Competitive antagonism associated with blockade of neuronal uptake: effects of indoramine in rat vas deferens and aorta

Abstract

Presented by A.C.M. PaivaDentate granule cells are generally considered to be relatively resistant to excitotoxicity and have been associated to robust synaptogenesis after neuronal damage. Synaptic reorganization of dentate granule cell axons, the mossy fibers, has been suggested to be relevant for hyperexcitability in human temporal lobe epilepsy and animal models. A recent hypothesis has suggested that mossy fiber sprouting is dependent on newly formed dentate granule cells. However, we have recently demonstrated that cycloheximide (CHX) can block the mossy fiber sprouting that would be otherwise induced by different epileptogenic agents and do not interfere with epileptogenesis in those models. Here, we investigated cell damage and neurogenesis in the dentate gyrus of pilocarpine-or kainate-treated animals with or without the co-administration of CHX. Dentate granule cells were highly vulnerable to pilocarpine induced-status epilepticus (SE), but hardly damaged by kainate induced-SE. CHX-pretreatment markedly reduced the number of injured neurons after pilocarpine-induced SE. Induction of SE dramatically increased the mitotic rate of KA and KA + CHX treated animals. Induction of SE in animals injected with pilocarpine alone led to increases of between two to sevenfold in the mitotic rate of dentate granule cells as compared to increases of between five and thirtyfold for pilocarpine+CHX animals. These observations indicate that in presence of cycloheximide the increase of the mitotic rate after pilocarpine-induced SE may be due to protection of a vulnerable precursor cell population that would otherwise degenerate. We further suggest that the mossy fiber sprouting and neurogenesis of granule cells are not necessarily related events. - ( September 14, 1999 The α1-adrenoceptor antagonist indoramin was used in the rat vas deferens and aorta, against contractions induced by noradrenaline. Indoramin behaved as a competitive antagonist yielding pA 2 values of 7.38 ± 0.05 in rat vas deferens and 6.78 ± 0.14 in aorta. In the presence of cocaine (6µM), the potency (pA 2 ) of indoramin in antagonizing the contractions of the vas deferens to noradrenaline was increased to 8.72 ± 0.07 while its potency remained pratically unchanged in the aorta (6.69 ± 0.12).