Dentate granule neuron apoptosis and glia activation in murine hippocampusinduced by trimethyltin exposure

We investigated the effect of trimethyltin (TMT), a well-known neurotoxican t, on murine hippocampal neurons and glial cells. Three days following intr aperitoneal (i.p.) injection of TMT into 1-month-old Balb/c mice at a dose of 2.5 mg/kg body weight we detected damage of the dentate gyrus granular n eurons. The dying cells displayed chromatin condensation and internucleosom al DNA fragmentation, which are the most characteristic features of apoptos is. To study, if prolyl oligopeptidase is engaged in neuronal apoptosis fol lowing TMT administration, we pretreated mice with the specific inhibitor - Fmoc-Pro-ProCN in doses of 5 and 10 mg/kg body weight (i.p. injection). Th ree days following injection we did not observe any attenuation of neurotox ic damage, regardless of inhibitor dose, indicating the lack of prolyl olig opeptidase contribution to neuronal injury caused by TMT. The neurodegenera tion was associated with reactive astrogliosis in whole hippocampus, but pa rticularly in injured dentate gyrus. The reactive astrocytes showed an incr eased nerve growth factor (NGF) expression in ventral as well as dorsal hip pocampal parts. NGF immunoreactivity was also augmented in neurons of CA3/C A4 areas. which were almost totally spared after TMT intoxication. It sugge sted a role for this neurotrophin in protection of pyramidal cells from los s of connection between CA3/CA4 and dentate gyrus fields. The granule neuro ns' death was accompanied by increased histochemical staining with isolecti n B4, a marker of microglia, in the region of neurodegeneration. The microg lial cells displayed ramified and ameboid morphology, characteristic of the ir reactive forms. Activated microglia were the main source of interleukin 1 beta (IL-1 beta). It is possible that this cytokine may participate in ne urodegeneration of granule cells. Alternatively, IL1 beta elaborated by mic roglia could play a role in increasing NGF expression, both in astroglia an d in CA3/CA4 neurons. (C) 2001 Elsevier Science B.V. All rights reserved.