Glycogen synthase kinase-3β inhibitor (TDZD-8) promotes axonal regeneration and functional recovery of hind limbs after spinal cord injury in rats

Abstract

Objective To explore the effect of glycogen synthase kinase-3β(GSK-3β) inhibitor (TDZD-8) on axonal regeneration and functional recovery of hind limbs after spinal cord injury (SCI) in rats.Methods Animal models of complete paraplegia at T9 level were nade in 108 adult female Sprague-Dawley rats which were subjected to weight-drop impact before they were randonly divided into even 3 groups.(Group A was treated with 1 mg/(kg · d) TDZD-8,group B with 60 μL/d PBS and group C was set as blank controls.All agents were respectively injected through subarachnoid catheters implanted via L4 at one hour after SCI and the injections lasted for 3 weeks.The expressions of GAP-43 were measured respectively by SP immunohistochemical staining on 7.14 and 28 days after injection.The expressions of neuronal apoptosis were observed respectively by TUNEL staining at 2,4,8,24 hours and 7 days after injeetion.The motor function of hind limbs in each group was evaluated bv Basso-Beattie-Bresnahan (BBB) scores at 1.2,3,6,8 and 12 weeks respectively after injection.Axonal regeneration was evaluated by immunofluorescence staining at 8 weeks respectively after iujection.Results The expressions of neuronal apoptosis were detected at 2 hours after SCI,and rose to the peak at 8 hours before they gradually decreased.The apoptotic cells in group A were significantly lower than in groups B and C (P ＜ 0.05) at all time points.The expressions of GAP-43 were increased gradually after SCI and rose to the peak on the 14 days before they gradually decreased.The GAP-43 expressions in group A were significantly higher than in groups B and C at all time points (P ＜ 0.05).The BBB scores in group A were significantly higher than in groups B and C from 3 weeks after injection (P ＜O.05).More regeneration neurofibers extended through the lesion area in group A while few neurofibers did in groups B and C.At 8 weeks after injection,the positive fiber area of corticospinal tracts was significantly larger in group A than in the other 2 groups (P ＜ 0.05).Conclusion TDZD-8 may inhibit neuronal apoptosis,reduce secondary spinal cord injury,up-regulate the expression of GAP-43,promote axonal regeneration and ameliorate function recovery of hind limbs in rats. Key words: Spinal cord injuries; Enzyme inhibitors; Apoptosis; Recovery of function