exenatide and Spinal-Cord-Injuries

Topics: Animals; Cicatrix; Exenatide; Glucagon-Like Peptide-1 Receptor; Mice; Microglia; Neuroinflammatory Diseases; Neuroprotective Agents; Spinal Cord Injuries

Current therapies for spinal cord injury (SCI) have limited efficacy, and identifying a therapeutic target is a pressing need. Sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2 (SERCA2) plays an important role in regulating calcium homeostasis, which has been shown to inhibit apoptosis. Exendin-4 has been shown to inhibit the apoptosis of nerve cells in SCI, which can also improve SERCA2 expression. In this study, we sought to determine whether exendin-4 plays a protective role in a rat model of SCI via SERCA2.. To investigate the effects of exendin-4 on SCI, a rat model of SCI was induced by a modified version of Allen's method. Spinal cord tissue sections from rats and western blot analysis were used to examine SERCA2 expression after treatment with the long-acting glucagon-like peptide 1 receptor exendin-4 or the SERCA2 antagonist 5(6)-carboxyfluorescein diacetate N-succinimidyl ester (CE). Locomotor function was evaluated using the Basso Beattie Bresnahan locomotor rating scale and slanting board test.. Cell apoptosis was increased with CE treatment and decreased with exendin-4 treatment. Upregulation of SERCA2 in female rats with SCI resulted in an improvement of motor function scores and histological changes.. These findings suggest that exendin-4 plays a protective role in a rat model of SCI through SERCA2 via inhibition of apoptosis. Existing drugs targeting SERCA2 may be an effective therapeutic strategy for the treatment of SCI.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Caspase 3; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Disease Models, Animal; Exenatide; Locomotion; Microscopy, Fluorescence; PC12 Cells; Peptides; Protective Agents; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Sprague-Dawley; Recovery of Function; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Signal Transduction; Spinal Cord Injuries; Venoms

Autophagy occurs prior to apoptosis and plays an important role in cell death regulation during spinal cord injury (SCI). This study aimed to determine the effects and potential mechanism of the glucagon-like peptide-1 (GLP-1) agonist extendin-4 (Ex-4) in SCI. Seventy-two male Sprague Dawley rats were randomly assigned to sham, SCI, 2.5 μg Ex-4, and 10 μg Ex-4 groups. To induce SCI, a 10-g iron rod was dropped from a 20-mm height to the spinal cord surface. Ex-4 was administered via intraperitoneal injection immediately after surgery. Motor function evaluation with the Basso Beattie Bresnahan (BBB) locomotor rating scale indicated significantly increased scores (p < 0.01) in the Ex-4-treated groups, especially 10 μg, which demonstrated the neuroprotective effect of Ex-4 after SCI. The light chain 3-II (LC3-II) and Beclin 1 protein expression determined via western blot and the number of autophagy-positive neurons via immunofluorescence double labeling were increased by Ex-4, which supports promotion of autophagy (p < 0.01). The caspase-3 protein level and neuronal apoptosis via transferase UTP nick end labeling (TUNEL)/NeuN/DAPI double labeling were significantly reduced in the Ex-4-treated groups, which indicates anti-apoptotic effects (p < 0.01). Finally, histological assessment via Nissl staining demonstrated the Ex-4 groups exhibited a significantly greater number of surviving neurons and less cavity (p < 0.01). To our knowledge, this is the first study to indicate that Ex-4 significantly enhances motor function in rats after SCI, and these effects are associated with the promotion of autophagy and inhibition of apoptosis.

Topics: Animals; Apoptosis; Autophagy; Beclin-1; Behavior, Animal; Caspase 3; Exenatide; Male; Microtubule-Associated Proteins; Motor Activity; Neurons; Peptides; Rats, Sprague-Dawley; Recovery of Function; Spinal Cord; Spinal Cord Injuries; Venoms

Spinal cord injury (SCI) is a devastating problem of health. Glucagon-like peptide-1 (GLP-1) is glucose-dependent insulinotropic hormone. Exendin-4 is the longacting GLP-1 receptor agonist that used as an anti-diabetic drug. Recent studies demonstrated exendin-4 has a series of beneficial neuroprotective properties. This study was designed to assess the neuroprotective effects of exendin-4 against spinal cord injury. 72 rats were randomly divided into three groups as follows: sham operation group, SCI group, and exendin-4 group (intraperitoneal injection of exendin-4 at 10 μg/rat immediately after SCI). First, a decrease of malodialdehyde (MDA) levels and an increase of glutathione (GSH) levels in the exendin-4 group demonstrated the anti-oxidation effect of exendin-4. Further, the preservation of mitochondrial membrane potential (ΔΨm) and the reduction of cytochrome c release suggested the protection for mitochondria. Moreover, a decline of the expression level of Bax, Bcl-2 and caspase-3 and the results of TUNEL staining indicated its anti-apoptosis role. Finally, behavioral assessment with Basso Beattle Bresnahan locomotor rating scale (BBB) showed that animals in exendin-4 group achieved a significant increase in BBB scores. Our results suggest that exendin-4 prevents against SCI-induced mitochondrial apoptotic pathway and contributes to functional improvement after SCI.

Topics: Animals; Apoptosis; Exenatide; Female; Glutathione; Malondialdehyde; Mitochondria; Models, Animal; Neuroprotective Agents; Oxidative Stress; Peptides; Rats; Rats, Sprague-Dawley; Spinal Cord Injuries; Venoms