title: Preservation of cholinergic activity and prevention of neuron death by CEP-1347/KT-7515 following excitotoxic injury of the nucleus basalis magnocellularis.
abstract: We have identified a class of small organic molecules, derived from the indolocarbazole K-252a, that promote the survival of cultured neurons. However, many of these indolocarbazoles inhibit protein kinase C and neurotrophin-activated tyrosine kinase receptors. These kinase inhibitory activities may limit the utility of these compounds for neurological disorders. A bis-ethyl-thiomethyl analogue of K-252a, CEP-1347/KT-7515, has been identified that lacks protein kinase C and tyrosine kinase receptor inhibitory activities, yet retains the ability to promote 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 vivo rats following excitotoxic insult. Ibotenate infusion into the nucleus basalis magnocellularis reduced levels of choline acetyltransferase activity in the cortex, as well as reduced numbers of choline acetyltransferase-immunoreactive and retrogradely (FluoroGold)-labelled cortically-projecting neurons in the nucleus basalis. Systemically administered CEP-1347/KT-7515 attenuated the loss of cortical choline acetyltransferase activity and the loss of the number of choline acetyltransferase-immunoreactive and retrogradely-labelled FluoroGold neurons in the nucleus basalis. Moreover, CEP-1347/KT-7515 ameliorated the loss of cortical choline acetyltransferase if administration was initiated one day, but not seven days post-lesion. Together, these results demonstrate that CEP-1347/KT-7515 protects damaged cortically-projecting basal forebrain neurons from degeneration. Thus, CEP-1347/KT-7515 may have therapeutic potential in neurodegenerative diseases, such as Alzheimer's disease, in which basal forebrain cholinergic neurons degenerate.
authors.affiliation: Cephalon Inc., West Chester, PA 19380, USA.
authors.forename: M S
authors.initials: MS
authors.lastname: Saporito
authors.forename: E R
authors.initials: ER
authors.lastname: Brown
authors.forename: S
authors.initials: S
authors.lastname: Carswell
authors.forename: A M
authors.initials: AM
authors.lastname: DiCamillo
authors.forename: M S
authors.initials: MS
authors.lastname: Miller
authors.forename: C
authors.initials: C
authors.lastname: Murakata
authors.forename: N T
authors.initials: NT
authors.lastname: Neff
authors.forename: J L
authors.initials: JL
authors.lastname: Vaught
authors.forename: F A
authors.initials: FA
authors.lastname: Haun
mesh_terms: D000818:Animals; D001370:Axonal Transport / Q000187:drug effects; D002227:Carbazoles / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002795:Choline O-Acetyltransferase / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005456:Fluorescent Dyes; D005625:Frontal Lobe / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D007839:Functional Laterality; D007051:Ibotenic Acid / Q000633:toxicity; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013266:Stilbamidines; D013377:Substantia Innominata / Q000187:drug effects / Q000473:pathology / Q000502:physiology*
chemical_list: C049774:2-hydroxy-4,4'-diamidinostilbene, methanesulfonate salt; D002227:Carbazoles; D004791:Enzyme Inhibitors; D005456:Fluorescent Dyes; D007211:Indoles; D013266:Stilbamidines; C106592:3,9-bis((ethylthio)methyl)-K-252a; D007051:Ibotenic Acid; D002795:Choline O-Acetyltransferase