Passage of peptides and cytokines across the blood-brain barrier and their interactions with the cerebral microvasculature
Description
The blood-brain barrier describes characteristics unique to the cerebral microvasculature. Together, these components regulate the passage of materials between the central nervous system and the periphery. Some material are able to penetrate the vascular barrier by nonsaturable processes such as passive diffusion and leakage. Saturable transport also serves as a mechanism for trafficking compounds, including certain peptides and proteins, between the blood and brain In this work, the fates of peptides and proteins relative to the blood-brain barrier were investigated after intravenous (IV) and intracerebroventicular (ICV) injection. A detailed autoradiographic investigation of distribution within the brain of radioiodinated substances, including lyrosine-MSH release-inhibiting factor-1 (Tyr-MIF-1), after ICV injection in rats was conducted. Rates of disappearance from the central nervous system (CNS) for the injected compounds were also determined by computer-assisted image analysis of the autoradiographic images. The unique patterns of distribution within the brain and disappearance from the CNS were compared for each of the compounds The ability of blood-borne amyloid $\beta$-protein, a compound implicated in the onset of Alzheimer's disease, to cross the BBB was also assessed. Amyloid $\beta$-protein accumulated in the brains of mice by a nonsaturable mechanism after IV administration. Amyloid $\beta$-protein was shown to have a high degree of association with the brain capillaries. Furthermore, intact amyloid $\beta$-protein was identified in cerebrospinal fluid (CSF) and cortical homogenates by acid precipitation, high performance liquid chromatography (HPLC) analysis, and gel electrophoresis The consequences of the saturable transport of blood-borne neuroimmunomodulatory cytokines, including interleukin (Il)-1$\alpha,$ into the parenchymal space of the brain was studied as well. Film autoradiography was used to demonstrate cytokine transport and sites of accumulation in the brain after IV administration in mice. Specific localization of Il-1$\alpha$ was detected within the caudal region of the septal nuclei Together, these observations describe processes involved in the transport of peptides and proteins across the blood-brain barrier and their distribution within the CNS, as well as assisting in identifying the ability of toxic compounds to penetrate the barrier. Such information may be useful in the prevention of certain neuropathologies. A fuller understanding of the routes of passage for proteins and peptides across the barrier elucidated with these methodologies may lead to their use as delivery systems for therapeutic agents