TIME-COURSE, LOCALIZATION AND PHARMACOLOGICAL MODULATION OF IMMEDIATE-EARLY INDUCIBLE GENES, BRAIN-DERIVED NEUROTROPHIC FACTOR AND TRKB MESSENGER-RNAS IN THE RAT-BRAIN FOLLOWING PHOTOCHEMICAL STROKE

A focal, unilateral thrombotic stroke was produced in the rat sensorim otor cortex. The time course of expression and localization of the imm ediate early inducible genes: c-fos, c-jun, zif268; nerve growth facto r, brain-derived neurotrophic factor and the related tyrosine kinase h igh-affinity receptor (trkB) messenger RNAs were studied by in situ hy bridization. The levels of messenger RNAs for c-fos, zif268, brain-der ived neurotrophic factor (but not nerve growth factor) and trkB were c onsistently increased in cortex ipsilaterally to the lesion, while c-j un messenger RNA content was only slightly increased. The brain-derive d neurotrophic factor messenger RNA was increased from 2 to 18 h follo wing the stroke, mainly in cells having a normal morphological appeara nce. The trkB messenger RNA displayed temporal and spatial increases s imilar to brain-derived neurotrophic factor messenger RNA. The time co urse and pattern of expression of immediate early inducible gene and t rophic factor messenger RNAs did not clearly support a causal relation ship between these two families of factors. The observed messenger RNA increases were greatly attenuated by the non-competitive N-methyl-D-a spartate-sensitive glutamate receptor antagonist 1-dihydroxy-5H-dibenz o(a,d)cyclohepten-5,10-imine, but substantially unaffected by the non- N-methyl-D-aspartate receptor antagonist 2,3-dihydroxy-6-nitrosulphano yl-benzoquinoxaline. The results suggest a major contribution of N-met hyl-D-aspartate-sensitive glutamate receptor activation to the transcr iptionally directed events subsequent to stroke. Future studies should clarify the contribution of these processes to either the progression of neuronal degeneration or the establishment of protective compensat ory responses.