The role of elevated prostaglandins in neuroinflammation-induced memory deficits: A complex picture

Cognitive dysfunction is a debilitating symptom in a number of neuroinflammatory conditions including aging, Alzheimer's disease, Down syndrome, and AIDS-related dementia. Animal studies have repeatedly shown that neuroinflammation, resulting from diverse insults including lipopolysaccharide, traumatic brain injury, stroke, drug abuse, aging, and models of Alzheimer's disease, impairs memory. Treatment with COX inhibitors, which inhibit prostaglandin synthesis, has improved memory in many of these neuroinflammatory states, indicating a potential role for elevated prostaglandins in these memory deficits. In this thesis, we examined the role of elevated prostaglandins in cognitive dysfunction following acute interleukin-1beta (IL-1beta) injection, Escherichia coli challenge in aged animals, and sustained IL-1beta overexpression in a transgenic mouse model. Here, we report that elevated prostaglandins are necessary to impair contextual fear memory following acute intra-hippocampal IL-1beta injection. Furthermore, prostaglandin e 2 itself is sufficient to impair contextual fear memory and reduce transcription of the memory-related gene, brain derived neurotrophic factor. In two models of prolonged neuroinflammation, E. coli challenge in aged rats and sustained hippocampal IL-1beta overexpression in transgenic mice, we show that elevated prostaglandins are not necessary for resulting memory deficits. Treatment with COX-2 selective, COX-1 selective, and non-selective COX inhibitors had no effect on memory, despite reducing hippocampal PGE 2 levels. Therefore, although elevated prostaglandins are required for memory impairments after acute neuroinflammatory conditions, they are not essential for cognitive dysfunction following prolonged or chronic neuroinflammation.