Naringin ameliorates doxorubicin-induced neurotoxicity In vitro and cognitive dysfunction In vivo

Objectives: The primary objective of the study was to study the neuroprotective potential of naringin (NAR) against doxorubicin (DOX)-induced neurotoxicity in vitro and DOX-induced cognitive deficits (chemobrain) in vivo. Materials and Methods: In vitro methods, viz., 3-[4,5dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide assay, flow cytometry, acridine orange/ethidium bromide staining, and neuritogenic and reactive oxygen species (ROS) assays, assessed neuroprotective potential of NAR and its aglycone naringenin (NGN) in IMR-32 cells. Chemobrain was developed in Wistar rats on chronic administration of ten cycles of DOX, and episodic memory was assessed using novel object recognition task. Serum cortisol, locomotor activity, and hematological biochemical and histological analysis were carried out. Results: A protective effect of NAR or NGN was observed upon pretreatment with the respective compounds in IMR-32 cells challenged with DOX. Flow cytometry revealed that flavonoids reduced cell cycle changes produced by DOX. In addition, an increase in apoptosis, intracellular ROS generation, and inhibition of neurite growth was noticed in IMR-32 cells with DOX treatment, which was significantly prevented by NAR or NGN pretreatment. Interestingly, NAR (50 mg/kg, p.o.) significantly ameliorated episodic memory deficit associated with DOX without influencing locomotion, upon chronic treatment. NAR also prevented histological changes to major organs observed with DOX. Conclusion: NAR showed neuroprotective potential and may be used as an adjuvant therapy for amelioration of neurocognitive complications associated with chemotherapy in cancer survivors. Abbreviations used: CKL: Creatine kinase level; COX: Cyclooxygenase; DMEM: Dulbecco's modified eagle media; DOX: Doxorubicin; FBS: Fetal bovine serum; MTT: 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide; NAR: Naringin; NGN: Naringenin; NORT: Novel object recognition task; NOS: Nitric oxide synthase; QOL: Quality of life; RA: retinoic acid.