Novel Strategies Targeting Inflammation for Pathological States

Abstract

The Renin-Angiotensin System (RAS) plays a critical role in regulating various physiological processes. Angiotensin (1-7) (Ang-(1-7), an important component of the RAS, acts as an agonist of the Mas receptor in the central nervous system (CNS), triggering beneficial biological responses including the reduction in inflammatory factors. There is little known about the inflammatory state of a mild Traumatic Brain Injury (mTBI) with very few treatments to reduce things like cognitive deficits. Studies here aimed to investigate the therapeutic effects of Ang-(1-7) in a murine model of mTBI. The findings revealed that Ang-(1-7) significantly improved neurological outcomes, presenting a promising therapeutic approach for preventing long-term complications following mTBI. However, the short half-life and limited brain penetration of Ang-(1-7) hinder its therapeutic potential. To address these limitations, a modified version of Ang-(1-7) called PNA6 was developed, which exhibits improved stability and brain penetration.In order to further investigate the anti-inflammatory activity of Ang-(1-7) in a long-acting model of chronic pain the modified peptide, PNA6, was evaluated for its potential to inhibit metastatic cancer pain utilizing a murine model. The study employed two approaches: investigating the pain-relieving effects of PNA6 in models of cancer-induced bone pain (CIBP), as well as assessing its analgesic efficacy in a mouse model of peripheral neuropathy induced by oxaliplatin. Results demonstrated that PNA6 exhibited significant and lasting attenuation of mechanical hypersensitivity, with limited bone loss and central side effects as compared to chronic opioid treatment. In addition to the peptide-based approach for cancer pain, studies here also investigated whether a lipid that is found in the bone-microenvironment, sphingosine-1-phospahate, and its G-protein coupled receptor, S1PR1, played a role in maintaining chronic pain in a model of CIBP. Studies here explored the therapeutic potential of FTY720, an S1PR1 antagonist, for pain management. Sustained morphine, current clinical practice, in CIBP was investigated, along with the impact of co-administering FTY720 on pain behavior and bone loss in the murine model of CIBP. The findings revealed that sustained morphine treatments induced tolerance, hyperalgesia, and osteolysis. However, concurrent administration of FTY720 with the Mu opioid agonist, morphine, effectively inhibited CIBP and reduced bone loss, indicating their potential as novel therapeutic options. In summary, our data strongly suggest FTY720, as well as PNA6, are novel potential candidates that can be used for CIBP as either adjunct therapy with opioids or as stand-alone, respectively, to reduce CIBP pain and bone loss while reducing opioid side effects. Further research and clinical investigations are warranted to validate the therapeutic potential of these novel compounds in human patients.