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Preservation of cholinergic activity and prevention of neuron death by CEP-1347/KT-7515 following excitotoxic injury of the nucleus basalis magnocellularis.
Neuroscience 1998; 86(2):461-72N

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+Show Affiliations

Cephalon Inc., West Chester, PA 19380, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

9881861

Citation

Saporito, M S., et al. "Preservation of Cholinergic Activity and Prevention of Neuron Death By CEP-1347/KT-7515 Following Excitotoxic Injury of the Nucleus Basalis Magnocellularis." Neuroscience, vol. 86, no. 2, 1998, pp. 461-72.
Saporito MS, Brown ER, Carswell S, et al. Preservation of cholinergic activity and prevention of neuron death by CEP-1347/KT-7515 following excitotoxic injury of the nucleus basalis magnocellularis. Neuroscience. 1998;86(2):461-72.
Saporito, M. S., Brown, E. R., Carswell, S., DiCamillo, A. M., Miller, M. S., Murakata, C., ... Haun, F. A. (1998). Preservation of cholinergic activity and prevention of neuron death by CEP-1347/KT-7515 following excitotoxic injury of the nucleus basalis magnocellularis. Neuroscience, 86(2), pp. 461-72.
Saporito MS, et al. Preservation of Cholinergic Activity and Prevention of Neuron Death By CEP-1347/KT-7515 Following Excitotoxic Injury of the Nucleus Basalis Magnocellularis. Neuroscience. 1998;86(2):461-72. PubMed PMID: 9881861.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Preservation of cholinergic activity and prevention of neuron death by CEP-1347/KT-7515 following excitotoxic injury of the nucleus basalis magnocellularis. AU - Saporito,M S, AU - Brown,E R, AU - Carswell,S, AU - DiCamillo,A M, AU - Miller,M S, AU - Murakata,C, AU - Neff,N T, AU - Vaught,J L, AU - Haun,F A, PY - 1999/1/9/pubmed PY - 1999/1/9/medline PY - 1999/1/9/entrez SP - 461 EP - 72 JF - Neuroscience JO - Neuroscience VL - 86 IS - 2 N2 - 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. SN - 0306-4522 UR - https://www.unboundmedicine.com/medline/citation/9881861/Preservation_of_cholinergic_activity_and_prevention_of_neuron_death_by_CEP_1347/KT_7515_following_excitotoxic_injury_of_the_nucleus_basalis_magnocellularis_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0306-4522(98)00059-1 DB - PRIME DP - Unbound Medicine ER -