Des-Aspartate-Angiotensin I Attenuates Mortality of Mice Exposed to Gamma Radiation via a Novel Mechanism of Action

Abstract

ACE inhibitors and ARBs (angiotensin receptor blockers) have been shown to attenuate radiation injuries in animal models of lethal gamma irradiation. These two classes of drug act by curtailing the actions of angiotensin II-linked inflammatory pathways that are up-regulated during gamma radiation in organ systems such as the brain, lung, kidney, and bone marrow. ACE inhibitors inhibit ACE and attenuate the formation of angiotensin II from angiotensin I; ARBs block the angiotensin AT1 receptor and attenuate the actions of angiotensin II that are elicited through the receptor. DAA-I (des-aspartate-angiotensin I), an orally active angiotensin peptide, also attenuates the deleterious actions of angiotensin II. It acts as an agonist on the angiotensin AT1 receptor and elicits responses that oppose those of angiotensn II. Thus, DAA-I was investigated for its anticipated radioprotection in gamma irradiated mice. DAA-I administered orally at 800 nmole/kg/day for 30 days post exposure (6.4 Gy) attenuated the death of mice during the 30-day period. The attenuation was blocked by losartan (50 nmole/kg/day, i.p.) that was administered sequential to DAA-I administration. This shows that the radioprotection was mediated via the angiotensin AT1 receptor. Furthermore, the radioprotection correlated to an increase in circulating PGE2 of surviving animals, and this suggests that PGE2 is involved in the radioprotection in DAA-I-treated mice. At the hematopoietic level, DAA-I significantly improved two syndromes of myelosuppression (leucopenia and lymphocytopenia), and mice pre-treated with DAA-I prior to gamma irradiation showed significant improvement in the four myelodysplastic syndromes that were investigated, namely leucopenia, lymphocytopenia, monocytopenia and thrombocytopenia. Based on the known ability of PGE2 to attenuate the loss of functional hematopoietic stem and progenitor cells in radiation injury, we hypothesize that PGE2 mediated the action of DAA-I. DAA-I completely attenuated the increase in circulating level of two inflammatory cytokines, TNFα and IL-6, in irradiated mice; and this shows that DAA-I exerted additional anti-inflammatory actions, which could also have contributed to its radioprotection. These findings show that DAA-I acts via a novel mechanism of action on the angiotensin AT1 receptor to specifically release PGE2, which mediates radioprotection in the gamma irradiated mice.

Potential Protective Effects of Ursolic Acid against Gamma Irradiation-Induced Damage Are Mediated through the Modulation of Diverse Inflammatory Mediators

“…Several phase I clinical trials have been conducted to evaluate the safety, tolerance and antitumor activity of intravenously administrated UAL. It was found that UAL was tolerable with manageable levels of toxicity, and could potentially improve remission rates in patients (Wang et al, 2013, 2015; Zhu et al, 2013; Qian et al, 2015). …”

A Single Dose-Escalation Study to Evaluate the Safety and Pharmacokinetics of Orally Administered Des-Aspartate Angiotensin I in Healthy Subjects

“…To confirm that oral DAA-I enters the systemic circulation in effective amounts and reaches its target, we anticipate a 2-week multi-dose phase I study of DAA-I that focuses on measuring PGE 2 and PGI 2 as surrogate biomarkers of DAA-I. This multi-dose study would hold much promise, as chronic oral administration of DAA-I 800 nmole/kg/day (0.95 mg/kg/day) to mice has been shown to cause a significant rise in plasma PGE 2 in the animals after 2 weeks of oral administration [11]. …”

“…Accordingly, DAA-I has been shown to be efficacious in animal models of cardiac hypertrophy [1], neointima formation [2], arteriosclerosis [2], renal failure [3], post-infarction injuries [4, 5], diabetes [6, 7], viral infection [8], chemical-induced inflammation [9], heat stroke [10], cancer [10] and gamma radiation lethality [11], where it has been found to significantly attenuate the severity of the pathology. At effective doses, DAA-I has no observable effects on the basal physiological and biochemical parameters that were measured in these studies and was found to lack secondary responses that could be considered adverse or side effects.…”

Celastrol Alleviates Gamma Irradiation-Induced Damage by Modulating Diverse Inflammatory Mediators

“…As a NF-κB pathway blocker and antioxidant, celastrol may represent a promising pharmacological agent with protective effects against gamma irradiation-induced injury. damage directly at a cellular level, or indirectly on water molecules, which then generate free radicals [1,2]. Free radicals further result in oxidation, DNA damage, and inflammation in the body [1,3,4].…”

“…damage directly at a cellular level, or indirectly on water molecules, which then generate free radicals [1,2]. Free radicals further result in oxidation, DNA damage, and inflammation in the body [1,3,4]. Currently, the probability of radiation exposure in human beings is increased due to the wide use of nuclear energy in modern society, which makes the development of effective radioprotective agents an urgent task [5][6][7].Celastrol, also known as tripterine, is a pentacyclic triterpenoid that belongs to the family of quinone methides [8][9][10][11][12][13][14][15].…”