pifithrin-mu and Inflammation

Treatments immediately after spinal cord injury (SCI) are anticipated to decrease neuronal death, disruption of neuronal connections, demyelination, and inflammation, and to improve repair and functional recovery. Currently, little can be done to modify the acute phase, which extends to the first 48 hours post-injury. Efforts to intervene have focused on the subsequent phases - secondary (days to weeks) and chronic (months to years) - to both promote healing, prevent further damage, and support patients suffering from SCI.. We used a contusion model of SCI in female mice, and delivered a small molecule reagent during the early phase of injury. Histological and behavioral outcomes were assessed and compared.. We find that the reagent Pifithrin-μ (PFT-μ) acts early and directly on microglia in vitro, attenuating their activation. When administered during the acute phase of SCI, PFT-μ resulted in reduced lesion size during the initial inflammatory phase, and reduced the numbers of pro-inflammatory microglia and macrophages. Treatment with PFT-μ during the early stage of injury maintained a stable anti-inflammatory environment.. Our results indicate that a small molecule reagent PFT-μ has sustained immunomodulatory effects following a single dose after injury.

Topics: Animals; Animals, Newborn; Behavior, Animal; Contusions; Female; Inflammation; Macrophage Activation; Mice; Mice, Inbred C57BL; Microglia; Neuroprotective Agents; Phagocytosis; Primary Cell Culture; Recovery of Function; Spinal Cord Injuries; Subcellular Fractions; Sulfonamides; Wound Healing

P53 is a tumour suppressor protein thought to be primarily involved in cancer biology, but recent evidence suggests it may also coordinate novel functions in the CNS, including mediation of pathways underlying neurodegenerative disease. In microglia, the resident immune cells of the brain, p53 activity can promote an activation-induced pro-inflammatory phenotype Jayadev et al. (2011) [1], as well as neurodegeneration Davenport et al. (2010) [2]. Synapse degeneration is one of the earliest pathological events in many chronic neurodegenerative diseases Conforti et al. (2007) and Clare et al. (2010) [3,4] and may be influenced by early microglial responses. Here we examined synaptic properties of neurons following modulation of p53 activity in rat microglia exposed to inflammatory stimuli. A significant reduction in the expression of the neuronal synaptic markers synaptophysin and drebrin, occurred following microglial activation and was seen prior to any visible signs of neuronal cell death, including neuronal cleaved caspase-3 activation. This synaptic marker loss together with microglial secretion of the inflammatory cytokines tumour necrosis factor α (TNF-α) and interleukin 1-β (IL-1β) was abolished by the removal of microglia or inhibition of microglial p53 activation. These results suggest that transcriptional-dependent p53 activities in microglia may drive a non-cell autonomous process of synaptic degeneration in neurons during neuroinflammatory degenerative diseases.

Topics: Animals; Apoptosis; Benzothiazoles; Brain; Cells, Cultured; Inflammation; Lipopolysaccharides; Microglia; Neurons; Rats, Sprague-Dawley; Sulfonamides; Synapses; Toluene; Transcription, Genetic; Tumor Suppressor Protein p53