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The Neuroprotective Compound P7C3 and its Analogue P7C3A20 Enhances Functional Recovery Following Neonatal Nerve Injury in a Dose Dependent Manner
Stephen W. P. Kemp; Andrew A. Pieper, MD; Matthew D. Wood; Mark Szynkaruk; Krisanne N. Stanoulis; Tessa Gordon; Gregory H. Borschel
The Hospital for Sick Children/ The University of Toronto, Toronto, ON, Canada
Sciatic nerve injury in neonatal rats results in a significant loss of both motor and sensory neurons, leading to impaired function and locomotor ability in adulthood. The majority of these neurons die rapidly following nerve injury through a glutamate induced, excitotoxic apoptotic mechanism. The neuroprotective compound P7C3, and its analogue P7C3A20, have been previously shown to display proneurogenic, neuroprotective properties following injury to the central nervous system. They exert their proneurogenic activity by protecting newborn neurons from apoptosis. However, these central neuroprotective agents have not yet been tested in a model of neonatal peripheral nerve injury. We therefore 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). In the first set of experiments, both the spinal cord and dorsal root ganglion (DRG) cells were characterized following retrograde labeling of the sciatic nerve with FluorGold (FG) at 1 month following initial injury. The number of retrogradely labeled motorneurons in vehicle administered controls was reduced to approximately 35% of normal animals. However, animals directly administered P7C3/A20 over a two week period followed a dose dependent regenerative response, with an optimal threshold effect occurring at a dose of 20 mg/kg. At this dose, improved motor and sensory regenerative properties were increased to approximately 80% of normal. The second set of experiments analyzed behavioral recovery of both overground and skilled locomotion (ladder rung task, walking track), following P7C3/A20 administration. Endpoint functional analysis consisted of electrophysiological and myological assessments, including both mean twitch and tetanic forces, wet muscle weights (gastrocnemius, tibialis anterior, soleus, extensor digitorum longus, plantaris), and motor unit number estimation (MUNE). Results indicate significant differences between treatment groups. Current studies are analyzing the mechanism behind P7C3/A20 neuroprotection following neonatal nerve injury.
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