Zinc supplementation ameliorates sorafenib-induced cognitive impairment through ROS/JNK signaling pathway

Zhou, Cancan; He, Yu-Qiong; Qiu, Yu-Shuang; Ni, Chenxu; Shen, Fu‐Ming; Li, Dongjie

doi:10.1007/s12011-022-03142-5

Cited by 4 publications

(4 citation statements)

References 47 publications

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“…This study showed that sorafenib administration severely impaired spatial recognition memory even in healthy, non-tumour-bearing mice. Our findings are supported by Zhou et al, who demonstrated that sorafenib induced learning and memory impairments in the novel object recognition and Y-maze tasks [ 26 ]. However, concomitant voluntary exercise implemented in this study could not restore sorafenib-induced learning and memory deficits.…”

Section: Discussionsupporting

confidence: 89%

“…It also suppresses angiogenesis by inhibiting vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptors [ 24 ]. Although sorafenib promotes patient survivorship [ 25 ], its apoptotic [ 26 ] and oxidative properties [ 27 ] may contribute to cognitive impairment [ 28 , 29 ] and muscular dysfunction [ 30 , 31 ]. Sorafenib can cross the blood-brain barrier [ 32 ], through which sorafenib can directly impair brain function [ 26 , 33 ].…”

Section: Introductionmentioning

confidence: 99%

“…The hippocampus is a neurogenic zone with active adult neurogenesis in the subregion dentate gyrus (DG), playing an important role in regulating learning and memory, as well as mood [ 34 , 35 ]. Previous studies have demonstrated that sorafenib administration induces motor and cognitive deficits and impairs hippocampal function [ 26 , 33 ]. In contrast, physical exercise is effective in preventing cancer cachexia and cognitive impairments [ 36 ], improving cancer survivorship and chemotherapy-induced muscle wasting [ 37 , 38 , 39 , 40 , 41 ].…”

Section: Introductionmentioning

confidence: 99%

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Effects of Voluntary Wheel Running Exercise on Chemotherapy-Impaired Cognitive and Motor Performance in Mice

Lee

Devaki

Formolo

et al. 2023

IJERPH

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Chemotherapy-induced cognitive impairment (chemobrain) and muscle wasting (cachexia) are persisting side effects which adversely affect the quality of life of cancer survivors. We therefore investigated the efficacy of physical exercise as a non-pharmacological intervention to reverse the adverse effects of chemotherapy. We examined whether physical exercise in terms of voluntary wheel running could prevent chemotherapy-induced cognitive and motor impairments in mice treated with the multi-kinase inhibitor sorafenib. Adult male BALB/c mice were subdivided into runner and non-runner groups and orally administered with sorafenib (60 mg/kg) or vehicle continuously for four weeks. Mice could freely access the running wheel anytime during sorafenib or vehicle treatment. We found that sorafenib treatment reduced body weight gain (% of change, vehicle: 3.28 ± 3.29, sorafenib: −9.24 ± 1.52, p = 0.0004), impaired hippocampal-dependent spatial memory in the Y maze (exploration index, vehicle: 35.57 ± 11.38%, sorafenib: −29.62 ± 7.90%, p < 0.0001), increased anhedonia-like behaviour in the sucrose preference test (sucrose preference, vehicle: 66.57 ± 3.52%, sorafenib: 44.54 ± 4.25%, p = 0.0005) and impaired motor skill acquisition in rotarod test (latency to fall on day 1: 37.87 ± 8.05 and day 2: 37.22 ± 12.26 s, p > 0.05) but did not induce muscle wasting or reduce grip strength. Concomitant voluntary running reduced anhedonia-like behaviour (sucrose preference, sedentary: 44.54 ± 4.25%, runners: 59.33 ± 4.02%, p = 0.0357), restored impairment in motor skill acquisition (latency to fall on day 1: 50.85 ± 15.45 and day 2: 168.50 ± 37.08 s, p = 0.0004), but failed to rescue spatial memory deficit. Immunostaining results revealed that sorafenib treatment did not affect the number of proliferating cells and immature neurons in the hippocampal dentate gyrus (DG), whereas running significantly increased cell proliferation in both vehicle- (total Ki-67+ cells, sedentary: 16,687.34 ± 72.63, exercise: 3320.03 ± 182.57, p < 0.0001) and sorafenib-treated mice (Ki-67+ cells in the ventral DG, sedentary: 688.82.34 ± 38.16, exercise: 979.53 ± 73.88, p < 0.0400). Our results suggest that spatial memory impairment and anhedonia-like behaviour precede the presence of muscle wasting, and these behavioural deficits are independent of the changes in adult hippocampal neurogenesis. Running effectively prevents body weight loss, improves motor skill acquisition and reduces anhedonia-like behaviour associated with increased proliferating cells and immature neurons in DG. Taken together, they support physical exercise rehabilitation as an effective strategy to prevent chemotherapy side effects in terms of mood dysregulation and motor deficit.

