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PNA6, a Lactosyl Analogue of Angiotensin-(1—7), Reverses Pain Induced in Murine Models of Inflammation, Metastatic Bone Disease, and Chemotherapy-Induced Peripheral Neuropathy
Sulaiman, M.I.; Alabsi, W.; Szabo, L.; Hay, M.; Polt, R.; Largent-Milnes, T.M.; Vanderah, T.W. PNA6, a Lactosyl Analogue of Angiotensin-(1-7), Reverses Pain Induced in Murine Models of Inflammation, Chemotherapy-Induced Peripheral Neuropathy, and Metastatic Bone Disease. Int. J. Mol. Sci.2023, 24, 15007.
Sulaiman, M.I.; Alabsi, W.; Szabo, L.; Hay, M.; Polt, R.; Largent-Milnes, T.M.; Vanderah, T.W. PNA6, a Lactosyl Analogue of Angiotensin-(1-7), Reverses Pain Induced in Murine Models of Inflammation, Chemotherapy-Induced Peripheral Neuropathy, and Metastatic Bone Disease. Int. J. Mol. Sci. 2023, 24, 15007.
Sulaiman, M.I.; Alabsi, W.; Szabo, L.; Hay, M.; Polt, R.; Largent-Milnes, T.M.; Vanderah, T.W. PNA6, a Lactosyl Analogue of Angiotensin-(1-7), Reverses Pain Induced in Murine Models of Inflammation, Chemotherapy-Induced Peripheral Neuropathy, and Metastatic Bone Disease. Int. J. Mol. Sci.2023, 24, 15007.
Sulaiman, M.I.; Alabsi, W.; Szabo, L.; Hay, M.; Polt, R.; Largent-Milnes, T.M.; Vanderah, T.W. PNA6, a Lactosyl Analogue of Angiotensin-(1-7), Reverses Pain Induced in Murine Models of Inflammation, Chemotherapy-Induced Peripheral Neuropathy, and Metastatic Bone Disease. Int. J. Mol. Sci. 2023, 24, 15007.
Abstract
The renin-angiotensin system (RAS) plays a role in cardiovascular homeostasis and hydro-electrolyte balance influencing organ function throughout the body. The classical view of RAS focused on a single biologically active metabolite, the octapeptide angiotensin (Ang)ll, created by the Angiotensin-converting enzyme (ACE). The past two decades have revealed new functions for intermediate products of the RAS beyond their role as substrates. Angiotensin 1-7 (Ang-(1—7), a RAS peptide product with actions at the Mas receptor, reportedly prevents cardiovascular disease-induced cognitive decline and cancer-induced bone pain (CIBP). However, Ang-(1—7) has a short half-life in vivo; here, we hypothesized that activating the MasR1 with a lactoside Ang-(1—7) analogue- PNA6-would attenuate inflammatory, cancer pain confined to the long bones, and chemotherapy-induced peripheral neuropathy (CIPN) for a longer-lasting efficacious therapeutic effect. PNA6, Asp-Arg-Val-Tyr-Ile-His-Ser-(O-β-Lact)-amide, was successfully synthesized on solid phase peptide synthesis (SPPS). PNA6 significantly reversed inflammatory pain induced by 2% carrageenan in mice. In a second study modeling a complex pain state, E0771 breast adenocarcinoma cells were implanted into the femur of female C57BLK/6J wild-type mice to induce cancer-induced bone pain (CIBP). Both acute and chronic dosing of PNA6 significantly reduced the spontaneous pain behaviors associated with CIBP. A third murine model of platinum drug-induced painful peripheral neuropathy was established using oxaliplatin. Mice in the oxaliplatin-vehicle treatment groups demonstrated significant mechanical allodynia compared to oxaliplatin- PNA6 treatment group mice. These data suggest that PNA6 is a viable lead candidate for treating chronic inflammatory and complex neuropathic pain.
Keywords
PNA6; angiotensin 1-7; Mas receptor; breast; cancer; pain
Subject
Medicine and Pharmacology, Medicine and Pharmacology
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
