Preservation of cholinergic activity and prevention of neuron death by CEP-1347/KT-7515 following excitotoxic injury of the nucleus basalis magnocellularis.

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.

Chronic sparing of delayed alternation performance and choline acetyltransferase activity by CEP-1347/KT-7515 in rats with lesions of nucleus basalis magnocellularis.

Peripheral injection of the indolocarbazole CEP-1347/KT-7515 into rats that have sustained ibotenic acid lesions of the nucleus basalis magnocellularis has been shown to prevent the loss of cortically-projecting neurons in that basal forebrain region. The present study tested whether this neuroprotective activity would lead to chronic sparing of a behaviour known to be impaired by that lesion, as well as to chronic maintenance of cholinergic activity in cortical target regions of the nucleus basalis. CEP-1347/KT-7515 was injected into adult rats that had sustained bilateral ibotenic acid lesions of the nucleus basalis magnocellularis; the first injection occurred 18-24 h after lesioning, with subsequent injections of CEP-1347/KT-7515 occurring every other day over 12 days. One day following the last injection the animals were tested for retention of a previously-learned delayed alternation task. Animals that received CEP-1347/KT-7515 committed significantly fewer errors than lesioned animals receiving vehicle. These same animals were tested again eight to 10 weeks later (which was 10-12 weeks post-dosing), without receiving further drug or behaviour training during the test-retest interval. The animals that had received CEP-1347/KT-7515 continued to commit significantly fewer errors than vehicle animals. Furthermore their performance at this time point was indistinguishable from normal controls. Analysis of errors showed that CEP-1347/KT-7515 prevented a lesion-induced increase in perseverative errors, suggesting the drug improved attention in the lesioned animals. Choline acetyltransferase activity in the frontal cortex of the behaviourally tested animals that received CEP-1347/KT-7515 three months previously showed a significant 40% recovery of the lesion-induced loss seen in the vehicle animals. These results demonstrate that treatment with CEP-1347/KT-7515 over 12 days following excitotoxic damage to the nucleus basalis magnocellularis produces long-term sparing of an attention-demanding behaviour.

Lesion of the habenular efferent pathway produces anxiety and locomotor hyperactivity in rats: a comparison of the effects of neonatal and adult lesions.

Recent studies have implicated the habenula in modulating states of arousal and chronic responses to stress. We examined whether lesion of the habenula efferent pathway, the fasciculus retroflexus (FR), at either 3 (P3) or 70 (P70) days of age affects stress-related anxiety (elevated plus-maze test) and activity levels (open-field test) in rats tested as adults. Both P3- and P70-lesioned rats showed chronically elevated plasma levels of corticosterone. Rats receiving FR lesions as neonates (P3) exhibited greater open arm avoidance on the elevated plus-maze than controls 2 months postoperatively, suggesting a heightened state of anxiety. In contrast, P70-lesioned rats behaved similarly to controls on the plus-maze, but showed increased locomotion and increased grooming in the open field, effects not observed in P3-lesioned rats. When an additional stressful condition was imposed (5 days of social isolation plus 24 h food deprivation) before testing, both FR-lesion groups showed an attenuation of the normal behavioral responses (decreased open-arm entries/time in open arms, increased freezing). The effects of FR lesions on activity and behavioral indices of anxiety may be due to disruption of lateral habenular projections to dopaminergic neurons in the ventral tegmentum and/or projections to regions containing high concentrations of benzodiazepine receptors, the median and dorsal raphe and dorsal periaqueductal gray. Behavioral differences observed as a function of lesion age suggest differential capabilities of P3- and P70-lesioned rats to utilize compensatory mechanisms to correct FR lesion-induced deficits.