GABAB receptor antagonists elevate both mRNA and protein levels of the neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) but not neurotrophin-3 (NT-3) in brain and spinal cord of rats
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Abstract
In this study we show that single, physiologically-active and non-convulsive doses
of the three GABA(B) receptor antagonists CGP 36742, CGP 56433A and CGP 56999A increase
NGF and BDNF mRNA levels by 200-400% and protein levels by 200-250% in rat neocortex,
hippocampus as well as spinal cord. In all areas examined the increase in NGF protein
preceded that of BDNF. Peak levels of both neurotrophins are transient and occur between
24 and 72 h, depending on the region. In contrast, NT-3 protein concentrations in
the neocortex and hippocampus were decreased significantly to 50% of control values
within 48-96 h. The decrease in the spinal cord was less than 30% and did not reach
significant levels. These data clearly demonstrate that GABA(B) receptor antagonists
induce a specific neurotrophin expression in the central nervous system at physiologically
relevant doses, as opposed to the extreme conditions of seizure paradigms. The results
are in line with the concept that neuronal neurotrophin synthesis and release in brain
are controlled by afferent nerve activity. GABA(B) receptor antagonists could therefore
be a valuable new approach to selectively increase endogenous neurotrophin levels
in the central nervous system.