Differential permeability of the blood-brain barrier to neurotrophic proteins
Description
Neurotrophic proteins such as neurotrophins and neurotrophic cytokines promote survival, differentiation and regeneration of cells within the central nervous system (CNS), and play crucial roles in functional recovery after insults to the CNS, such as spinal cord injury, multiple sclerosis and degenerative disorders (e.g., Parkinson's and Alzheimer's diseases). By convention, the blood-brain barrier (BBB) has been considered impermeable to neurotrophic proteins. This dissertation addressed the blood-to-CNS passage of neurotrophic proteins: (a) Neurotrophins NGF, NT3, NT5 and BDNF; (b) Neurotrophic cytokines TNF, IFN$\alpha$ and IFN$\gamma.$ The studies include characterization of: (1) kinetics of passage, (2) relative amount of neurotrophic proteins available to brain parenchyma, (3) stability and integrity of the proteins in blood and brain, (4) presence of saturable transport systems on the BBB, and (5) changes of saturable transport systems after disruption of the BBB. Three experimental conditions of mice were studied: physiological state, animal model of spinal cord injury, and animal model of multiple sclerosis - experimental autoimmune encephalomyelitis (EAE). This dissertation revealed the differential permeability of the BBB at different regions and to different neurotrophic proteins, and suggested the autoregulatory function of BBB by upregulating the transport systems after partial disruption. This research provided a basis for further research of delivery of neurotrophic proteins through the BBB as therapeutic agents