Abstract
Lead intoxication in humans is characterized by cognitive impairments, particularly in the domain of memory, where evidence indicates that glutamatergic neurotransmission may be impacted. Animal and cell culture studies have shown that lead decreases the expression and activity of glutamine synthetase (GS) in astrocytes, yet the basis of this effect is uncertain. To investigate the mechanism responsible, the present study exposed primary astrocyte cultures to a range of concentrations of lead acetate (0–330 μM) for up to 24 h. GS activity was significantly reduced in cells following 24 h incubation with 100 or 330 μM lead acetate. However, no reduction in GS activity was detected when astrocytic lysates were co-incubated with lead acetate, suggesting that the mechanism is not due to a direct interaction and involves intact cells. Since GS is highly sensitive to oxidative stress, the capacity of lead to inhibit the clearance of hydrogen peroxide (H2O2) was investigated. It was found that exposure to lead significantly diminished the capacity of astrocytes to degrade H2O2, and that this was due to a reduction in the effectiveness of the glutathione system, rather than to catalase. These results suggest that the inhibition of GS activity in lead poisoning is a consequence of slowed H2O2 clearance, and supports the glutathione pathway as a primary therapeutic target.
Highlights
A primary function of astrocytes is to recycle synaptically-released glutamate (Pow and Robinson, 1994)
Studies have linked the toxicity of lead to elevated oxidative stress, with lead exposure correlating with increased production of free radicals and a lowering of antioxidant reserves
We demonstrated that lead limits the capacity of astrocytes to degrade H2O2, and that this appears to be due to an impairment of the GSH system
Summary
A primary function of astrocytes is to recycle synaptically-released glutamate (Pow and Robinson, 1994). Studies have linked the toxicity of lead to elevated oxidative stress, with lead exposure correlating with increased production of free radicals and a lowering of antioxidant reserves. Astrocytes pre-incubated with buthionine sulfoximine (BSO), a GSH synthesis inhibitor, show a marked reduction in their rate of H2O2 clearance and an increase in cell death (Liddell et al, 2006). Lead can bind to the catalytic site of GR, irreversibly inhibiting the enzyme and preventing it from reducing GSSG to GSH (Rubino, 2015). Impairment of the glutathione system will decrease cellular antioxidative capacity and reduce protection from oxidative stress (Scortegagna et al, 1998; Aykin-Burns et al, 2003). We demonstrated that lead limits the capacity of astrocytes to degrade H2O2, and that this appears to be due to an impairment of the GSH system
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