ABSTRACT
OBJECTIVE: Topical cytidine-5'-diphosphocholine (CDP-choline) improves functional recovery and promotes nerve regeneration in sciatic nerve injury in rats. The aims of this study were to test whether systemic treatment with CDP-choline was effective in improving the recovery of injured sciatic nerve, and to determine whether the cytidine and/or choline moieties of CDP-choline contribute to its beneficial actions. METHODS: Seventy Sprague-Dawley rats underwent a surgical procedure that involved transectioning and immediate surgical repairing of the right sciatic nerve. Rats were assigned to one of five groups and administered intraperitoneally 1 ml/kg of saline (control) or saline containing 600 µmol/kg of each of CDP-choline, cytidine, choline, or cytidine+choline. RESULTS: Recovery in sciatic function index score was greater in rats treated with CDP-choline, choline, or cytidine+choline at 8 and 12 weeks after the interventions. Peripheral nerve regeneration evaluated by electromyography at 12 weeks was also greater in rats receiving CDP-choline (228% of control), choline (168% of control), or cytidine+choline (221% of control). Axon counts and axon density increased significantly following CDP-choline, choline, or cytidine+choline, respectively. Treatment with equivalent dose of cytidine failed to affect sciatic function index, electromyography, and axon counts. Treatment with CDP-choline, but not its metabolites improved nerve adherence and separability score. CONCLUSION: These data show that intraperitoneal CDP-choline, as well as the combination of its metabolites, cytidine+choline, improves functional recovery and promotes regeneration of injured sciatic nerves in rats. CDP-choline also improves nerve adherence and separability.
Subject(s)
Choline/pharmacology , Cytidine Diphosphate Choline/pharmacology , Cytidine/pharmacology , Nerve Regeneration/drug effects , Nootropic Agents/pharmacology , Recovery of Function/drug effects , Sciatic Neuropathy/drug therapy , Animals , Axotomy , Choline/administration & dosage , Cytidine/administration & dosage , Cytidine Diphosphate Choline/administration & dosage , Disease Models, Animal , Drug Therapy, Combination , Female , Injections, Intraperitoneal , Nootropic Agents/administration & dosage , Rats , Rats, Sprague-Dawley , Sciatic Nerve/injuries , Sciatic Neuropathy/pathologyABSTRACT
Ts65Dn mice are partially trisomic for the distal region of MMU16, which is homologous with the obligate segment of HSA21 triplicated in Down syndrome (DS). Ts65Dn mice are impaired in learning tasks that require an intact hippocampus. In order to investigate the neural basis of these deficits in this mouse model of Down syndrome, quantitative light and electron microscopy were used to compare the volume densities of neurons and synapses in the hippocampus of adult Ts65Dn (n=4) and diploid mice (n=4). Neuron density was significantly lower in the CA1 of Ts65Dn compared to diploid mice (p<0.01). Total synapse density was significantly lower in the dentate gyrus (DG; p<0.001), CA3 (p<0.05) and CA1 (p<0.001) of Ts65Dn compared to diploid mice. The synapse-to-neuron ratio was significantly lower in the DG (p<0.001), CA3 (p<0.01) and CA1 (p<0.001) of Ts65Dn compared to diploid mice. When the data were broken down by synapse type, asymmetric synapse density was found to be significantly lower in the DG (p<0.001), CA3 (p<0.05) and CA1 (p<0.001) of Ts65Dn compared to diploid mice, while such a difference in symmetric synapse density was only present in the DG (p<0.01). The asymmetric synapse-to-neuron ratio was significantly lower in the DG (p<0.001), CA3 (p<0.01) and CA1 (p<0.001) of Ts65Dn compared to diploid mice, but there were no such significant differences in symmetric synapse-to-neuron ratios. These results suggest that impaired synaptic connectivity in the hippocampus of Ts65Dn mice underlies, at least in part, their cognitive impairment.