الفهرس 
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Abstract
Cisplatin (Cis-Diaminedichloroplatinumii) Is One Of The Most Effective Chemotherapeutic Agents And Plays A Major Role In The Treatment Of A Variety Of Human Solid Tumors. Despite Its Remarkable Chemotherapeutic Properties, The Clinical Use Of CP Is Frequently Restricted By Severe Neurotoxicity As Well As Hepatotoxicity That Include Decreased Protein Synthesis, Membrane Peroxidation, DNA Injury And Mitochondrial Dysfunction. Reactive Oxygen Species (ROS), Especially The Superoxide Anion (O2˙‾) Have Been Revealed To Play A Significant Part In Neurotoxicity.
Administration Of CP Activates Mitogen-Activated Protein Kinase (MAPK) Pathways Through ROS Production And Cross-Linking With DNA, Thus Leading To Apoptotic Cell Death. Several Studies Have Demonstrated That The Activation Of The MAPK Family By High Doses Of CP Leads To The Activation Of Other Pathways, Such As The JNK/SAPK, ERK And P38 MAPK Pathways, Which Further Phosphorylate The Tumor Suppressor Gene P53, Resulting In Its Activation And Stabilization. In Response To A Great Variety Of Stimuli, The MAPK Pathway Acts As A Proapoptotic Factor.
The Present Study Aimed To Investigate The Role Of P38 MAPK, P53, STAT-1, P21, MMP9 And FMO3 In CP-Induced Neurotoxicity In Rats And The Biochemical Effects Of Some Antioxidants Such As Thymoquinone (TQ), Geraniol (Ger) And Their Roles On The Expression Of The Previous Proteins And Genes In CP-Induced Neurotoxicity In Rats.
Forty Male Wistar-Albino Rats Weighing 150-200 G; 3 Months Old Were Divided Randomly Into Four Groups Of Ten Rats In Each group And Treated As Follows:
group I (Normal Control Group): Rats Were Given Corn Oil In A Dose Of 2 Ml/Kg Per Day Orally For 33 Consecutive Days And Injected I.P. With Saline Starting On 5th Day At A Dose Of 2 Ml/Kg Twice Weekly (A Total Of Nine Injections).
group II (CP-Administrated Group): Rats Were Injected I.P With CP Starting On 5th Day In A Dose Of 2 Mg/Kg Body Weight Twice A Week (A Total Of Nine Injections).
group III (TQ-Treated Group): Rats Were Received TQ In A Dose Of 20 Mg/Kg Body Weight Orally In Corn Oil Three Times A Week As Well As CP As Mentioned Before In group II.
group IV (Ger-Treated Group): Rats Were Treated With Ger In A Dose Of 100 Mg/Kg Body Weight Orally In Corn Oil For 33 Consecutive Days As Well As CP As Mentioned Before In group II.
The Present Study Showed That CP Administration Significantly Increased Protein Expression Of P38 MAPK, P53, STAT-1 Levels And Increased The Gene Expression Of P21, MMP9 And FMO3. While Brain Function Markers, The Ache Activity Decreased, The Glutamate Levels And LDH Activity Increased Significantly In Brain Tissues, Oxidative And Antioxidant Parameters Significantly Increased MPO Activity, SOD Reduced Significantly And The 8-Isoprostane Levels Were Significantly Elevated In The Rats Exposed To CP Compared To The Normal Control Group.
Simultaneous Treatment With Either TQ Or Ger And CP Significantly Down-Regulated The Apoptotic Markers P38 MAPK, P53, STAT-1, P21 And MMP9; However, FMO3 Significantly Decreased Only In Case Of TQ-Treated Group, While Brain Function Markers, Ache Activity Increased In Brain Tissues But This Increase Was Only Significant In Case Of TQ Treatment, The Glutamate Levels And LDH Activity Decreased Significantly In TQ Or Ger-Treated Groups Plus CP. Also, Oxidative And Antioxidant Parameters, MPO Decreased Significantly, While SOD Significantly Increased And Treatment With Ger Only Significantly Decreased The 8-Isoprostane Levels. In Addition, Behavioural And Histopathological Findings Were Reported, Which Confirmed The Protective Effect Of TQ And Ger Against The Brain Damage Induced By CP.
In Conclusion, The Present Study Provides Good Help And Suggests A Great Approach In Controlling The Neurotoxicity Caused By Administration Of CP, One Of The Most Potent Antineoplastic Drug Through Supplementation Of Two Powerful Natural Antioxidants, TQ And Ger. The Current Study Demonstrated That Simultaneous Treatment With Either TQ Or Ger Plus CP Are Considered Effective Adjuvant Therapies Against CP-Induced Neurotoxicity In Rats.