chronic inflammation that aggravates the rate of degeneration of DA neurons. Activated microglia may produce excessive amounts of pro-inflammatory cytokines, complement proteins, prostaglandins, adhesion molecules and reactive oxygen species (ROS) all of which are neurotoxic.

Cyclooxygenase (COX) is the rate-limiting enzyme in the synthesis of prostaglandins that are neurotoxic in excessive amounts [59]. The inducible isoforms COX-2 is up-regulated in the DA neurons of the autopsied brain samples of PD patients. The levels of COX-2 are also increased in DA neurons of chemical- induced animal PD models. The studies presented in this section clearly show that chronic inflammation plays an important role in degeneration and apoptosis of DA neurons in PD.

Neuromelanin granules accumulate in the substantia nigra of PD patients. Neuromelanin can cause degeneration in DA neurons by generating H2O2 when it is intact, or by releasing redox active metals such as iron, if it is disintegrated. In addition, dying DA neurons can release melanin that can initiate chronic inflammatory responses by activating microglia cells.

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