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BBB DYSFUNCTION RESULTING FROM LEAD of the brain. LRP-1 knockout mice show higher levels of
INSULT AND NEUROINFLAMMATION amyloid protein following lead exposure. [71] Lead could
induce a significant reduction in LRP-1 expression
Inflammatory cytokines and the inflammatory response by interfering with the LRP-1 gene promoter. These
are critical in the neurovascular unit and may result studies, therefore, suggest that lead neurotoxicity might
in alteration of BBB function. Brain microvascular also be related to memory deficits in the pathogenesis
endothelial cells (BMECs) are considered to be the of Alzheimer’s disease. [72]
anatomical and functional basis of the BBB. [63] As
they are in direct contact with the circulating blood, NEURONAL DAMAGE INDUCED BY LEAD
BMECs are highly vulnerable to the impact of the EXPOSURE AND NEUROINFLAMMATION
blood environment. Studies have revealed that lead
toxicity in the BBB or BMECs might influence tight Lead-induced inflammatory reaction cascades
junction proteins. [64] Tight junctions are key functional within the neurovascular unit may cause neuronal
structures that bond BMECs together. Adhesion proteins damage. [21] It has been hypothesized that TNF-a, IL-1β,
are a component of tight junctions, and the zonula and IL-6 could cause neuronal apoptosis through glial
occludens (ZO) family plays a key role in connecting activation. [73] Possible mechanisms of injury might be
transmembrane proteins with actins inside the ECs ROS production due to the pro-inflammatory cytokine
to complete the structure of tight junctions. [65] In the IL-1β or increased glycogen consumption in astrocytes
cultured brain microvessel endothelial cell line RBE4, due to TNF-a and IL-1, thereby causing increased levels
lead reduces the expression of tight junction proteins of toxic substances and affecting the metabolism of the
[74]
and lowers TEER, causing changes in ion permeability cells. TNF might also be involved in the expression of
at the BBB and brain interstitial fluid ion regulation. As NO, suggesting another way by which could inactivate
ZO-1 and ZO-2 are intracellular proteins, this suggests LTP. Furthermore, IL-1β acts on endothelial cell tight
that cytoplasmic mechanisms may be associated with junction proteins, reducing the amount and location
this process. Increased permeability of endothelial of occludin and increasing the permeability of the
cells along with a decrease in occludin proteins has BBB. [75] Inflammatory reactions could also change the
been detected following lead exposure. [65] The ZO transport of multiple substances by affecting the role
family also seems to be susceptible to oxidative stress, of glutamate receptors. [76] Lead-induced chemokines,
and tight junctions are destroyed by lead-induced mainly secreted from neurons, have been shown to
inflammation and ROS, leading to long-term BBB act on microglial receptors and participate in the
damage. However, other in vitro and in vivo experiments interactions between neurons and glial cells, resulting
have revealed that claudin-1 mRNA and protein levels in changes in microglial and astrocyte morphology. [77]
are downregulated without significant changes to ZO-1
and atresia proteins. [65,66] Oxidative damage is fatal to brain neurons. In pathological
conditions such as hypoxia, traumatic injury, and lead
The divalent iron ion channel [divalent metal insult, these toxic free radicals might be over-generated
transporter (DMT)] is a key element for the transport and cause secondary injuries to neurons. Compared with
of iron across the BBB. [67] Many experiments have neurons, astrocytes have higher levels of antioxidants
indicated that lead could also pass through DMT in a such as glutathione (GSH), heme-oxygenase 1 and GSH
competitive way and may occupy this transporter when S-transferase. Neurons may maintain their antioxidant
[78]
iron is deficient. Lead affects the offset of iron-regulated capacity by transporting and utilizing these substances,
proteins, which allows it to more easily access endothelial among which the GSH shuttle pathway is likely to be
cells. [68,69] When the concentration of iron is elevated, the paramount. [79,80] GSH, the most abundant antioxidant in
[70]
transport of lead is effectively inhibited. Interestingly, the brain, is mainly generated in astrocytes. Astrocytes
expression of fractalkine (CX3CL1), a mediator of store a much higher content of GSH-related enzymes in
neuron-glial signaling, is also enhanced after exposure order to guarantee a supply to neurons. GSH-depleted
[78]
[10]
to lead, especially in the hippocampus and forebrain. astrocytes display a reduced ability to protect neurons
In addition, lead also passes through and interferes with against oxidative injury. [78]
calcium channels, suggesting that lead might be able
to cross the BBB in multiple or unknown other ways. When lead enters astrocytes, it could directly
deplete NADPH. More importantly, it affects glucose
In one model involving exposure to lead, increased 6 phosphate dehydrogenase, a key enzyme of the
β-amyloid (Aβ) levels were found in the choroid pentose phosphate pathway, reducing the production
[2]
plexus. On the choroid epithelial cell surface, a critical of NADPH. [15] Both effects might result in a lack of
transporter known as lipoprotein receptor-related GSH support from astrocytes to neurons. Lead is
protein-1 (LRP-1) is responsible for transporting Aβ out able to bind to GSH sulfhydryl groups and disable its

134 Neuroimmunol Neuroinflammation | Volume 2 | Issue 3 | July 15, 2015 Neuroimmunol Neuroinflammation | Volume 2 | Issue 3 | July 15, 2015 135