Congeners of nitrogen monoxide (NO) are neuroprotective and neurodestructive. To address this apparent paradox, we considered the effects on neurons of compounds characterized by alternative redox states of NO: nitric oxide (NO.) and nitrosonium ion (NO+). Nitric oxide, generated from NO. donors or synthesized endogenously after NMDA (N-methyl-D-aspartate) receptor activation, can lead to neurotoxicity. Here, we report that NO.- mediated neurotoxicity is engendered, at least in part, by reaction with superoxide anion (O2.-), apparently leading to formation of peroxynitrite (ONOO-), and not by NO. alone. In contrast, the neuroprotective effects of NO result from downregulation of NMDA-receptor activity by reaction with thiol group(s) of the receptor's redox modulatory site. This reaction is not mediated by NO. itself, but occurs under conditions supporting S-nitrosylation of NMDA receptor thiol (reaction or transfer of NO+). Moreover, the redox versatility of NO allows for its interconversion from neuroprotective to neurotoxic species by a change in the ambient redox milieu. The details of this complex redox chemistry of NO may provide a mechanism for harnessing neuroprotective effects and avoiding neurotoxicity in the central nervous system.

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 ...

Prions are proteins that can assume at least two distinct conformational states, one of which is dominant and self-perpetuating. Previously we found that a translation regulator CPEB from Aplysia, ApCPEB, that stabilizes activity-dependent changes in synaptic efficacy can display prion-like properties in yeast. Here we find that, when exogenously expressed in sensory neurons, ApCPEB can form an amyloidogenic self-sustaining multimer, consistent with it being a prion-like protein. In addition, we find that conversion of both the exogenous and the endogenous ApCPEB to the multimeric state is enhanced by the neurotransmitter serotonin and that an antibody that recognizes preferentially the multimeric ApCPEB blocks persistence of synaptic facilitation. These results are consistent with the idea that ApCPEB can act as a self-sustaining prion-like protein in the nervous system and thereby might allow the activity-dependent change in synaptic efficacy to persist for long periods of time.