Ischemic stroke triggers lipid peroxidation and neuronal injury. Docosahexaenoic acid released from membrane phospholipids during brain ischemia is a major source of lipid peroxides. Leukocyte infiltration and pro-inflammatory gene expression also contribute to stroke damage. In this study using lipidomic analysis, we have identified stereospecific messengers from docosahexaenoate-oxygenation pathways in a mouse stroke model. Aspirin, widely used to prevent cerebrovascular disease, activates an additional pathway, which includes the 17R-resolvins. The newly discovered brain messenger 10,17S-docosatriene potently inhibited leukocyte infiltration, NFB, and cyclooxygenase-2 induction in experimental stroke and elicited neuroprotection. In addition, in neural cells in culture, this lipid messenger also inhibited both interleukin 1-␤-induced NFB activation and cyclooxygenase-2 expression. Thus, the specific novel bioactive docosanoids generated in vivo counteract leukocyte-mediated injury as well as pro-inflammatory gene induction. These results challenge the view that docosahexaenoate only participates in brain damage and demonstrate that this fatty acid is also the endogenous precursor to a neuroprotective signaling response to ischemia-reperfusion.

Although the function of sleep remains elusive, there is compelling evidence to suggest that sleep plays an important role in learning and memory. A number of studies have now shown that sleep deprivation (SD) results in significant impairment of long-term potentiation (LTP) in the hippocampus. In this study, we have attempted to determine the mechanisms responsible for this impairment. After 72 h SD using the multiple-platform technique, we observed a reduction in the whole-cell recorded NMDA/AMPA ratio of CA1 pyramidal cells in response to Schaffer collateral stimulation. This impairment was specific to sleep deprivation as rats placed over a single large platform, which allowed sleep, had a normal NMDA/AMPA ratio. mEPSCs evoked by local application of a high osmolarity solution revealed no differences in the AMPA receptor function. NMDA currents recorded from outside-out patches excised from the distal dendrites of CA1 cells displayed a reduction in amplitude after SD. While there were no alterations in the glutamate sensitivity, channel open probability or the single channel conductance of the receptor, a crosslinking assay demonstrated that the NR1 and NR2A subunits of NMDA receptors were preferentially retained in the cytoplasm after SD, indicating that SD alters NMDAR surface expression. In summary, we have identified a potential mechanism underlying SD-induced LTP impairment. This synaptic alteration may underlie the cognitive deficits seen following sleep deprivation and could represent a target for future intervention studies.

Glutamate receptor (GluR) channels are responsible for a number of fundamental properties of the mammalian central nervous system, including nearly all excitatory synaptic transmission, synaptic plasticity, and excitotoxin-mediated neuronal death. Although many human and rodent neuroblast cell lines are available, none has been directly shown to express GluR channels. We report here that cells from the human teratocarcinoma line NT2 are induced by retinoic acid to express neuronal N-methyl-D-aspartate (NMDA) and non-NMDA GluR channels concomitant with their terminal differentiation into neuron-like cells. The molecular and physiologic characteristics of these human GluR channels are nearly identical to those in central nervous system neurons, as demonstrated by PCR and patch damp recordings, and the cells demonstrate glutamate-induced neurotoxicity.

We demonstrate by reverse transcriptase‐polymerase chain reaction and Southern blotting that an immortalized rat oligodendroglial cell line (CG‐4) expresses the non‐N‐methyl‐d‐aspartate (non‐NMDA) glutamate receptor (GluR) genes GluR2–7, KA‐1, and KA‐2 and that nonimmortalized cells of the rat oligodendroglial lineage express the GluR1–3, GluR5–7, KA‐1, and KA‐2 genes. Lactic dehydrogenase release assays show that both immortalized and nonimmortalized cells of the oligodendroglial lineage are damaged by a 24‐h exposure to 500 µM kainate or 5 mMl‐glutamate, but not by a 24‐h exposure to up to 10 mMα‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionate (AMPA). Damage is prevented by the non‐NMDA GluR channel inhibitor 6‐cyano‐7‐nitroquinoxaline‐2,3‐dione and is also averted if Ca2+ is removed from the culture medium. Cyclothiazide, which blocks desensitization of AMPA‐preferring GluRs, increases cytotoxicity of kainate as well as inducing toxicity of AMPA. We conclude that cells of the oligodendroglial lineage express a population of AMPA‐preferring and possibly also kainate‐preferring GluR channels that are capable of mediating Ca2+‐dependent excitotoxicity and that AMPA‐induced cytotoxicity is blocked by desensitization of AMPA‐preferring GluRs.