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Background: An accumulating body of evidence is consistent with the hypothesis that excessive or prolonged increases in proinflammatory cytokine production by activated glia is a contributor to the progression of pathophysiology that is causally linked to synaptic dysfunction and hippocampal behavior deficits in neurodegenerative diseases such as Alzheimer's disease (AD). This raises the opportunity for the development of new classes of potentially disease-modifying therapeutics. A logical candidate CNS target is p38 MAPK, a well-established drug discovery molecular target for altering proinflammatory cytokine cascades in peripheral tissue disorders. Activated p38 MAPK is seen in human AD brain tissue and in AD-relevant animal models, and cell culture studies strongly implicate p38 MAPK in the increased production of proinflammatory cytokines by glia activated with human amyloid-beta (A ) and other disease-relevant stressors. However, the vast majority of small molecule drugs do not have sufficient penetrance of the bloodbrain barrier to allow their use as in vivo research tools or as therapeutics for neurodegenerative disorders. The goal of this study was to test the hypothesis that brain p38 MAPK is a potential in vivo target for orally bioavailable, small molecules capable of suppressing excessive cytokine production by activated glia back towards homeostasis, allowing an improvement in neurologic outcomes.

Despite considerable amount of research, the poor prognosis of patients diagnosed with glioblastoma multiforme (GBM) critically needs new drug development to improve clinical outcomes. The development of an inflammatory microenvironment has long been considered important in the initiation and progression of glioblastoma; however, the success of developing therapeutic approaches to target inflammation for GBM therapy has yet been limited. Here, we summarize the accumulating evidence supporting a role for inflammation in the pathogenesis of glioblastoma, discuss anti‐inflammatory targets that could be relevant for GBM treatment and provide a perspective on the challenges faced in the development of drugs that target GBM inflammation. In particular, we will review the function of IL‐1β, IL‐6 and IL‐8 as well as the potential of kinase inhibitors targeting key players in inflammatory cell signalling cascades such as JAK, JNK and p38 MAPK.