We have considered the extracellular serine protease thrombin and its receptor as endogenous mediators of neuronal protection against brain ischemia. Exposure of gerbils to prior mild ischemic insults, here two relatively short-lasting occlusions (2 min) of both common carotid arteries applied at 1-day intervals 2 days before a severe occlusion (6 min), caused a robust ischemic tolerance of hippocampal CA1 neurons. This resistance was impaired if the specific thrombin inhibitor hirudin was injected intracerebroventricularly before each short-lasting insult. Thus, efficient native neuroprotective mechanisms exist and endogenous thrombin seems to be involved therein. In vitro experiments using organotypic slice cultures of rat hippocampus revealed that thrombin can have protective but also deleterious effects on hippocampal CA1 neurons. Low concentrations of thrombin (50 pM, 0.01 unit/ml) or of a synthetic thrombin receptor agonist (10 μM) induced significant neuroprotection against experimental ischemia. In contrast, 50 nM (10 units/ml) thrombin decreased further the reduced neuronal survival that follows the deprivation of oxygen and glucose, and 500 nM even caused neuronal cell death by itself. Degenerative thrombin actions also might be relevant in vivo , because hirudin increased the number of surviving neurons when applied before a 6-min occlusion. Among the thrombin concentrations tested, 50 pM induced intracellular Ca ²⁺ spikes in fura-2-loaded CA1 neurons whereas higher concentrations caused a sustained Ca ²⁺ elevation. Thus, distinct Ca ²⁺ signals may define whether or not thrombin initiates protection. Taken together, in vivo and in vitro data suggest that thrombin can determine neuronal cell death or survival after brain ischemia.

Extracellular matrix (ECM) is an extraordinarily complex and unique meshwork composed of structural proteins and glycosaminoglycans. The ECM provides essential physical scaffolding for the cellular constituents, as well as contributes to crucial biochemical signaling. Importantly, ECM is an indispensable part of all biological barriers and substantially modulates the interchange of the nanotechnology products through these barriers. The interactions of the ECM with nanoparticles (NPs) depend on the morphological characteristics of intercellular matrix and on the physical characteristics of the NPs and may be either deleterious or beneficial. Importantly, an altered expression of ECM molecules ultimately affects all biological processes including inflammation. This review critically discusses the specific behavior of NPs that are within the ECM domain, and passing through the biological barriers. Furthermore, regenerative and toxicological aspects of nanomaterials are debated in terms of the immune cells-NPs interactions.

Background and Purpose Transforming growth factor-β1 (TGF-β1) has been shown to rescue cultured neurons from excitotoxic and hypoxic cell death and to reduce infarct size after focal cerebral ischemia in mice and rabbits. The present study investigated the effects of TGF-β1 in a different pathophysiological setting and the delayed neuronal death of hippocampal pyramidal cells after transient global ischemia in rats, and evaluated the potential mechanisms of the neuroprotective activity of TGF-β1. Methods Transient forebrain ischemia was induced in male adult Wistar rats with bilateral occlusion of both common carotid arteries combined with systemic hypotension for 10 minutes. Seven days after ischemia, brains were perfusion-fixed and stained for histological evaluation. TGF-β1 or vehicle was injected intracerebroventricularly (ICV; 0.5, 4, and 50 ng) or intrahippocampally (4 ng) 1 hour before ischemia. For in vitro studies, hippocampal neurons were derived from E17 rat embryos and cultured for 10 to 14 days. Cells were exposed to (1) S -nitrosocysteine (SNOC; 30 μmol/L) to induce nitric oxide–induced oxidative injury and (2) staurosporine (0.03 μmol/L) to induce apoptotic cell death. Results Transient forebrain ischemia caused extensive degeneration of CA1 hippocampal pyramidal cells in vehicle-treated control animals. Ischemic injury was not significantly reduced after ICV administration of 0.5 ng TGF-β1 (71±7% damaged neurons versus 84±3% in vehicle-treated controls; n=9 and 11, respectively; P =.07, Mann-Whitney U test). Administration of 4 ng TGF-β1 reduced the percentage of damaged CA1 pyramidal cells from 71±10% in controls to 52±7% in TGF-β1–treated animals (n=11 and 12, respectively; P =.04). TGF-β1 (4 ng) also produced significant protection when injected directly into the hippocampal tissue. In contrast, ICV administration of 50 ng TGF-β1 failed to show a protective effect in two separate sets of experiments. In vitro, a 24-hour pretreatment of the cultured hippocampal neurons with TGF-β1 (0.1 to 10 ng/mL) significantly inhibited both nitric oxide and staurosporine neurotoxicity. Posttreatment with TGF-β1 (10 ng/mL) also inhibited staurosporine neurotoxicity but actually potentiated nitric oxide–induced neuronal injury. Conclusions We demonstrated that TGF-β1 in a surprisingly low dose range has the capacity to reduce injury to CA1 hippocampal neurons caused by transient global ischemia in rats. This protective action could well be associated with the antioxidative and antiapoptotic effects of TGF-β1 demonstrated in vitro.