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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effects of Voluntary Wheel Running Exercise on Chemotherapy-Impaired Cognitive and Motor Performance in Mice

Lee

Devaki

Formolo

et al. 2023

IJERPH

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“…As they are multiple tyrosine kinases inhibitors, they can interact with many signaling pathways on various levels, therefore one main mechanism of toxicity is difficult, if not impossible, to determine. However, it has been demonstrated in some studies that one of the mechanisms of this toxicity may be associated with reactive oxygen species (ROS) generation [ 13 , 14 ]. It has been also confirmed that sorafenib used in chronic treatment induces liver toxicity by activation of oxidative stress [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

Sorafenib versus Lenvatinib Causes Stronger Oxidative Damage to Membrane Lipids in Noncancerous Tissues of the Thyroid, Liver, and Kidney: Effective Protection by Melatonin and Indole-3-Propionic Acid

et al. 2022

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Sorafenib and lenvatinib are multi-targeted tyrosine kinase inhibitors which are currently approved to treat advanced hepatocellular carcinoma, renal cell carcinoma and radioiodine-refractory differentiated thyroid carcinoma. However this treatment is often limited due to common adverse events which may occur via oxidative stress. The study aims to compare sorafenib- and lenvatinib-induced oxidative damage to membrane lipids (lipid peroxidation, LPO) in homogenates of porcine noncancerous tissues of the thyroid, the liver, and the kidney and to check if it can be prevented by antioxidants melatonin and indole-3-propionic acid (IPA). Homogenates of individual tissues were incubated in the presence of sorafenib or lenvatinib (1 mM, 100 µM, 10 µM, 1 µM, 100 nM, 10 nM, 1 nM, 100 pM) together with/without melatonin (5.0 mM) or IPA (5.0 mM). The concentration of malondialdehyde + 4-hydroxyalkenals, as the LPO index, was measured spectrophotometrically. The incubation of tissue homogenates with sorafenib resulted in a concentration-dependent increase in LPO (statistically significant for concentrations of 1mM and 100 µM in the thyroid and the liver, and of 1 mM, 100 µM, and 10 µM in the kidney). The incubation of thyroid homogenates with lenvatinib did not change LPO level. In case of the liver and the kidney, lenvatinib increased LPO but only in its highest concentration of 1 mM. Melatonin and IPA reduced completely (to the level of control) sorafenib- and lenvatinib-induced LPO in all examined tissues regardless of the drug concentration. In conclusion, sorafenib comparing to lenvatinib is a stronger damaging agent of membrane lipids in noncancerous tissues of the thyroid, the liver, and the kidney. The antioxidants melatonin and IPA can be considered to be used in co-treatment with sorafenib and lenvatinib to prevent their undesirable toxicity occurring via oxidative stress.

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Zinc alleviates cadmium-induced reproductive toxicity via regulating ion homeostasis, metallothionein expression, and inhibiting mitochondria-mediated apoptosis in the freshwater crab Sinopotamon henanense

Liu

Wang

Cheng

et al. 2023

Ecotoxicology and Environmental Safety

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Zinc supplementation ameliorates sorafenib-induced cognitive impairment through ROS/JNK signaling pathway

Cited by 4 publications

References 47 publications

Effects of Voluntary Wheel Running Exercise on Chemotherapy-Impaired Cognitive and Motor Performance in Mice

Effects of Voluntary Wheel Running Exercise on Chemotherapy-Impaired Cognitive and Motor Performance in Mice

Sorafenib versus Lenvatinib Causes Stronger Oxidative Damage to Membrane Lipids in Noncancerous Tissues of the Thyroid, Liver, and Kidney: Effective Protection by Melatonin and Indole-3-Propionic Acid

Zinc alleviates cadmium-induced reproductive toxicity via regulating ion homeostasis, metallothionein expression, and inhibiting mitochondria-mediated apoptosis in the freshwater crab Sinopotamon henanense

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