The Potential Therapeutic Approach of Ursodeoxycholic Acid as a Potent Activator of ACE‐2 on Cerebral Disorders Induced by γ‐irradiation in Rats

Abstract

The present investigation assesses ursodeoxycholic acid's efficacy (UDCA) as an ACE2 activator against gamma irradiation through activating the renin‐angiotensin system's (RAS) beneficial axis, ACE2/Ang‐(1–7)/Mas1 via its profitable influence on inflammation, oxidative stress, and neuronal damage caused by irradiation (IRR). Four groups of rats were treated as follows: control group, group receiving UDCA (100 mg/kg/day) for 14 days by gavage, group irradiated at 6 Gy, and group receiving UDCA post‐irradiation for 14 days. The results revealed that gamma‐irradiation (6 Gy) caused a substantial drop in the cerebral ACE2/Ang‐(1–7)/Mas1 axis and remarkably increased the expression of cerebral inflammatory mediators: tumor necrosis factor‐α (TNF‐α), nuclear factor kappa‐B (NF‐κB), interleukin‐6 (IL‐6) and interleukin‐1β (IL‐1β) combined with significant elevation in cyclooxygenase‐II (COX‐II), (NADPH) oxidases (NOX4), lipooxygenase (LOX) activities and nitric oxide (NO) content. Moreover, it greatly enhanced the reduction in N‐methyl‐d‐aspartate (NMDA) level, while dramatically increasing gamma‐aminobutyric acid (GABA) level and neuronal nitric oxide synthases (nNOS) enzyme activity in cerebral tissue homogenate. Irradiated rats’ brain sections underwent histological investigation using hematoxylin and eosin staining, which revealed cellular damage and a pathological appearance. The administration of UDCA inverts these unusual alterations. In conclusion, UDCA treatment efficiently normalizes the above‐mentioned pathological abnormalities and avoids the development of IRR‐associated neurological dysfunction by upregulating the beneficial axis of RAS in the brain. Hence, ursodeoxycholic acid presents a novel option for patient care during radiotherapy.