Blood-brain barrier metals

Involvement of several proteolytic enzymes, secretases, is probably crucial for this process but other hypotheses, including, for example, cholinergic transmission or accumulation of metal ions, have also been considered. Future perspectives in this area concern the search for novel pharmaceuticals that cross the blood-brain barrier, without side effects (e.g., the dyskinesias of L-Dopa), or potent and selective inhibitors of improper cleavage of amyloid protein, or even stem cell therapy to restore neuronal cells. 

Metal ions are particularly toxic in a complex with organic molecules, because the latter increase their lipid solubility so that they readily cross the plasma membrane to enter cells. They also cross the blood-brain barrier so that they very effectively gain access to nerve cells in the brain. 

Paramagnetic metal chelating agent in NMRI Transport across the blood brain barrier... 

Elemental mercury vapor is relatively lipid soluble and is readily absorbed from the lungs following inhalation and is oxidized in the red blood cells to Hg2+. Elemental mercury may also be transported from red blood cells to other tissues such as the CNS. Elemental mercury readily passes across the blood-brain barrier into the CNS and also into the fetus. The metallic compound is only poorly absorbed from the gastrointestinal tract, however. 

Nervous System. The nervous system is also a common target of toxic metals particularly, organic metal compounds (see Chapter 16). For example, methylmercury, because it is lipid soluble, readily crosses the blood-brain barrier and enters the nervous system. By contrast, inorganic mercury compounds, which are more water soluble, are less likely to enter the nervous system and are primarily nephrotoxicants. Likewise organic lead compounds are mainly neurotoxicants, whereas the first site of inorganic lead is enzyme inhibition (e.g., enzymes involved in heme synthesis). 

Biomethylation of Elements. The biomethylation of elements is carried out principally by microorganisms and is important in environmental toxicology, particularly in the case of heavy metals, because the methylated compounds are absorbed through the membranes of the gut, the blood-brain barrier, and the placenta more readily than are the inorganic forms. For example, inorganic mercury can be methylated first to monomethylmercury and subsequently, to dimethylmercury ... 

With respect to distribution in the body, the methylmercury species behave more like mercury metal, Hg(0), than inorganic mercury(II), Hg2+. Like elemental mercury, methylmercury compounds traverse the blood-brain barrier and affect the central nervous system. However, the psychopatho-logical effects of methylmercury compounds (laughing, crying, impaired intellectual abilities) are different from those of elemental mercury (irritability, shyness). 

Rosenberg GA, Estrada EY, Dencoff JE (1998) Matrix metal-loproteinases and TIMPs are associated with blood-brain barrier opening after reperfusion in rat brain. Stroke 29 2189-2195... 

TfR-mediated endocytosis is a well-known uptake system Tf binds one or two Fe atoms, but only diferric Tf (Fe2Tf) has a high affinity for TfR to be taken up by the receptor-mediated endocytosis. This system uses a mobilization pathway that involves endosomal acidification, reduction of ferric Fe, and ferrous Fe transport [8]. Recently, it was clarified that divalent cation/ metal ion transporter (DCT1) or Nramp2 involves iron transport from the endosome to the cytosol [9, 10]. Al resembles Fe in chemical characteristics ionic radius, charge density, and coordination number [11]. Therefore, Al binds with Tf to form di—Al—Tf. Al bound to Tf even passes through the blood-brain barrier to enter the neuronal cells via Tf receptor-mediated endocytosis [12]. 

Keywords Alzheimer s disease Astrocytes Blood-brain barrier (BBB) Central nervous system (CNS) Chaperone proteins Chemokines Cytokines Heavy metals Inflammation Lead (Pb) Map kinases Microglia Neurons Nitric oxide (NO) Reactive oxygen species (ROS)... 

The existence of the blood-brain barrier does not preclude the passage of chemicals into the brain. As is the case with all other cellular membranes in the body, lipid-soluble nonionized chemicals enter the brain by passive diffusion. Anesthetics, ethanol, and CNS depressants, for instance, rapidly diffuse into the brain in a matter of a few seconds or minutes. They also exit the brain rapidly when the concentration gradient between blood and brain is reversed. Elemental mercury, methylmercury, and tetraethyl lead are examples of lipid-soluble forms of metals that easily enter the brain, while the ionized, much less lipid-soluble inorganic salts of mercury and lead penetrate only poorly. 

Inorganic salts of mercury do not readily cross the blood-brain barrier or the placenta. They are, therefore, ultimately less toxic to the central nervous system and the developing fetus than either absorbed metallic mercury or organic mercury compounds. Metallic mercury is more readily oxidized to... 

Following exposure and absorption, metallic mercury is distributed primarily to the kidneys. Elemental mercury is highly soluble in lipids and easily crosses cell membranes (Gossel and Bricker 1984), particularly those of the alveoli (Florentine and Sanfilippo 1991). Once in the blood, this form of mercury can distribute throughout the body, as well as penetrate the blood-brain barrier, thus accumulating in the brain (Berlin et al. 1969). The body burden half-life of metallic mercury is about 1-2 months (Clarkson 1989). The kidney is also the primary organ of accumulation for compounds of inorganic mercury, but the liver, spleen, bone marrow, red blood cells, intestine, and respiratory mucosa... 

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