8-hydroxyguanine and Epilepsy

This study was carried out to determine the effects of valproate (VPA), carbamazepine, and levetiracetam (LEV) on antioxidant and oxidant enzyme activities and the clinical importance of these effects.. We enrolled 32 patients receiving VPA, 17 receiving carbamazepine, 8 receiving LEV, 11 on multidrug therapy, and 30 sex- and age-matched healthy volunteers. We measured the serum activities of paraoxonase and arylesterase and the levels of 8-hydroxyguanine (8-OHG) and oxidized low-density lipoprotein in all the subjects. We also determined the clinical features of the patients.. The serum paraoxonase and arylesterase activities were significantly lower (P = 0.003 and P = 0.0001, respectively), and the oxidized low-density lipoprotein and 8-OHG levels were higher (P = 0.029 and P = 0.0001, respectively) in the patients than in the controls. The serum antioxidant activity was low, and the oxidant activity was high in the monotherapy patients (P < 0.05). Comparing the monotherapy with the polytherapy, only the combination of VPA-LEV was associated with a high 8-OHG level (P = 0.04). The serum 8-OHG level was higher in the patients taking antiepileptic drugs (AEDs) for the first 2 months than in the controls (P = 0.0001) and positively correlated with the duration of epilepsy (r = 0.387, P < 0.01).. Oxidative stress is seen in each of the AEDs after the first 2 months. There was no dominance of the monotherapy over the polytherapy, except for the VPA-LEV combination. None of the patients' characteristic features were related to oxidative damage, except for the duration of the epilepsy and the AED therapy.

Topics: Adolescent; Adult; Anticonvulsants; Antioxidants; Aryldialkylphosphatase; Biomarkers; Carbamazepine; Carboxylic Ester Hydrolases; Drug Therapy, Combination; Epilepsy; Female; Guanine; Humans; Levetiracetam; Lipoproteins, LDL; Male; Middle Aged; Oxidation-Reduction; Oxidative Stress; Piracetam; Valproic Acid; Young Adult

We examined metallothionein (MT)-induced neuroprotection during kainic acid (KA)-induced excitotoxicity by studying transgenic mice with MT-I overexpression (TgMT mice). KA induces epileptic seizures and hippocampal excitotoxicity, followed by inflammation and delayed brain damage. We show for the first time that even though TgMT mice were more susceptible to KA, the cerebral MT-I overexpression decreases the hippocampal inflammation and delayed neuronal degeneration and cell death as measured 3 days after KA administration. Hence, the proinflammatory responses of microglia/macrophages and lymphocytes and their expression of interleukin (IL)-1, IL-6, IL-12, tumor necrosis factor-alpha and matrix metalloproteinases (MMP-3, MMP-9) were significantly reduced in hippocampi of TgMT mice relative to wild-type mice. Also by 3 days after KA, the TgMT mice showed significantly less delayed damage, such as oxidative stress (formation of nitrotyrosine, malondialdehyde, and 8-oxoguanine), neurodegeneration (neuronal accumulation of abnormal proteins), and apoptotic cell death (judged by TUNEL and activated caspase-3). This reduced bystander damage in TgMT mice could be due to antiinflammatory and antioxidant actions of MT-I but also to direct MT-I effects on the neurons, in that significant extracellular MT presence was detected. Furthermore, MT-I overexpression stimulated astroglia and increased immunostaining of antiinflammatory IL-10, growth factors, and neurotrophins (basic fibroblastic growth factor, transforming growth factor-beta, nerve growth factor, brain-derived neurotrophic factor, glial-derived neurotrophic factor) in hippocampus. Accordingly, MT-I has different functions that likely contribute to the increased neuron survival and improved CNS condition of TgMT mice. The data presented here add new insight into MT-induced neuroprotection and indicate that MT-I therapy could be used against neurological disorders.

Topics: Amyloid beta-Peptides; Analysis of Variance; Animals; Astrocytes; Cell Count; Cell Death; Central Nervous System Diseases; Epilepsy; Gene Expression Regulation; Glial Fibrillary Acidic Protein; Growth Substances; Guanine; Hippocampus; Immunohistochemistry; In Situ Nick-End Labeling; Interleukins; Kainic Acid; Matrix Metalloproteinase 3; Matrix Metalloproteinase 9; Metallothionein; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neurodegenerative Diseases; Neurofibrillary Tangles; Staining and Labeling; Tyrosine