4-benzyl-2-methyl-1-2-4-thiadiazolidine-3-5-dione and Spinal-Cord-Injuries

The reparative process following spinal cord injury (SCI) is extremely complicated. Cells in the microenvironment express multiple inhibitory factors that affect axonal regeneration over a prolonged period of time. The axon growth inhibitory factor glycogen synthase kinase-3 (GSK-3) is an important factor during these processes. TDZD-8 (4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione) is the most effective and specific non-ATP-competitive inhibitor of GSK-3. Here, we show that administering TDZD-8 after SCI was associated with significantly inhibited neuronal apoptosis, upregulated GAP-43 expression, increased density of cortical spinal tract fibers around areas of injury, and increased Basso, Beattie, and Bresnahan (BBB) scores in the lower limbs. These findings support the notion that GSK-3 inhibitors promote neuronal cell regeneration and lower limb functional recovery.

Topics: Animals; Apoptosis; Axons; Disease Models, Animal; GAP-43 Protein; Gene Expression Regulation; Glycogen Synthase Kinase 3; Humans; Motor Activity; Nerve Regeneration; Neurons; Rats; Recovery of Function; Spinal Cord; Spinal Cord Injuries; Thiadiazoles

Glycogen synthase kinase-3 (GSK-3) has recently been identified as an ubiquitous serine-threonine protein kinase that participates in a multitude of cellular processes and plays an important role in the pathophysiology of a number of diseases. The aim of this study was to investigate the effects of GSK-3beta inhibition on the degree of experimental spinal cord trauma induced by the application of vascular clips (force of 24 g) to the dura via a four-level T5-T8 laminectomy. Spinal cord injury (SCI) in mice resulted in severe trauma characterized by edema, neutrophil infiltration, production of a range of inflammatory mediators, tissue damage, and apoptosis. Treatment of the mice with 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8), a potent and selective GSK-3beta inhibitor, significantly reduced the degree of 1) spinal cord inflammation and tissue injury (histological score); 2) neutrophil infiltration (myeloperoxidase activity); 3) inducible nitric-oxide synthase, nitrotyrosine, and cyclooxygenase-2 expression; and 4) and apoptosis (terminal deoxynucleotidyl transferase dUTP nick-end labeling staining and Bax and Bcl-2 expression). In a separate set of experiments, TDZD-8 significantly ameliorated the recovery of limb function (evaluated by motor recovery score). Taken together, our results clearly demonstrate that treatment with TDZD-8 reduces the development of inflammation and tissue injury associated with spinal cord trauma.

Topics: Animals; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Male; Mice; Motor Skills; Spinal Cord Injuries; Thiadiazoles