Under healthy conditions, the blood-brain barrier (BBB) limits the passage of solutes and cells from the blood to the CNS. During neurological diseases, BBB permeability increases dramatically and it has been hypothesized that drug carrier systems such as polymeric nanoparticles could cross the BBB and penetrate into the CNS. PEGylated polyalkylcyanoacrylate nanoparticles (long-circulating carrier) are one such system and have been investigated during experimental allergic encephalomyelitis (EAE). Brain and spinal cord concentrations of [(14)C]-radiolabelled PEGylated polyalkylcyanoacrylate nanoparticles were compared with another blood long-circulating carrier (poloxamine 908-coated polyalkylcyanoacrylate nanoparticles) and with conventional non-long-circulating polyalkylcyanoacrylate nanoparticles. The microscopic localization of fluorescent nanoparticles in the CNS was also investigated in order to further understand the mechanism by which the particles penetrate the BBB. The results demonstrate that the concentration of PEGylated nanoparticles in the CNS, especially in white matter, is greatly increased in comparison to conventional non-PEGylated nanoparticles. In addition, this increase was significantly higher in pathological situations where BBB permeability is augmented and/or macrophages have infiltrated. Passive diffusion and macrophage uptake in inflammatory lesions seems to be the mechanism underlying such particles' brain penetration. Based on their long-circulating properties in blood and on their surface characteristics that allow cell interactions, PEGylated nanoparticles penetrated into CNS to a larger extent than all the other formulations tested. Thus, PEGylated polycyanoacrylate nanoparticles are proposed here as a new brain delivery system for neuroinflammatory diseases.
Reactive gliosis was revealed by immunocytochemistry using antibodies against the glial fibrillary acidic protein (GFAP) after a stab or an electrolytic lesion administered to the cerebral cortex, corpus callosum, striatum, or hippocampus of a 6-day-old rat. The intensity of the gliosis was about the same in the various structures injured and did not change with the delay of 3, 7, or 20 days between the injury and the sacrifice of the animals. When basic fibroblast growth factor (bFGF) was injected in the lesion locus just after the lesion was performed, it resulted (as soon as 3 days after injury) in a strong astrogliosis that was enhanced after a delay of 7 days, the astrocytes in the lesion area exhibiting enlarged cell processes and intense GFAP-positive immunoreactivity. After a delay of 20 days, the astrocytes were not dispersed any more but packed in three or four layers along the borders of the lesion, thus reducing its extension. This suggests a possible role for bFGF in promoting scar formation following brain injury.
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