Blood-brain barrier permeability factors

Nonallergic hyperreactivity corresponds to the traditional notion of food intolerance. It is a syndrome in which dysfunctions are similar to those observed in the course of allergic diseases, induced by various mechanisms, excluding immunology-related factors. Nonallergic hyperreactivity occurs more frequently than allergy. Morbidity rate in children is approximately 20%-50%, while in adults it is estimated to be approximately 20%. Attention is drawn to the fact that the enzymatic system in children is less mature, so the capacity to bind chemical compounds by plasma proteins is poorer, and so is the blood-brain barrier permeability by low molecular weight compounds. 

Megyeri P, Abraham CS, Temesvari P, Kovacs J, Vas T, Speer CP (1992) Recombinant human tumor necrosis factor alpha constricts pial arterioles and increases blood-brain barrier permeability in newborn piglets. Neurosci Lett 148 137—140. 

Freshly isolated or subcultured brain microvascular endothelial cells offer a notable in vitro tool to study drug transport across the blood-brain barrier. Cells can be grown to monolayers on culture plates or permeable membrane supports. The cells retain the major characteristics of brain endothelial cells in vivo, such as the morphology, specific biochemical markers of the blood-brain barrier, and the intercellular tight junctional network. Examples of these markers are y-glutamyl transpeptidase, alkaline phosphatase, von-Willebrandt factor-related antigen, and ZO-1 tight junctional protein. The methods of... 

The entry of toxins into the brain and central nervous system (CNS) is frequently more difficnlt than into other tissues. The function of this blood-brain barrier is related to impaired permeability of the blood capillaries in brain tissne, the necessity for toxins to penetrate glial cells, and the low protein content of the CNS interstitial flnid (Klaassen, 1986). Lipid solnbihty of a toxin is an important factor in the penetration of the blood-brain barrier. 

Older patients are particularly susceptible to hypoglycemia (87). Factors such as cerebral blood flow, blood P02 and PC02, permeability of the blood-brain barrier, and the presence of underlying neurological defects influence the hypoglycemic effects. 

EXHIBIT A Anatomical and Physiological Considerations Unique to Children. differences in anatomy. allometric scaling factors (e.g. increased surface area-to-volume ratio) cardiovascular status permeability of the pediatric blood-brain barrier (BBB). dermatologic factors (e.g. increased cutaneous blood flow) (Fluhr et al., 2000 Simonen et al, 1997). increased skin pH (Fluhr et al., 2004 Behrendt and Green, 1958) plasma protein binding volume of distribution (V ) organ size and maturity pharmacokinetic maturity (e.g. metabolic differences) (Fairley and Rasmussen, 1983)... 

Poduslo JF, Curran GL (1996) Permeability at the blood-brain barrier and blood-nerve barriers of the neurotrophic factors NGF, CNTF, NT-3, BDNF. Mol Brain Res 36 280-286. 

Figure 3.1. Schematic representation of the cellular components of the blood-hrain (Panel A) and blood-cerehral spinal fluid (Panel B) barriers. The blood-brain barrier consists of continuous type endothelial cells with complex tight junctions to limit paracellular diffusion. The astrocytes and pericytes located in close proximity to the brain endothelial cells release various endogenous factors that modulate endothelial cell permeability. In contrast, the choroid endothelial cells are fenestrated and the blood-cerebral spinal fluid barrier properties are provided by the tight junctions formed between the choroid epithelial cells.

Evidence indicates exposure to nanoparticles can induce an inflammatory response in the CNS. For example, when a sample of mice were exposed to airborne particle matter, increased levels of pro-inflammatory cytokines (TNF-a IL-la), transcription factor, and nuclear factor-kappa beta (NF-k/3) were observed (114). TNF-a serves a neuroprotective function (115), but given certain pathogens TNF-a can be neurotoxic (116-120). IL-a activates cyclooxygenase (COX)-2, phospholipase A2, and inducible nitric oxide synthase (iNOS) activity, which are all associated with inflammation and immune response (121). IL-a is also partially responsible for increasing the permeability of the blood-brain barrier (122, 123). Thus, there is great interest in better understanding how nanoparticles enter the body and translocate as this will impact all organs and thus the toxicity of nanomaterials. 

The net result of these turnover studies is to show that lipids in brain are a part of the dynamic biochemistry of the body — even though they may function primarily as structural components. These data strongly suggest that considerable caution must be exerted in the interpretation of isotopic experiments conducted in vivo, especially when complex compounds are being studied. It emphasizes the need to know more than the radioactivity in the lipid. Other perimeters, such as pool sizes, turnover rates of the pools themselves, permeability, cellular barriers (such as the blood-brain barrier) and other related factors must be determined before a full explanation of the isotope data can be made. 

Poduslo JF, Curran GL, Gill JS. Pu-trescine-modified nerve growth factor bioactivity, plasma pharmacokinetics, blood-brain/nerve barrier permeability and nervous system biodistribution. 

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