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Vol. 24. Num. 1.January - February 2013
Pages 1-50
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Vol. 24. Num. 1.January - February 2013
Pages 1-50
Clinical Research
DOI: 10.1016/j.neucir.2011.12.006
AR-A014418 as a glycogen synthase kinase-3 inhibitor: Anti-apoptotic and therapeutic potential in experimental spinal cord injury
AR-A014418 como inhibidor de la glucógeno sintasa quinasa 3: potencial anti-apoptótico y terapéutico en lesión medular
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Matem Tunçdemira, Aziz Yıldırımb, Alper Karaoğlanc,??
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drkaraoglan@yahoo.com

Corresponding author.
, Osman Akdemird, Melek Öztürka
a Department of Medical Biology, Cerrahpasa Faculty of Medicine, Istanbul University, Istanbul, Turkey
b Department of Neurosurgery, Bingöl State Hospital, Bingöl, Turkey
c Department of Neurosurgery, Maltepe University, School of Medicine, Istanbul 34857, Turkey
d Department of Neurosurgery, Taksim Education and Research Hospital, Istanbul, Turkey
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Abstract
Objectives

We aimed to investigate the effects of AR-A014418, a strong inhibitor specific to GSK-3beta, on neuronal apoptosis and neuroprotection in the traumatic SCI model.

Materials and methods

In this study, three groups were generated from 36 Wistar rats; (1) control, (2) spinal cord trauma group created by clip compression technique after laminectomy, and (3) AR-A014418 (4mg/kg, i.p., DMSO) treatment group after laminectomy and spinal cord trauma. The TUNEL assay for apoptosis detection, immunohistochemical staining for bax and TGF-beta were applied in spinal cord tissues. For light microscopic examination, necrotic, and apoptotic cells were counted, and PMNL counting was applied to detect inflammation. Functional recovery was tested by field locomotor test in the 3rd and 7th days following surgery.

Results

In the trauma group, diffuse hemorrhage, cavitation, necrosis and edematous regions, degeneration in motor neurons and leukocyte infiltration were observed in gray matter. In the AR-A014418-treated groups, healthy cells were observed in more places compared to the trauma groups, however, cavitation, hemorrhagic, and edematous areas were seen in gray matter. In the AR-A014418-treatment groups, the number of apoptotic cells in the 3rd and 7th days (respectively; p<0.05, p<0.01), were significantly decreased compared to the trauma groups, as were the levels of bax (p<0.01) and TGF-beta 1 immunoreactivity. Results of the locomotor test were significantly increased in the treatment group (p<0.001) as compared to the trauma group.

Conclusions

In this experimental spinal cord trauma model study neural apoptosis was significantly triggered in secondary damage developed after trauma, however, neurological healing was expedited by preventing mitochondrial apoptosis and reducing the inflammation by the potent inhibitor AR-A014418, which is GSK-3beta selective.

Keywords:
Spinal cord injury
GSK-3beta
AR-A014418
Apoptosis
TGF-beta
Abbreviations:
SCI
GSK-3
DMSO
PMNL
H+E
CV
TUNEL
Resumen
Objetivo

Este trabajo tuvo como objetivo investigar los efectos del AR-A014418, un potente inhibidor específico de la GSQ-3beta, en la apoptosis y neuroprotección neuronales en el modelo de lesión medular traumática.

Materiales y métodos

Se generaron tres grupos a partir de 36 ratas Wistar: (1) control, (2) grupo de traumatismo medular obtenido mediante técnica de pinzamiento post-laminectomía, y (3) grupo de tratamiento mediante AR-A014418 (4mg/kg, i.v., DMSO) post-laminectomía y traumatismo medular. Se aplicaron el test TUNEL para la detección de la apoptosis, tinción inmunohistoquímica para bax y TGF-beta en los tejidos medulares. Se llevo a cabo un examen microscópico y recuento de células necróticas y apoptóticas, así como recuento de LPMN para detectar inflamación. La recuperación funcional fue verificada mediante la prueba de campo del aparato locomotor en los días 3 y 7 después de la cirugía.

Resultados

Se observo hemorragia difusa, cavitación, necrosis y regiones edematosas, degeneración de las neuronas motoras e infiltración leucocítica en la materia gris en los grupos traumáticos. En los grupos con tratamiento AR-A014418 se observaron células sanas con mayor abundancia en comparación con los grupos traumáticos. Sin embargo, se observaron áreas de cavitación, hemorragia y edema en la materia gris. En los grupos con tratamiento AR-A014418, el número de células apoptóticas en los días 3 y 7 (p<0,05 y p<0,01, respectivamente), se redujo significativamente en comparación con los grupos traumáticos, así como los niveles de bax (p<0,01) y las células inmunopositivas para TGF-beta 1. Los resultados de la prueba del aparato locomotor se incrementaron significativamente en el grupo de tratamiento (p<0,001) en comparación con el grupo traumático.

Conclusiones

Mediante un estudio experimental de un modelo de traumatismo medular se observó como la apoptosis neuronal era desencadenada de manera significativa por daños secundarios postraumáticos. Sin embargo, la mejora neurológica se vio acelerada por la prevención de la apoptosis mitocondrial y reducción de la inflamación causadas por el inhibidor de GSQ-3beta, AR-A014418.

Palabras clave:
Lesión medular
GSQ-3beta
AR-A014418
Apoptosis
TGF-beta

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