Abstract-The expression of a large panel of selected genes hypothesized to play a central role in post-traumatic cell death was shown to be differentially altered in response to a precisely controlled, mechanical injury applied to an organotypic slice culture of the rat brain. Within 48 h of injury, the expression of nerve growth factor messenger RNA was significantly increased whereas the levels of bcl-2, a-subunit of calcium/calmodulin-dependent protein kinase II, cAMP response element binding protein, 65,000 mol. wt isoform of glutamate decarboxylase, 1b isoform of protein kinase C, and ubiquitin messenger RNA were significantly decreased. Because the expression levels of a number of other messenger RNAs such as the neuron-specific amyloid precursor protein, b 2 microglobulin, bax, bcl xl , brain-derived neurotrophic factor, cyclooxygenase-2, interleukin-1b, interleukin-6, tumor necrosis factor-a, receptor tyrosine kinase A, and receptor tyrosine kinase B were unaffected, these selective changes may represent components of an active and directed response of the brain initiated by mechanical trauma.Interpretation of these co-ordinated alterations suggests that mechanical injury to the central nervous system may lead to disruption of calcium homeostasis resulting in altered gene expression, an impairment of intracellular cascades responsible for trophic factor signaling, and initiation of apoptosis via multiple pathways. An understanding of these transcriptional changes may contribute to the development of novel therapeutic strategies to enhance beneficial and blunt detrimental, endogenous, post-injury response mechanisms. ᭧ 2000 IBRO. Published by Elsevier Science Ltd.Key words: genomic expression, in vitro model, traumatic brain injury, organotypic culture, stretch injury, cDNA array.The primary mechanical event associated with traumatic injury to the CNS initiates a cascade of molecular and cellular events which include changes in gene expression, culminating in cell dysfunction and/or death. Although the initial injury occurs in less than 1 s, the post-traumatic sequelae may take hours or days to develop, thereby providing an opportunity to therapeutically attenuate detrimental or augment beneficial endogenous responses in an attempt to limit resultant cell death. A detailed analysis of these specific molecular events may aid in the rational development of novel therapies for the brain-injured patient. Many genes which have been reported to be up-regulated following experimental models of traumatic brain injury (TBI), such as c-fos, c-jun, junB or zif/ 268, 24,54,58,69 are transcription factors that control the expression of other genes, suggesting that the expression of a large number of genes, including those involved in cell death or survival, may be affected by trauma.In this regard, expression of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), necessary for neuronal and other cell survival, has been shown to be increased after controlled cortical impact (CCI) injury in the rat. ...