Organotins Disrupt Components of Glutamate Homeostasis in Rat Astrocyte Cultures

Abstract

A rat cortical astrocyte preparation was used to investigate the effects of organotins on glutamate regulation by astrocytes. Exposure of astrocytes to low levels of organotins produced significant changes in two key components of glutamate homeostasis: glutamine synthetase (CS) activity and the high-affinity transport of L-glutamate. Trimethyltin (TMT), triethyltin (TET), and triphenyltin (TPT) exhibited differential abilities to reduce GS activity and glutamate uptake. Cultures incubated with 1 microM TET or TPT, but not TMT, exhibited a marked decrease in GS activity. Exposure to TET or TPT also produced a significant decrease in glutamate transport activity that was not observed with TMT. These declines in activity were not attributable to cell loss as measured by MTT reduction and lactate dehydrogenase (LDH) leakage. Since the loss of GS activity and transporter activity was not seen with acute organotin exposure, it is most likely attributable to a decreased presence of fully functioning protein. While the attenuation of GS and glutamate transporter activities by organotins does not match their pattern of neurotoxicity, the results indicate the potential for subtoxic concentrations of these compounds to increase extracellular glutamate and interact with other excitotoxic episodes.

Tyrosine Kinase Inhibitors Ameliorate Autoimmune Encephalomyelitis in a Mouse Model of Multiple Sclerosis

“…It is also possible that these inhibitors provide benefit in EAE by suppressing PDGFR activity in other cell types or by modulating other astrocyte functions. Astrocytes are mediators of glutamate homeostasis [33, 64], and imbalances in glutamate secretion and reabsorption play an important role in the demyelinating stages of MS [8, 9, 61]. Astrocytes can also contribute to the breakdown of the BBB by producing MMPs [61, 62].…”

MAP kinase cell signaling pathway as biomarker of environmental pollution in the sponge Suberites domuncula

“…Tributyltin (TBT), a lipophilic organotin compound, is often profusely used in wood preservation, antifouling paints, circulating industrial water disinfection and slime control in paper mills (Kannan et al 1998;Karpiak et al 2001). Widespread and significant pollution of marine and freshwater environments by TBT has been reported in water (Shim et al 2005), sediments (Harino et al 2007) and aquatic organisms (Dorneles et al 2008;Harino et al 2007Harino et al , 2008.…”

Hypoxia‐like transcriptional activation in TMT‐induced degeneration: microarray expression analysis on PC12 cells

“…The molecular and cellular pathogenesis of TMTintoxication syndrome is believed to be a composite picture involving several steps, as TMT is able to affect multiple processes in sensitive cells. Different theories have been formulated to explain the neurotoxic actions of TMT, including glutamate excitotoxicity and impairment of neurotransmission (Brown et al 1979;Naalsund and Fonnum 1986;Cannon et al 1994;Noraberg et al 1998;Gasso et al 2000;Karpiak et al 2001;Nishimura et al 2001;Kruger et al 2005), along with oxidative stress and caspase activation, which might mediate TMT-induced apoptosis in vivo (Geloso et al 2002;Jenkins and Barone 2004). TMTinduced apoptosis could be considered the expected final step of a degenerative process sustained by the early activation of reactive cellular mechanisms able to trigger cell death.…”