Melatonin Protects against the Side-Effects of 5-Fluorouracil on Hippocampal Neurogenesis and Ameliorates Antioxidant Activity in an Adult Rat Hippocampus and Prefrontal Cortex

Abstract

Melatonin is an endogenous hormone that exhibits antioxidant functions and neuroprotective effects. The hippocampus and the prefrontal cortex (PFC) play an important role linked to working memory. 5-fluorouracil (5-FU) can induce oxidative stress and reduce neurogenesis in the subgranular zone (SGZ) of the dentate gyrus in a rat hippocampus and these alterations are related to working memory deficits. This study aimed to determine the effect of melatonin on 5-FU-induced oxidative stress that interferes with the antioxidant enzymes and protein expression levels in a rat hippocampus and PFC. A total of 68 male Sprague Dawley rats were divided into four groups: vehicle, 5-FU, melatonin and melatonin+5-FU groups. Rats were administered 5-FU (25 mg/kg, i.v.) on days 9, 12, 15, 18 and 21 and received melatonin (8 mg/kg, i.p.) at 19:00 from day 1 to day 21 of the experiment. Lipid peroxidation was assessed by measuring malondialdehyde (MDA) levels. Antioxidant enzyme levels including glutathione peroxidase (GPX), catalase (CAT) and superoxide dismutase (SOD) were determined. p21 immunofluorescence staining and Western blotting were used to detect the cell cycle arrest and protein expression of the nuclear factor erythroid 2-related factor 2 (Nrf2), doublecortin (DCX) and brain derived neurotrophic factor (BDNF), respectively. The results showed that melatonin reduced the number of p21-positive cells in the SGZ of the dentate gyrus and increased Nrf2, DCX and BDNF protein expression in rats treated with 5-FU. Moreover, melatonin restored antioxidant enzyme levels and reduced oxidative stress in the hippocampus and PFC caused by 5-FU. These findings reveal a mechanism of the neuroprotective properties of melatonin against 5-FU in a rat hippocampus and PFC.

Chemotherapy-Induced Cognitive Impairment and Hippocampal Neurogenesis: A Review of Physiological Mechanisms and Interventions

“…At this timepoint, 5-FU treated rats displayed impaired memory for the novel object location task, indicative of spatial memory impairment [ 97 ]. Using this same treatment protocol, this group also identified a reduction in p21 expressing cells in the SGZ four days [ 98 ] and one month [ 99 ] following the end of 5-FU treatment, indicating both early and persistent disruption of mitotic activity and apoptosis. p21 may be an early indication of arrested mitotic activity that is not captured at the early post-treatment timepoint by conventional endogenous protein markers of neurogenesis Ki-67 and DCX.…”

“…As with MTX, no cumulative benefit was evident when melatonin was administered throughout both the pre- and post-5-FU treatment period, suggesting that melatonin supplements are equally effective at preventing memory deficits and neurotoxicity induced by MTX or 5-FU when proactively administered prior to or following the initiation of chemotherapy treatment. Melatonin treatment also prevented the increases in p21 expressing cells within the SGZ seen in rats treated with 5-FU alone, indicating reduced cell cycle arrest within the neurogenic zone [ 98 ].…”

The Effects of 5-Fluorouracil/Leucovorin Chemotherapy on Cognitive Function in Male Mice

“…Based on the information received from the network and pathways found to be involved in the 5-FU/LV treatment suggest antioxidant therapies to combat oxidative stress. Studies suggest melatonin can be used to attenuate cognitive impairments caused by 5-FU treatments by increasing antioxidant activity by restoring antioxidant-dependent pathways such as Nrf2 (Sirichoat et al, 2020;Suwannakot et al, 2021). Based on the data presented, we can only assume the roles polyamines play in model as this proteomics analysis purely descriptive and further analysis must be applied.…”

Celastrol and Melatonin Modify SIRT1, SIRT6 and SIRT7 Gene Expression and Improve the Response of Human Granulosa-Lutein Cells to Oxidative Stress

“…Melatonin is a hormone synthesized by a wide variety of animal cells and tissues [ 26 ] with antioxidant and free radical scavenger activity [ 27 , 28 ]. There is evidence that melatonin as an anti-oxidative regulator, plays a role in the reproductive system during oocyte maturation [ 29 ], steroidogenesis capacity acquisition [ 30 ] or embryo implantation [ 31 ].…”