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NEUROPROTECTIVE EFFICACY OF AMINOPROPYL CARBAZOLES IN A NEONATAL RAT MODEL OF NERVE INJURY
Presenter: Stephen W Kemp, PhD
Co-Authors: Pieper AA; Wood MD; Szynkaruk M; Liu EH; Gordon T; Borschel GH
The Hospital for Sick Children University of Toronto

Motorneurons of adult rats are able to survive following crush type nerve injuries. However, sciatic nerve injury in neonatal rats results in a significant loss of motorneurons and leads to impaired muscle development and function. The majority of these neurons die rapidly following nerve injury through an apoptotic mechanism. P7C3, a novel aminopropyl carbazole, and its analogue P7C3A20, have been recently shown to display proneurogenic, neuroprotective properties in the subgranular zone of the hippocampus. P7C3/A20 exerts their proneurogenic activity by protecting newborn neurons from apoptosis. However, it is currently unknown what effect P7C3/A20 has on the protection and survival of motorneurons following neonatal nerve injury. In this experiment, we sought to assess the possible neuroprotective effects of daily administration of P7C3/A20 for a two week period, and examined both axonal and Schwann cell (SC) regenerative properties following unilateral sciatic nerve crush at postnatal day 3 (P3) in neonatal rats. Animals were randomly assigned to one of nine experimental groups: 1 mg/kg P7C3 (Group 1); 5 mg/kg P7C3 (Group 2); 10 mg/kg P7C3 (Group 3); 20 mg/kg P7C3 (Group 4); 1 mg/kg P7C3A20 (Group 5); 5 mg/kg P7C3A20 (Group 6); 10 mg/kg P7C3A20 (Group 7); 20 mg/kg P7C3A20 (Group 8); vehicle controls (Group 9). Following the initial surgery, animals were returned to their home cages and their body weights, and food/water intake were monitored for a one month period. At 1 month, anatomical parameters of both the spinal cord and dorsal root ganglion (DRG) cells were characterized following retrograde labeling of the sciatic nerve with FluorGold (FG). Following nerve injury with vehicle administration, the number of retrogradely labeled motorneurons was reduced to approximately 35%. Results indicate that animals directly administered P7C3/A20 over a two week period follow a dose dependent response, with an optimal threshold effect occurring at a dose of 20 mg/kg. At this dose, improved regenerative properties were seen following neonatal sciatic nerve crush.


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