PRESERVATION OF CHOLINERGIC ACTIVITY AND PREVENTION OF NEURON DEATH BY CEP-1347 KT-7515 FOLLOWING EXCITOTOXIC INJURY OF THE NUCLEUS BASALISMAGNOCELLULARIS/

We have identified a class of small organic molecules, derived from th e indolocarbazole K-252a, that promote the survival of cultured neuron s. However, many of these indolocarbazoles inhibit protein kinase C an d neurotrophin-activated tyrosine kinase receptors. These kinase inhib itory activities may limit the utility of these compounds for neurolog ical disorders. A bis-ethyl-thiomethyl analogue of K-252a, CEP-1347/KT -7515, has been identified that lacks protein kinase C and tyrosine ki nase receptor inhibitory activities, yet retains the ability to promot e survival of cultured neurons, including cholinergic neurons derived from the basal forebrain. In the present studies, CEP-1347/KT-7515 was assessed for neurotrophic activity on basal forebrain neurons of in v ivo rats following excitotoxic insult. Ibotenate infusion into the nuc leus basalis magnocellularis reduced levels of choline acetyltransfera se activity in the cortex, as well as reduced numbers of choline acety ltransferase-immunoreactive and retrogradely (FluoroGold)-labelled cor tically-projecting neurons in the nucleus basalis. Systemically admini stered CEP-1347/KT-7515 attenuated the loss of cortical choline acetyl transferase activity and the loss of the number of choline acetyltrans ferase-immunoreactive and retrogradely-labelled FluoroGold neurons in the nucleus basalis. Moreover, CEP-1347/KT-7515 ameliorated the loss o f cortical choline acetyltransferase if administration was initiated o ne day, but rot seven days post-lesion. Together, these results demons trate that CEP-1347/KT-7515 protects damaged cortically-projecting bas al forebrain neurons from degeneration. Thus, CEP-1347/KT-7515 may hav e therapeutic potential in neurodegenerative diseases, such as Alzheim er's disease, in which basal forebrain cholinergic neurons degenerate. (C) 1998 IBRO. Published by Elsevier Science Ltd.