Sarin causes early differential alteration and persistent overexpression in mRNAs coding for glial fibrillary acidic protein (GFAP) and vimentin genes in the central nervous system of rats.

Abstract

Neurotoxic effects of single dose of 0.5 x LD50 sarin (O-isopropylmethylphosphonoflouridate) on central nervous system (CNS) of male Sprague-Dawley rats were studied. We investigated the mRNA expression of the astroglial marker genes glial fibrillary acidic protein (GFAP) and vimentin to evaluate the fate of astroglial and neuronal cells, because reactive gliosis is very often used to assess the extent of CNS damage. Rats were treated with 50 microg/kg/ml of sarin and terminated at the time-points 1 and 2 hours and 1, 3, and 7 days post-treatment. Control rats were treated with normal saline. Total RNA was extracted and Northern blots were hybridized with cDNA probes for GFAP and vimentin, as well as 28S RNA (control). The data obtained indicate that a single dose of sarin (0.5 x LD50) showed induction in the transcript levels of GFAP and vimentin in the cortex, cerebellum, brainstem and midbrain, and spinal cord. The induction showed distinct spatial-temporal differences for each tissue studied. Both GFAP and vimentin were induced at 1 hour in all the tissues studied except brainstem, where moderate and high levels of GFAP induction were noted at 1 and 3 days. Overexpressed transcript levels of GFAP and vimentin remained high in more responsive tissues such as the brainstem and midbrain. Other tissues, such as the cortex, spinal cord, and cerebellum showed a more downward trend for either GFAP or vimentin, or both, transcript levels at 7 days. It is noteworthy that both cortex (318 +/- 12%) and spinal cord (368 +/- 12%) showed relatively higher induction of GFAP, whereas cortex alone showed the highest level of overexpressed vimentin transcript levels (284 +/- 11%). Overall it is also clear that both GFAP and vimentin are needed for the effective recovery involving co-ordinated alternating up- and downregulation of these two key astrocyte genes, depending on tissue specificity. The changes seen in the transcript levels of GFAP and vimentin may be the result of astrocyte dysfunction and loss, accompanied by compensatory proliferation and dedifferentiation of the astroglia. These changes could affect the neuronal cell types, thus altering the neuron-glia homeostasis.