Severely elevated levels of total homocysteine (approximately millimolar) in the blood typify the childhood disease homocystinuria, whereas modest levels (tens of micromolar) are commonly found in adults who are at increased risk for vascular disease and stroke. Activation of the coagulation system and adverse effects of homocysteine on the endothelium and vessel wall are believed to underlie disease pathogenesis. Here we show that homocysteine acts as an agonist at the glutamate binding site of the N-methyl-Daspartate receptor, but also as a partial antagonist of the glycine coagonist site. With physiological levels of glycine, neurotoxic concentrations of homocysteine are on the order of millimolar. However, under pathological conditions in which glycine levels in the nervous system are elevated, such as stroke and head trauma, homocysteine's neurotoxic (agonist) attributes at 10-100 M levels outweigh its neuroprotective (antagonist) activity. Under these conditions neuronal damage derives from excessive Ca 2؉ inf lux and reactive oxygen generation. Accordingly, homocysteine neurotoxicity through overstimulation of N-methyl-D-aspartate receptors may contribute to the pathogenesis of both homocystinuria and modest hyperhomocysteinemia.Elevated levels of homocysteine in the blood predispose to arteriosclerosis and stroke. In children with the relatively rare condition of homocystinuria, levels of total homocysteine approach millimolar concentrations. However, more modest levels (Ϸ15-50 M) are found very commonly in the general population (a condition known as hyperhomocysteinemia) (1, 2), and a concentration of up to 10 M has been measured in brain (3). Indeed, it has been recently estimated that as many as 47% of patients with arterial occlusions manifest these modest elevations in plasma homocysteine (1, 2). Included among the many causes are genetic alterations in enzymes such as cystathionine ␤-synthase, a defect found in 1-2% of the general population, and deficiencies in vitamins B 6 , B 12 , and folate, whose intake is suboptimal in perhaps 40% of the population (4). The strength of the association between homocysteine and cerebrovascular disease appears to be greater than that between homocysteine and coronary heart disease or peripheral vascular disease (1, 5). Current theories on homocysteine arteriosclerosis do not explain this predilection, nor do they give insight into the cognitive deficits seen in some patients. In the present study, we show that homocysteine causes direct neurotoxicity by activating the N-methyl-Daspartate (NMDA) subtype of glutamate receptor. Excessive stimulation of these receptors is known to mediate brain damage in focal ischemia (6, 7). Thus homocysteine may not only be associated with the vascular injury leading to stroke but may also participate in the ensuing neurotoxic response in the brain. MATERIALS AND METHODSHomocysteine and Derivatives. D,L-Homocysteine was used here because the L-form was not commercially available. However, based upon previous data, it is ...

Oxidative stress resulting from excessive free-radical release is likely implicated in the initiation and progression of epilepsy. Therefore, antioxidant therapies aimed at reducing oxidative stress have received considerable attention in epilepsy treatment. However, much evidence suggests that oxidative stress does not always have the same pattern in all seizures models. Thus, this review provides an overview aimed at achieving a better understanding of this issue. We summarize work regarding seizure models (i.e., genetically epilepsy-prone rats, kainic acid, pilocarpine, pentylenetetrazol, and trimethyltin), oxidative stress as an etiologic factor in epileptic seizures (i.e., impairment of antioxidant systems, mitochondrial dysfunction, involvement of redox-active metals, arachidonic acid pathway activation, and aging), and antioxidant strategies for seizure treatment. Combined, this review highlights pharmacological mechanisms associated with oxidative stress in epileptic seizures and the potential for neuroprotection in epilepsy that targets oxidative stress and is supported by effective antioxidant treatment.

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