Inflammation in the brain is characterized by the activation of microglia and astroglia, and is thought to be associated with the pathogenesis of a number of neurological diseases, including Parkinson's disease (PD), Alzheimer's disease and cerebral ischemia. Epidemiological studies have shown a positive correlation between PD and inflammation early in life. For example, the increase in the incidence of PD in 1945-50's was highly correlated to the flu pandemic in 1910-20's. It was also found that a higher PD incidence appeared among populations who were professional boxers at a young age.
It is thought that such primary insults and inflammation activate glial cells, specifically microglia. The activated microglia secrete various cytokines and free radicals, such as superoxide and nitric oxide (NO), resulting in cerebral inflammation and subsequent neuronal death and damage. Accumulation and/or overproduction of these factors impact neurons to induce their degeneration.
One specific inflammatory agent that is often implicated in inflammatory conditions is lipopolysaccharide (LPS). LPS can activate microglia and other cells to overproduce proinflammatory cytokines and free radicals, such as NO, PGE2, TNFα, superoxide, and other reactive oxygen species (ROS). Cerebral inflammation sustained by microglia activation triggered by LPS results in a delayed and progressive degeneration of nigra dopaminergic neurons. Dopaminergic neurons, in particular, can be especially vulnerable to oxidative damage due to antioxidant capacity It is also believed that decreased neurotrophic factor released from astroglia could play a role in susceptibility to inflammation. For example, glial cell line-derived neurotrophic factor (GDNF) is synthesized and released from astroglia. GDNF is believed to at least partly mediate neurotrophic effects on dopaminergic (DA) neurons.
Therefore, there remains a need for a greater understanding of the mechanisms involved in these disease states and inflammation. There is also a need for development of agents and treatments that activate neuronal-survival signaling pathways that may enhance the resilience and plasticity of brain cells.
USPTO Backgrounds
USPTO Backgrounds