Curcumin Ameliorates Chemotherapy-induced Cognitive Impairment And The Underlying Mitochondrial Mechanism

Chemotherapy-induced cognitive impairment,also known as “Chemofog” or “Chemobrain”,exerts a devastating effect on the quality of patient's life for a long time,and the mechanism and effective intervention of this phenomenon are still not clear.Curcumin,a multi-target polyphenol,is widely used as spices and pigments,and it possesses various bioacticities implicated in prevention or treatment of pathological conditions such as tumors and neurodegenerative diseases.Our previous studies have shown that curcumin could alleviates cognitive impairment of mice induced by 5-Fu and Oxaliplatin,which are commonly used in the treatment of gastrointestinal tumors.Given that neuronal mitochondrial dysfunction in neurodegenerative disease and the critical role of PARL in the modulation of mitochondrial function,mitochondrial apoptosis and mitophagy,we hypothesized that curcumin could reduce neurotoxicity of 5-Fu and Oxaliplatin and hereby improve chemobrain by regulating mitochondrial apoptosis and mitophagy.In this study,we investigated effects of curcumin on the neurotoxicity as well as cognitive decline induced by 5-fu and oxaliplatin in vivo and in vitro.We further explored the role of PARL in response to chemo-and curcumin-treatments in modulating mitochondrial apoptotic signaling and mitophagy process.The results may give insights into the molecular explainations underlying the chemobrain,which may further provide with potential targets towards the prevention and/or treatment of the chemotherapy-deliveried cognitive impairment.In the first part of the study,BALB/c mice were treated with 5-Fu,Oxaliplatin and curcumin in different combinations.Behavioral experiments were used to test changes in motor ability,mood,learning and memory of the mice.The hippocampus sections were then obtained from the mice and histologically examined the effects of the agents in different combination on morphological alterations of neuronal cells.The results showed that the chemo-treatment,at the behavioral level,would impair the motor abilility and long time memory,and at tissue level,resulted in cell degeneration in the mice.By contrast,curcumin treatment could rescue both behavioral and cellular injuries against the neurotoxicity of 5-Fu/oxaliplatin in the mice.In the second part of the study,primary cultured neurons and astrocytes were treated with 5-Fu,Oxaliplatin and curcumin in different combinations.Hippocampal tissue obtained from the mice and the primary cultured cells were used to analyze the effect of different combinations on PARL-related mitochondria apoptosis.The results showed that both of 5-Fu and Oxaliplatin could promote cell apoptosis by decreasing PARL levels in mitochondria and curcumin could impede this.In the third part of the study,primary cultured neurons,primary cultured astrocytes and SH-SY5 Y cells were treated with 5-Fu and curcumin in different combinations.Hippocampal tissue obtained from the mice and the cells were used to analyze the effect of different combinations on mitophagy.The results showed curcumin could inhibit mitophagy induced by 5-Fu but the effect of mitophagy on 5-Fu's neurotoxicity need further study.