seventy albino rats were divided into seven equal groups each containing 10 rats (G1:control received distilled water) ; (G2: 0.1 LD50 of CuSO4) ; (G3: 0.2 LD50 of CuSO4) ; (G4: 0.4 LD50 of CuSO4) ; (G5: 0.1 LD50 of CuSO4 +100mg/kg/day of penicillamine) ; (G6: LD50 of CuSO4.+100 mg/kg/day of penicillamine) and (G7: LD50 of CuSO4+ 100 mg /kg/day of penicillamine) for 30 days and at the end of the experiment all rats were sacrificed and blood samples and brain tissues were collected for biochemical assaying of Fasting Blood Glucose (FBG), Serum Cu level, serum tyrosinase activity, oxidative stress marker Malondialdehyde (MDA) and Total Antioxidant Activity (TAC). also, DNA determination of relative gene expression of cerebral Adenosine monophosphate-activated Protein Kinase (AmpK), Protein Kinase (AKT), Phosphatidylinositol-3-Kinase (PI3K), Cytochrome c oxidase (Cyto co ), and Glucose -6- Phosphate Dehydrogenase (G6PD). Results: The result showed that administration of copper sulphate with different levels induced a significant increase in fasting blood glucose level, lipid peroxidation marker MDA, serum copper level, and serum tyrosinase activity, and a significant decrease in TAC. Moreover, copper sulphate administration elicited a significant downregulation ( AmpK, AKT, PI3K, Cytochrome c oxidase, G6PD).it could be approved that penicillamine could abolish the negative impact of copper sulphate on neural tissues and serum enzymes. Conclusion: D-penicillamine can reduce neurotoxicity and oxidative stress caused by copper pollution.