Investigation of spinal prostaglandin D2 biosynthesis

Systemic responses to inflammatory disease, such as fever, fatigue, and increased pain sensitivity are mediated by the central nervous system and involve also the adaptation of central prostaglandin (PG) biosynthesis. At least three different isoforms of cyclooxygenases (COX-1, 2, 3) convert arachidonic acid to PGH2, which, in turn, is metabolized by terminal PG synthases to individual PGs. PGD2, the major product of PG biosynthesis in the CNS, has received only little attention so far, largely because appropriate investigational tools were missing. However, recently there have been considerable advances in the knowledge about PGD2 pharmacology. In particular, synthases that mediate PGD2 formation, and PGD2 receptors have been cloned and their occurrence in the CNS has been demonstrated. Furthermore, it has been shown that in peripheral tissue, PGD2 is rapidly metabolized to bioactive metabolites with pharmacological properties different from PGD2 which seem to include anti- inflammatory activity. Within the CNS the spinal cord is a particularly promising field for research into the regulation of PG biosynthesis, because it is known that spinal PG biosynthesis affects the transmission of nociceptive stimuli; investigations into the regulation of spinal PG biosynthesis in inflammatory disease can be expected to provide the basis to identify novel targets for pharmacological treatment of inflammatory pain. Therefore, this project will investigate in the spinal cord the cellular localization of PGD2 receptors and enzymes involved in PGD2 biosynthesis. In addition, the regulation of the spinal biosynthesis of PGD2 and its metabolites in response to systemic inflammation will be investigated; pharmacological studies in wild type and COX-1 or COX-2 deficient mice will provide evidence for the COX isoform that is involved in spinal PG biosynthesis. In view of the increasing clinical use of selective COX-2 inhibitors and the intriguing possibility of a participation of an acetaminophen-sensitive COX-3, these pharmacological studies seem of considerable relevance. In conclusion, it can be expected, that this research project will provide results that add to current knowledge by determining cellular sources and targets of spinal PGD2, the regulation of spinal PGD2 biosynthesis in systemic inflammation including the characterization of COX isoforms involved. These data thus can provide an essential basis for further studies about the function of spinal PGD2.

Systemic responses to inflammatory disease, such as fever, fatigue, and increased pain sensitivity are mediated by the central nervous system and involve also the adaptation of central prostaglandin (PG) biosynthesis. At least three different isoforms of cyclooxygenases (COX-1, 2, 3) convert arachidonic acid to PGH2, which, in turn, is metabolized by terminal PG synthases to individual PGs. PGD2, the major product of PG biosynthesis in the CNS, has received only little attention so far, largely because appropriate investigational tools were missing. However, recently there have been considerable advances in the knowledge about PGD2 pharmacology. In particular, synthases that mediate PGD2 formation, and PGD2 receptors have been cloned and their occurrence in the CNS has been demonstrated. Furthermore, it has been shown that in peripheral tissue, PGD2 is rapidly metabolized to bioactive metabolites with pharmacological properties different from PGD2 which seem to include anti- inflammatory activity. Within the CNS the spinal cord is a particularly promising field for research into the regulation of PG biosynthesis, because it is known that spinal PG biosynthesis affects the transmission of nociceptive stimuli; investigations into the regulation of spinal PG biosynthesis in inflammatory disease can be expected to provide the basis to identify novel targets for pharmacological treatment of inflammatory pain. Therefore, this project will investigate in the spinal cord the cellular localization of PGD2 receptors and enzymes involved in PGD2 biosynthesis. In addition, the regulation of the spinal biosynthesis of PGD2 and its metabolites in response to systemic inflammation will be investigated; pharmacological studies in wild type and COX-1 or COX-2 deficient mice will provide evidence for the COX isoform that is involved in spinal PG biosynthesis. In view of the increasing clinical use of selective COX-2 inhibitors and the intriguing possibility of a participation of an acetaminophen-sensitive COX-3, these pharmacological studies seem of considerable relevance. In conclusion, it can be expected, that this research project will provide results that add to current knowledge by determining cellular sources and targets of spinal PGD2, the regulation of spinal PGD2 biosynthesis in systemic inflammation including the characterization of COX isoforms involved. These data thus can provide an essential basis for further studies about the function of spinal PGD2.