Social and Behavioral Sciences Commons^™

The P38alpha Mitogen-Activated Protein Kinase Limits The Cns Proinflammatory Cytokine Response To Systemic Lipopolysaccharide, Potentially Through An Il-10 Dependent Mechanism, Adam D. Bachstetter, Bin Xing, Linda J. Van Eldik

Sanders-Brown Center on Aging Faculty Publications

BACKGROUND: The p38α mitogen-activated protein kinase (MAPK) is a well-characterized intracellular kinase involved in the overproduction of proinflammatory cytokines from glia. As such, p38α appears to be a promising therapeutic target for neurodegenerative diseases associated with neuroinflammation. However, the in vivo role of p38α in cytokine production in the CNS is poorly defined, and prior work suggests that p38α may be affecting a yet to be identified negative feedback mechanism that limits the acute, injury-induced proinflammatory cytokine surge in the CNS.

METHODS: To attempt to define this negative feedback mechanism, we used two in vitro and two in vivo models …

Microglial P38Α Mapk Is Critical For Lps-Induced Neuron Degeneration, Through A Mechanism Involving Tnfα, Bin Xing, Adam D. Bachstetter, Linda J. Van Eldik

Sanders-Brown Center on Aging Faculty Publications

BACKGROUND: The p38α MAPK isoform is a well-established therapeutic target in peripheral inflammatory diseases, but the importance of this kinase in pathological microglial activation and detrimental inflammation in CNS disorders is less well understood. To test the role of the p38α MAPK isoform in microglia-dependent neuron damage, we used primary microglia from wild-type (WT) or p38α MAPK conditional knockout (KO) mice in co-culture with WT cortical neurons, and measured neuron damage after LPS insult.

RESULTS: We found that neurons in co-culture with p38α-deficient microglia were protected against LPS-induced synaptic loss, neurite degeneration, and neuronal death. The involvement of the proinflammatory …

Microglial P38Α Mapk Is A Key Regulator Of Proinflammatory Cytokine Up-Regulation Induced By Toll-Like Receptor (Tlr) Ligands Or Beta-Amyloid (Aβ), Adam D. Bachstetter, Bin Xing, Lucia De Almeida, Edgardo R. Dimayuga, D. Martin Watterson, Linda J. Van Eldik

Sanders-Brown Center on Aging Faculty Publications

BACKGROUND: Overproduction of proinflammatory cytokines from activated microglia has been implicated as an important contributor to pathophysiology progression in both acute and chronic neurodegenerative diseases. Therefore, it is critical to elucidate intracellular signaling pathways that are significant contributors to cytokine overproduction in microglia exposed to specific stressors, especially pathways amenable to drug interventions. The serine/threonine protein kinase p38α MAPK is a key enzyme in the parallel and convergent intracellular signaling pathways involved in stressor-induced production of IL-1β and TNFα in peripheral tissues, and is a drug development target for peripheral inflammatory diseases. However, much less is known about the quantitative …