sincalide and Nerve-Degeneration

Major aspects of temporal lobe epilepsy (TLE) can be reproduced in mice following a unilateral injection of kainic acid into the dorsal hippocampus. This treatment induces a non-convulsive status epilepticus and acute lesion of CA1, CA3c and hilar neurons, followed by a latent phase with ongoing ipsilateral neuronal degeneration. Spontaneous focal seizures mark the onset of the chronic phase. In striking contrast, the ventral hippocampus and the contralateral side remain structurally unaffected and seizure-free. In this study, functional and neurochemical alterations of the contralateral side were studied to find candidate mechanisms underlying the lack of a mirror focus in this model of TLE. A quantitative analysis of simultaneous, bilateral EEG recordings revealed a significant decrease of theta oscillations ipsilaterally during the latent phase and bilaterally during the chronic phase. Furthermore, the synchronization of bilateral activity, which is very high in control, was strongly reduced already during the latent phase and the decrease was independent of recurrent seizures. Immunohistochemical analysis performed in the contralateral hippocampus of kainate-treated mice revealed reduced calbindin-labeling of CA1 pyramidal cells; down-regulation of CCK-8 and up-regulation of NPY-labeling in mossy fibers; and a redistribution of galanin immunoreactivity. These changes collectively might limit neuronal excitability in CA1 and dentate gyrus, as well as glutamate release from mossy fiber terminals. Although these functional and neurochemical alterations might not be causally related, they likely reflect long-ranging network alterations underlying the independent evolution of the two hippocampal formations during the development of an epileptic focus in this model of TLE.

Topics: Action Potentials; Animals; Brain Chemistry; Calbindins; Chronic Disease; Disease Models, Animal; Down-Regulation; Electroencephalography; Epilepsy; Epilepsy, Temporal Lobe; Functional Laterality; Galanin; Hippocampus; Kainic Acid; Mice; Mossy Fibers, Hippocampal; Nerve Degeneration; Neural Pathways; Neuropeptide Y; Neurotoxins; Pyramidal Cells; S100 Calcium Binding Protein G; Sincalide; Status Epilepticus; Theta Rhythm; Up-Regulation

SUT-8701 is a cholecystokinin octapeptide (CCK8) analog and a more lipophilic peptide than CCK8. We previously demonstrated that intra-ventricularly administered CCK8 protected against the degeneration of the cholinergic neurons in the cortex of the nucleus basalis magnocellularis (nbm)-lesioned rat. We determined whether SUT-8701 and CCK8 have the ability to protect against cholinergic degeneration in the cerebral cortex of nbm-lesioned rats. Systemically administered SUT-8701 (0.1-1 micrograms/day/animal, s.c.) preserved choline acetyltransferase activity and K(+)-evoked acetylcholine release in nbm-lesioned rats. SUT-8701 was more potent than CCK8. However, SUT-8701 was much less potent than CCK8 in satiety action. The affinity of SUT-8701 to the cholecystokinin (CCK) receptors assessed by using [125I]-CCK8 was almost the same as that of CCK8 in the mouse cerebral cortex, but was 107 times less than that of CCK8 in guinea pig pancreas. These results suggest that SUT-8701 may be effective in slowing down the degenerative processes in Alzheimer's disease by preserving the integrity of cholinergic neurons in the nucleus basalis.

Topics: Acetylcholine; Animals; Cerebral Cortex; Choline O-Acetyltransferase; Eating; Iodine Radioisotopes; Male; Nerve Degeneration; Parasympathetic Nervous System; Prosencephalon; Rats; Rats, Sprague-Dawley; Satiety Response; Sincalide