Experimental lead encephalopathy in the suckling rat: Concentration of lead in cellular fractions enriched in brain capillaries

Toews, Arrel D.; Kolber, Alan R.; Hayward, Jean; Krigman, Martin R.; Morell, Pierre

doi:10.1016/0006-8993(78)90777-1

Cited by 90 publications

(29 citation statements)

References 14 publications

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“…15,30,31 Susceptibility diminishes markedly as vessel growth slows and the BBB matures. 32,33 The differential susceptibility of cerebellum to Pb 2ϩ is believed to be because of the relatively delayed postnatal developmental maturation of cerebellum and cerebellar microvasculature compared with cerebrum. Although it appears that developing and relatively undifferentiated brain microvessels are particularly sensitive to the vasotoxic effects of Pb 2ϩ , 29 -31,33 the biochemical basis of this selective vulnerability has not been determined.…”

Section: Discussionmentioning

confidence: 99%

Vascular endothelial growth factor mediates vasogenic edema in acute lead encephalopathy

Hossain

Russell

Miknyoczki³

et al. 2004

Annals of Neurology

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Brain injury from inorganic Pb(2+) is considered the most important environmental childhood health hazard worldwide. The microvasculature of the developing brain is uniquely susceptible to high level Pb(2+) toxicity (ie, Pb(2+) encephalopathy) characterized by cerebellar hemorrhage, increased blood-brain barrier permeability, and vasogenic edema. However, the specific molecular mediators of Pb(2+) encephalopathy have been elusive. We found that Pb(2+) induces vascular endothelial growth factor/vascular permeability factor (VEGF) in cultured astrocytes (J Biol Chem, 2000;275:27874-27882). The study presented here asks if VEGF dysregulation contributes mechanistically to Pb(2+) encephalopathy. Neonatal rats exposed to 4% Pb-carbonate develop the histopathological features of Pb(2+) encephalopathy seen in children. Cerebellar VEGF expression increased approximately twofold (p < 0.01) concurrent with the development of cerebellar microvascular hemorrhage, enhanced vascular permeability to serum albumin, and vasogenic cerebellar edema (p < 0.01). No change in VEGF expression occurred in cerebral cortex that does not develop these histopathological complications of acute Pb(2+) intoxication. Pb(2+) exposure increased phosphorylation of cerebellar Flk-1 VEGF receptors and the Flk-1 inhibitor CEP-3967 completely blocked cerebellar edema formation without affecting microhemorrhage formation or blood-brain barrier permeability. This establishes that Pb(2+)-induced vasogenic edema formation develops via a Flk-1-dependent mechanism and suggests that the vascular permeability caused by Pb(2+) is Flk-1 independent.

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Section: Discussionmentioning

confidence: 99%

Vascular endothelial growth factor mediates vasogenic edema in acute lead encephalopathy

Hossain

Russell

Miknyoczki³

et al. 2004

Annals of Neurology

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“…Interestingly, exposure to high levels of Pb 2+ appears to result in the disruption of the blood-brain barrier (Goldstein, 1984), leading to edema, and possibly brain damage. Importantly, the endothelial cells in the brain accumulate Pb 2+ preferentially (Toews et al, 1978), which can account, in part, for the severe neurological symptoms observed with Pb 2+ poisoning.…”

Section: Leadmentioning

confidence: 99%

Molecular and ionic mimicry and the transport of toxic metals

Bridges

Zalups

2005

Toxicology and Applied Pharmacology

676

460

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Despite many scientific advances, human exposure to, and intoxication by, toxic metal species continues to occur. Surprisingly, little is understood about the mechanisms by which certain metals and metal-containing species gain entry into target cells. Since there do not appear to be transporters designed specifically for the entry of most toxic metal species into mammalian cells, it has been postulated that some of these metals gain entry into target cells, through the mechanisms of ionic and/or molecular mimicry, at the site of transporters of essential elements and/or molecules. The primary purpose of this review is to discuss the transport of selective toxic metals in target organs and provide evidence supporting a role of ionic and/or molecular mimicry. In the context of this review, molecular mimicry refers to the ability of a metal ion to bond to an endogenous organic molecule to form an organic metal species that acts as a functional or structural mimic of essential molecules at the sites of transporters of those molecules. Ionic mimicry refers to the ability of a cationic form of a toxic metal to mimic an essential element or cationic species of an element at the site of a transporter of that element. Molecular and ionic mimics can also be sub-classified as structural or functional mimics. This review will present the established and putative roles of molecular and ionic mimicry in the transport of mercury, cadmium, lead, arsenic, selenium, and selected oxyanions in target organs and tissues.

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“…Susceptibility to these vascular effects in the suckling rat coincides with the period of active microvessel growth and blood-brain barrier development (5,9). Conversely, susceptibility diminishes markedly as vessel growth slows and the blood-brain barrier matures (3,5). Thus, it appears that lead interferes with the development and differentiation of brain microvessels.…”

mentioning

confidence: 97%

“…The brain microvasculature of the suckling rat preferentially accumulates lead relative to brain parenchyma (3) and is particularly sensitive to its toxic effects (4,5). Acute neonatal exposure to lethal lead concentrations results in cerebellar hemorrhage, cerebral edema, and increased blood-brain barrier permeability (6,7).…”

mentioning

confidence: 99%

Inhibition of astroglia-induced endothelial differentiation by inorganic lead: a role for protein kinase C.

Laterra¹,

Bressler²,

Indurti³

et al. 1992

Proc. Natl. Acad. Sci. U.S.A.

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Experimental lead encephalopathy in the suckling rat: Concentration of lead in cellular fractions enriched in brain capillaries

Cited by 90 publications

References 14 publications

Vascular endothelial growth factor mediates vasogenic edema in acute lead encephalopathy

Vascular endothelial growth factor mediates vasogenic edema in acute lead encephalopathy

Molecular and ionic mimicry and the transport of toxic metals

Inhibition of astroglia-induced endothelial differentiation by inorganic lead: a role for protein kinase C.

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