Excessive accumulation of glutamate in the CNS leads to excitotoxic neuronal damage. However, glutamate clearance is essentially mediated by astrocytes through Na+-dependent high-affinity glutamate transporters (excitatory amino acid transporters (EAATs)). Nevertheless, EAAT function was recently shown to be developmentally restricted in astrocytes and undetectable in mature astrocytes. This suggests a need for other cell types for clearing glutamate in the brain. As blood monocytes infiltrate the CNS in traumatic or inflammatory conditions, we addressed the question of whether macrophages expressed EAATs and were involved in glutamate clearance. We found that macrophages derived from human blood monocytes express both the cystine/glutamate antiporter and EAATs. Kinetic parameters were similar to those determined for neonatal astrocytes and embryonic neurons. Freshly sorted tissue macrophages did not possess EAATs, whereas cultured human spleen macrophages and cultured neonatal murine microglia did. Moreover, blood monocytes did not transport glutamate, but their stimulation with TNF-α led to functional transport. This suggests that the acquisition of these transporters by macrophages could be under the control of inflammatory molecules. Also, monocyte-derived macrophages overcame glutamate toxicity in neuron cultures by clearing this molecule. This suggests that brain-infiltrated macrophages and resident microglia may acquire EAATs and, along with astrocytes, regulate extracellular glutamate concentration. Moreover, we showed that EAATs are involved in the regulation of glutathione synthesis by providing intracellular glutamate. These observations thus offer new insight into the role of macrophages in excitotoxicity and in their response to oxidative stress.

Excessive levels of PAF and cells of macrophage lineage appear to play an important role in neuronal cell injury, inflammatory syndrome, and HIV replication in CNS resulting in AIDS dementia complex (ADC). The beneficial effects of PAF receptor antagonists are evident and give rise to expected therapeutic strategies for neurotrauma. Piperazine derivatives bearing a "cache-oreilles" (ear-muff) electronic distribution are able to inhibit in vitro PAF effects and, thus, could be used in pathologies where this mediator is involved. Therefore, their potential anti-HIV activity was investigated, and we find that (i) these PAF antagonists are effectively active in HIV-infected monocyte-derived macrophages (MDM) but there is no correlation between both anti-HIV and anti-PAF activities; (ii) the presence of a carbamate function (compounds 1a-d) is favorable to the antiviral activity; (iii) the lipophilicity of the substituent on the piperazinic cycle seems to be less important for the anti-PAF activity than for the antiviral one. Our leading compound, PMS 601 (compound 1a), presents a dual activity with IC(50) of 8 and 11 microM for anti-PAF and anti-HIV activity, respectively, without cytotoxic events at 1000 microM in MDM. Although its mode of action is not clearly defined, these data suggest that PMS 601, which displays no effect on acellular reverse transcriptase or protease tests, deserves further investigation in the treatment of HIV-1-associated dementia.

Tau interferon (IFN-)

We assessed the anti-human immunodeficiency virus (anti-HIV) activity in vitro of new platelet-activating factor (PAF) receptor antagonists, as PAF and viral replication are thought to be involved in HIV neuropathogenesis. We found that PMS-601 inhibited proinflammatory cytokine synthesis and HIV replication in macrophages and potentiated the antiretroviral activity of zidovudine. These results suggest that PMS-601 is of potential value as an adjuvant treatment for HIV infection.

Interleukin (IL)-10 is a potent immunosuppressant of monocyte/macrophage function and may help control the inflammatory response induced by bacterial infection. To analyze whether IL-10 is detectable in plasma of patients with septic shock and to evaluate its relationship with endotoxin (lipopolysaccharide [LPS])-induced and monocyte/macrophage-induced inflammatory response, plasma IL-10, tumor necrosis factor (TNF)-alpha, IL-1 beta, IL-6, IL-8, LPS, and neopterin were studied in 24 patients with septic shock and in 12 critically ill patients. Eighty-three percent of patients with septic shock and 25% of critically ill patients had detectable levels of IL-10 (P < .001). There was a significant correlation between plasma IL-10, neopterin (r = .72), TNF-alpha (r = .76), IL-6 (r = .68), and IL-8 (r = .61) levels in patients with septic shock. Monocyte/macrophage activation leads to massive secretion of IL-10, which, however, seems to be unable to control the increased production of proinflammatory mediators during septic shock.

A general synthetic approach to vinylogous 4-carboxy- and 4-keto-2,3-dihydropyrroles is reported using Ni(ClO4)2·6H2O as a Lewis acid catalyst for nucleophilic amine ring-opening cyclizations of donor-acceptor (D-A) cyclopropanes. This methodology provided good to excellent yields of functionalized 2,3-dihydropyrroles under milder reaction conditions than previously reported and is amenable to a variety of D-A cyclopropanes and primary amines.

The structure of Cu(II) complex 3 formed within the course of a stereoselective Diels-Alder reaction was investigated by EXAFS, CW-EPR at X- and W-band, HYSCORE, pulsed ENDOR, and UV-vis spectroscopy. The experimental techniques indicate that the chiral bis(sulfoximine) ligand (S,S)-1 and the dienophile form a tetragonally distorted complex in CH(2)Cl(2). The ligand binds to the Cu(II) center via the imine nitrogens, whereas the dienophile interacts via the carbonyl oxygen atoms. The additional sites of the first coordination sphere are occupied by counterions and, presumably, solvent molecules. At the axial position, a triflate anion binds via an oxygen atom.

[reaction: see text] Bissulfoximines have been used as chiral ligands in copper-catalyzed enantioselective Diels-Alder reactions between acryloyl-2-oxazolidinones and cyclopentadiene. After optimizing the ligand structure, the metal source, the counterions, and the solvent, products with up to 93% ee have been obtained.