Role of bone marrow mesenchymal stem cell-derived exosomes in reducing neurotoxicity and depression-like behaviors induced by doxorubicin in rats

Doaa R I Abdel-Gawad; Fatma Khalil; Olfat Shehata; Marwa A Ibrahim; SalmaI El-Samannoudy; Emad A Mahdi; Nema S Shaban

doi:10.1093/toxres/tfae159

Role of bone marrow mesenchymal stem cell-derived exosomes in reducing neurotoxicity and depression-like behaviors induced by doxorubicin in rats

Toxicol Res (Camb). 2024 Oct 3;13(5):tfae159. doi: 10.1093/toxres/tfae159. eCollection 2024 Oct.

Authors

Doaa R I Abdel-Gawad¹, Fatma Khalil², Olfat Shehata³, Marwa A Ibrahim⁴, SalmaI El-Samannoudy⁵, Emad A Mahdi⁶, Nema S Shaban⁷

Affiliations

¹ Department of Toxicology and Forensic Medicine, Faculty of Veterinary Medicine, Beni-Suef University, Shamla St. next to the Directorate of Roads and Bridges, Beni Suef 62511, Egypt.
² Department of Animal and Poultry Management and Wealth Development, Faculty of Veterinary Medicine, Beni-Suef University, Shamla St. next to the Directorate of Roads and Bridges, Beni-Suef 62511, Egypt.
³ Department of Clinical Pathology, Faculty of Veterinary Medicine, Beni-Suef University, Shamla St. next to the Directorate of Roads and Bridges, Beni-Suef 62511, Egypt.
⁴ Department of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, Cairo University, Block 17102 8th district Obour city, Giza 12211, Egypt.
⁵ Department of Physiology, Faculty of Veterinary Medicine, Cairo University, 81 District 9 Neighborhood 4 sheikh zayed, Giza 12211, Egypt.
⁶ Department of Pathology, Faculty of Veterinary Medicine, Beni-Suef University, Shamla St. next to the Directorate of Roads and Bridges, Beni-Suef 62511 Egypt.
⁷ Department of Pharmacology, Faculty of Veterinary Medicine, Beni-suef University, PO Box 62511, Shamla St. next to the Directorate of Roads and Bridges, Beni-Suef, Egypt.

PMID: 39371677
PMCID: PMC11447378 (available on 2025-10-03)
DOI: 10.1093/toxres/tfae159

Abstract

Background: Doxorubicin (DOX) is a broad-spectrum antitumor drug while its use is limited nowadays due to its neurobiological side effects associated with depression. Bone marrow mesenchymal stem cells (BM-MSCs) derived exosomes are a promising regenerative therapy. In this study, we investigated the therapeutic potentiality of BM-MSCs derived exosomes against the neurotoxicity induced by DOX.

Methods: Twenty-four male albino rats were divided equally in to three groups as follow: group 1 (control), group 2 (rats injected intraperitoneally (i.p|) with DOX at a dose 2.5mg/Kg), and group 3 (rats injected with DOX and BM-MSCs derived exosomes i.p at a dose 1.5ml/Kg). During the experiment the behavior tests were noted, after three weeks rats were sacrificed, serum and brain samples were collected for biochemical, molecular and histopathological examinations.

Results: The results revealed that DOX causing impairment of the locomotor and increasing the anxiety like behavior of rats, marked neuropathological changes, significant elevation of MDA content and TNF-α concentration, reduction of phospholipase (PLD) and acetylcholinesterase (AChE) protein concentration in addition, there were up regulation of JNK, NF-κB and p38 genes and down regulation of Erk1.

Conclusion: Exosomal therapy improved the substantial neurotoxicity of DOX through modulating the markers involved in the neurotoxic signalling pathway of DOX that resulting in improving the pathological lesions and the animal behaviours.

Keywords: BM-MSCs derived exosomes; Behavioral tests; Doxorubicin; ELISA; Neurotoxicity; RT-PCR.