Melatonin Selectively Attenuates Histopathological Alterations in a Humanized Mouse Model of Sickle Cell Anemia
Year: 2026
Type: article
Abstract: Introduction Sickle cell anemia (SCA) is characterized by chronic hemolysis, inflammation, oxidative stress, and recurrent vaso-occlusive events that promote progressive damage to multiple organs. Melatonin (MEL) exhibits antioxidant, anti-inflammatory, and cytoprotective properties that may limit chronic tissue injury associated with SCA. This study evaluated the effects of prolonged MEL supplementation on histopathological alterations in target organs of humanized SCA mice. Methods Humanized SCA mice were generated by transplantation of bone marrow mononuclear cells from Berkeley SS or SA donors into lethally irradiated recipients (CEUA/UNICAMP, protocol 5955-1/2022). Animals were allocated into SA controls, untreated SS, and SS treated with MEL (10 mg/kg/day, orally, for 60-days, n=5/group). Histopathological evaluation of spleen, liver, and kidney sections was performed using hematoxylin-eosin and Masson's trichrome staining. Tissue organization, perivascular erythrocyte accumulation, fibrosis, megakaryocyte infiltration, hemosiderin deposition, necrosis, and hepatic hyperplasia were assessed using a blinded three-point semiquantitative scoring system. Group comparisons were performed using the Kruskal-Wallis test followed by Dunn's multiple-comparison test with Holm correction. Results MEL selectively reduced histopathological lesions in humanized SCA mice. In the spleen, MEL significantly decreased fibrosis (p=0.005), megakaryocyte infiltration (p=0.011), and hemosiderin deposition (p=0.013) compared with untreated SS mice, whereas no significant effect was observed on tissue organization or perivascular erythrocyte accumulation. In the liver, MEL significantly reduced hyperplasia (p=0.013) and hemosiderin deposition (p=0.044), while perivascular erythrocyte accumulation remained unchanged. Renal architecture was preserved in all groups; however, MEL significantly reduced perivascular erythrocyte accumulation compared with untreated SS animals (p=0.002). No significant differences were detected for parameters that showed no variability among experimental groups. Conclusion Prolonged melatonin supplementation selectively attenuated chronic histopathological alterations in target organs of humanized SCA mice, with the most consistent effects observed in splenic fibrosis, megakaryocyte infiltration and hemosiderin deposition, hepatic hyperplasia and hemosiderin deposition, and renal vascular congestion. These findings reinforce the role of oxidative stress in chronic organ injury and support melatonin as a promising adjunctive strategy to mitigate tissue damage associated with SCA.
Language: English
Subfield: Genetics (clinical)
Field: Medicine
Domain: Health Sciences
Open Access status: diamond
OpenAlex ID: W7223144297