Highlight► A unique catalogue of phenotype markers and neuronotoxic effects of polarised primary microglia, as a comparative tool to screen neurotherapies.

Hypoxia-ischaemia in the developing brain results in brain injury with prominent features of apoptosis. In the present study, a third generation dipeptidyl broad-spectrum caspase inhibitor, quinoline-Val-Asp(Ome)-CH2-O-phenoxy (Q-VDOPh), was tested in a model of unilateral focal ischaemia with reperfusion in 7-day-old rats. Q-VD-OPh (1 mg/kg, i.p.) reduced cell death, resulting in significant neuroprotection at 48 h of recovery (infarct volume of 12.6 ± 2.8 vs. 24.3 ± 2.2%, p ¼ 0.006). The neuroprotective effects observed at 48 h post-ischaemia hold up at 21 days of survival time and attenuate neurological dysfunction. Analysis by gender revealed that females were strongly protected (6.7 ± 3.3%, p ¼ 0.006), in contrast to males in which there was no significant effect, when Q-VD-OPh was given after clip removal on the left common carotid artery. Immunoblot analysis demonstrated that Q-VD-OPh inhibits caspase 3 cleavage into its p17 active form and caspase 1 up-regulation and cleavage in vivo. Following ischaemia in P7 rats, males and females displayed different time course and pattern of cytochrome c release and active p17 caspase 3 during the first 24 h of recovery. In contrast, no significant difference was observed for caspase 1 expression between genders. These results indicate that ischaemia activates caspases shortly after reperfusion and that the sex of the animal may strongly influences apoptotic pathways in the pathogenesis of neonatal brain injury. The specificity, effectiveness, and reduced toxicity of Q-VD-OPh may determine the potential use of peptide-derived irreversible caspase inhibitors as promising therapeutics.

mentioned that embryonic bodies cultured in the presence of rotenone were smaller than those lacking AIF, suggesting subtle differences between the acute complex I defect induced by rotenone (that might affect homeostatic systems in the cell other than respiration) and the chronic defect induced by the AIF knockout.These results illustrate the difficulty to separate the two functions of AIF, first as a mitochondrial redox enzyme required for normal respiratory function and, second, as a factor that can participate in the apoptotic execution phase, after its translocation to the nucleus. The observation that AIF participates in cavitation-associated apoptosis 9 implicitly suggested that cavitation would depend on the lethal action of AIF. Based on recent insights on AIF biology, however, it is possible that at least some of the lethal processes that were interrupted by the removal of AIF from the experimental system actually were suppressed due to defective bioenergetic and/or redox metabolism. As a result, we recommend the use of rotenone as an internal control in experiments, in which the apoptosis-modulatory effects of human or mouse AIF are assessed. Only when rotenone fails to modify the apoptotic response, the interpretation that the lethal (rather than the vital) action of AIF is involved in the process can be maintained.Knock-in mutations that affect only the lethal function of AIF yet do not interfere with its metabolic activity in mitochondria are being prepared in several laboratories, 2 and the use of such mutants will yield important insights into the contribution of AIF to lethal signal transduction processes. Such knock-in mutations will also help to decipher the contribution of AIF, alone or in combination with mutations of the apoptosome components, to programmed cell death in physiological and pathological cell death.

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The CD4 molecule is essential for binding HIV particles, but is not sufficient for efficient viral entry and infection. The cofactor was shown to be dipeptidyl peptidase IV (DPP IV), also known as CD26. This serine protease cleaves its substrates at specific motifs; such motifs area also highly conserved in the V3 loops of HIV-1, HIV-2, and related simian isolates. Entry of HIV-1 or HIV-2 into T lymphoblastoid and monocytoid cell lines was inhibited by a specific monoclonal antibody against DPP IV or specific peptide inhibitors of this protease. Coexpression of human CD4 and CD26 in murine NIH 3T3 cells rendered them permissive to infection by HIV-1 and HIV-2. These observations could provide the basis for developing simple and specific inhibitors of HIV and open a possibility for vaccine development.