Signal transducer and activator of transcription selleck compound 3 (STAT3) is activated in response to growth factors, cytokines, and hormones that are known to play protective role after nerve injury and to mediate nerve regeneration [54]. COX-1 deficient mice show reduced neuroinflammatory and microglial responses to insults, through reduced activation of both Nf-��B and STAT3 [56]. PGE2 is known to regulate the activation of STAT3, and PGE2 inhibition alters a signal required for dendritic cell survival and development, leading to apoptosis [57]. Survivin, a regulator of cell survival, is regulated by COX-2-generated PGE2 in part trough a STAT3 pathway [58]. PGE2 also mediates survival of nonneural cells, such as myocytes, through a STAT3 pathway [59].

The phosphoinositide 3-kinase (PI3K) and the mitogen-activated protein kinase (MAPK) pathways are activated in injured neurons, and act as intracellular cascades that modulate regeneration associated genes. Indomethacin treatment in tumor cells has been shown to decrease expression of PI3K [60]. Latanoprost, the synthetic derivative of PGF2a, is able to promote retinal ganglion cell survival and promote neurite outgrowth through a PGF receptor-mediated modulation of the PI3K pathway [61]. PI3K inhibition leads to enhanced protsnoids production in activated microglia, and additionally, PI3K can regulate the expression of COX-2 in microglia as a response to neuroinflammation [62]. MAPK pathways are involved in neuroinflammation in many ways, including the enhancement of sensory neuron interleukin-6 production [63] and the regulation of interleukin-1-mediated COX-2 expression [64].

Latanoprost also uses a MAPK pathway in order to rescue nuroglial cells from apoptosis [65]. Specificity protein-1 (Sp1) is a transcription machinery theorized to act as a general regulator of many of the nerve injury-inducible transcription factors, including some discussed above [54]. COX inhibitors Entinostat are also known to alter Sp1 phosphorylation and lead to arrested cell growth in tumor cells [66], and PGE2 can stimulate cell growth through induction of Sp1 DNA-binding activity [67]. PGE2 enhances the phosphorylation, DNA binding, and transcriptional activity of Sp1, and it leads to enhanced neurotrophin production through a Sp1 pathway [68], suggesting a possible mechanism for PGE2-induced reinnervation. These finding illustrate the complex interactions between inflammatory and neuroregenerative signaling.