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Abstract: We previously reported that a single subcutaneous (s.c.) injection of the neurotoxicant, 1-methyl-4-(2′-methylphenyl)-1,2,3,6-tetrahydropyridine or 2′-CH3-MPTP, to postnatal day 4 (PD4) mice caused acute and transient gliosis in the brain, which can be noninvasively monitored during a course of 8h immediately after the dosing [Ho, G., Zhang, C.Y., Zhuo, L., 2007. Non-invasive fluorescent imaging of gliosis in transgenic mice for profiling developmental neurotoxicity. Toxicol. Appl. Pharmacol. 221, 76–85]. In the current study, we examined the consequence of PD4 mice receiving multiple injections (4×8mg/kg, s.c. in 2h intervals) of the same neurotoxicant 24–72h after the last injection. Here we showed that the multiple dosing scheme (with a higher cumulative dose) triggered a severe gliosis not only in the striatum and substantia nigra pars compacta (SNpc), but also in hippocampus and cerebellum when examined by noninvasive in vivo imaging and by immunohistochemistry (IHC), respectively, in the PD5 to PD7 mice. When neonates treated with the neurotoxicant at PD4 were allowed to develop to 10 weeks of age and examined with IHC, a majority of the dopaminergic (DA) neurons were found to be permanently depleted from the adult SNpc. Our findings suggest that neurotoxicant-elicited neonatal gliosis can be used as an early molecular signature to predict the permanent loss of DA neurons in the developed brain. Since 2′-CH3-MPTP is an inducer of Parkinsonism in mice, the molecular imaging method described here is a relatively simple and powerful tool for longitudinally studying the developmental aspect of Parkinsonism. [Copyright &y& Elsevier]

Abstract: Gliosis is a universal response of the brain to almost all types of neural insults, including neurotoxicity, neurodegeneration, viral infection, and stroke. A hallmark of gliotic reaction is the up-regulation of the astrocytic biomarker GFAP (glial fibrillary acidic protein), which often precedes the anatomically apparent damages in the brain. In this study, neonatal transgenic mice at postnatal day (PD) 4 expressing GFP (green fluorescent protein) under the control of a widely used 2.2-kb human GFAP promoter in the brain are treated with two model neurotoxicants, 1-methyl-4(2′-methylphenyl)-1,2,3,6-tetrahydropyridine (2′-CH3-MPTP), and kainic acid (KA), respectively, to induce gliosis. Here we show that the neurotoxicant-induced acute gliosis can be non-invasively imaged and quantified in the brain of conscious (un-anesthetized) mice in real-time, at 0, 2, 4, 6, and 8 h post-toxicant dosing. Therefore the current methodology could be a useful tool for studying the developmental aspects of neuropathies and neurotoxicity. [Copyright &y& Elsevier]