AR42 has entered Phase I clinical trials

it showed cytotoxicity to cultured neurones Celecoxib which was ablated by PGE2. Also, in a cell type of Alzheimers illness, butaprost prevented neurotoxicity in a cAMP dependent fashion following contact with beta amyloid protein. Furthermore, in Alzheimers infection, there was improved PGE2 in CSF of patients who survived longer indicating a protective role for PGE2. This has implications for the design of EP2R selective agonists with neuro-protective action in neurodegenerative illness and stroke. However, as EP2R is involved in several other features, it might be too general a target. Cytoprotective activities of PGD and 15 deoxy PGJ Recently, PGD2 has attracted attention as a molecule with fewer potential unwanted effects than PGE2. PGD2 is abundant in brain, and its receptors might be a suitable CNS target.

Indeed, PGD2 protected cultured neurones from toxicity, an action dependent Eumycetoma on cAMP. Two PGD2 receptors, DP1 and DP2, have now been recognized, and the DP1 agonist BW245C mimicked the cytoprotective effects of PGD2. Similarly, in reperfusionischaemia, DP1 receptor knockout animals showed bigger necrotic lesions following cerebral artery occlusion, without alterations in cerebral blood flow. These studies confirmed protective actions of PGD2 via DP1 receptors. Thus, DP1R may possibly provide another target for therapeutic suppression of neuronal cell death. A problem in understanding PGD2 action arises from metabolism of PGD2 to 15 deoxy PGJ2, which also offers cytoprotective activity.

15d PGJ2 paid off infarct size following cerebral ischaemia in BAY 11-7082 rats, coincident with up enhanced nuclear binding of PPAR g and regulation of transcription factor PPAR g. This suggested that PPARg mediated a few of the cytoprotective actions of 15d PGJ2. Nevertheless, 15d PGJ2 may also act independently of PPAR g via cell death signalling pathways. Pereira et al. showed PPAR gary service paid off necrosis following cerebral artery occlusion individually of 15d PGJ2. Also, 15d PGJ2 associated neuroprotection through PPAR g independent mechanisms was described, and PPAR g independent actions of 15d PGJ2 are supported by proof of 15d PGJ2 action in PPAR g knockout cells, and concentrations of 15d PGJ2 required to exert an action several orders of magnitude below those causing PPAR g in the same tissues. An additional site of action of 15d PGJ2 in cell death signalling is nuclear issue NF kB signalling.

15d PGJ2 reacts with nucleophiles such as free sulfhydryls of glutathione and cysteine residues in cellular proteins, and restricted activation of NF kB via inhibition of phosphorylation and degradation of IkBa. Indeed, it's been found that 15d PGJ2 can covalently bind to the cysteine residues of PPAR h. A gastro-intestinal aftereffect of 15d PGJ2 continues to be identified, also involving NF kB and Bcl 2 signalling.