Mechanism Of Sulforaphane Alleviating Glioma-associated Cognitive Impairment

Background:Various types of brain tumors are highly associated with cognitive impairment.It affects the central nervous system through mass effect and abnormal metabolism,leading to global brain dysfunction,characterized as multiple types of cognitive impairment.As the aging level of China’s society deepens,the incidence of brain tumors also rises year by year,resulting in a significant burden on health careers in health.Although multiple treatment modalities have resulted in great survival benefits for patients with brain tumors,few studies have focused on the condition of cognitive impairment in patients,the underlying impaired mechanisms,and effective interventions.Objective:To explore the type and mechanism of brain tumor-induced cognitive impairment;To demonstrate the alleviating effect of sulforaphane on brain tumor-associated cognitive impairment;To explore the potential mechanism of sulforaphane in cognitive protection.Methods:This study was conducted at cellular,animal,and clinical levels.The oxidative stress injury induced by glioma cells in hippocampal neuronal cells and the alleviation effect of sulforaphane were demonstrated by in vitro cell experiments.A model of oxidative stress in mouse hippocampal neuronal cells was constructed using the induction of H₂O₂.Transwell chambers（0.4μM）were used to build a murine glioma cell（GL261）-murine hippocampal cell（HT22）non-contact co-culture model.Levels of reactive oxygen species,lipid peroxidation,and glutathione in hippocampal cells were detected using corresponding kits.Transcriptome sequencing was used to explore the genes and pathways upregulated by sulforaphane,and real-time fluorescence quantitative polynucleotide chain reaction and Western blotting were employed to validate the sequencing results.In this study,in vivo experiments were conducted to explore the cognitive impairment of glioma orthotopic xenograft animal models and the alleviating effect of sulforaphane on cognitive function.The glioma orthotopic xenograft model was constructed using a stereotaxic device.For the sham,tumor,sulforaphane groups（glioma model that received intraperitoneal injection of sulforaphane）,cognitive function was assessed by Morris water maze.The target protein expression in the hippocampus region was detected using immunofluorescence.This study explored the postoperative cognitive dysfunction in patients with brain tumors and the improvement effect of sulforaphane on cognitive function through clinical trials.We strictly adhered to the inclusion and exclusion criteria of this double-blind randomized controlled trial,and a total of 29 patients with brain tumors were included.Their demographic data and primary examination results were collected.They were randomized to the sulforaphane group（taking sulforaphane）and placebo group（taking a starchy placebo with consistent traits）.They were administered the MATRICS consensus cognitive battery（MCCB）and neuropsychiatric tests at baseline and the 3-month follow-up,and relevant adverse effects were recorded.Results:Oxidative stress injury was induced in hippocampal neurons by treatment with H₂O₂ as well as by co-culture of glioma cells,whereas sulforaphane（10μM）could upregulate the expression of antioxidant enzymes,increase the content of reduced glutathione,and reduce oxidative stress injury by activating the nuclear factor E2 related factor 2（nfe2l2 or Nrf2）pathway.Nrf2 was overexpressed explicitly in the hippocampal CA3region of orthotopic glioma models.Their spatial learning,as well as memory performance,were significantly impaired（P<0.05）,while sulforaphane promoted Nrf2 expression and significantly enhanced their learning and memory performance（P<0.05）.In clinical trials,glioma patients had higher deficit scores in the domains of verbal learning and speed of processing than meningioma patients（P<0.05）.MCCB deficit scores for visual learning,reasoning and problem-solving,and speed of processing were significantly lower in the sulforaphane group than in the placebo group.And we observed improvement in patients’ability to live and decreased depression and anxiety scores only in the sulforaphane group.In addition,no drug-related adverse events have been observed in this trial.Conclusions:1.Brain tumors induce oxidative stress injury in hippocampal neurons,causing cognitive dysfunction;2.Glioma patients were more cognitively impaired in the domains of word learning and speed of processing than meningioma patients;3.Sulforaphane can alleviate brain tumor-associated cognitive impairment by reducing oxidative stress levels via activating endogenous antioxidant pathways,which holds promise as a routine medication in the postoperative period for brain tumor patients to prevent or alleviate cognitive impairment.