RESUMO
Although lipid peroxidation has long been associated with spinal cord injury (SCI), the specific role of lipid peroxidation-derived byproducts such as acrolein in mediating damage remains to be fully understood. Acrolein, an α-ß unsaturated aldehyde, is highly reactive with proteins, DNA, and phospholipids and is considered as a second toxic messenger that disseminates and augments initial free radical events. Previously, we showed that acrolein increased following traumatic SCI and injection of acrolein induced tissue damage. Here, we demonstrate that microinjection of acrolein into the thoracic spinal cord of adult rats resulted in dose-dependent tissue damage and functional deficits. At 24h (acute) after the microinjection, tissue damage, motoneuron loss, and spinal cord swelling were observed on sections stained with Cresyl Violet. Luxol fast blue staining further showed that acrolein injection resulted in dose-dependent demyelination. At 8weeks (chronic) after the microinjection, cord shrinkage, astrocyte activation, and macrophage infiltration were observed along with tissue damage, neuron loss, and demyelination. These pathological changes resulted in behavioral impairments as measured by both the Basso, Beattie, and Bresnahan (BBB) locomotor rating scale and grid walking analysis. Electron microscopy further demonstrated that acrolein induced axonal degeneration, demyelination, and macrophage infiltration. These results, combined with our previous reports, strongly suggest that acrolein may play a critical causal role in the pathogenesis of SCI and that targeting acrolein could be an attractive strategy for repair after SCI.
Assuntos
Acroleína/toxicidade , Locomoção/efeitos dos fármacos , Traumatismos da Medula Espinal/induzido quimicamente , Traumatismos da Medula Espinal/patologia , Acroleína/administração & dosagem , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Axônios/efeitos dos fármacos , Axônios/ultraestrutura , Relação Dose-Resposta a Droga , Feminino , Bainha de Mielina/efeitos dos fármacos , Bainha de Mielina/ultraestrutura , Ratos , Ratos Sprague-DawleyRESUMO
Reliable animal models of traumatic brain injury (TBI) are essential to test novel hypotheses and therapeutic interventions. In this study, based on advantages of both the closed head injury (CHI) and controlled cortical impact (CCI) models, we developed a bilateral head injury model in mice. C57BL/6 mice were used in this study. A midline craniotomy (5mm diameter) was performed extending 2mm anteriorly and 3mm posteriorly from the bregma, centered over the sagittal suture. The skull flap was left in place. A cortical impact on the surface of the skull flap was performed using an electromagnetic impactor. Here we report that the injury significantly decreased the neuroscore and increased foot drops in a severity-dependent manner. Severity-related deficits in performance on a rotarod device were also found at both slow and fast accelerations. These findings suggest that our TBI model can produce graded motor deficits. In addition, Morris water maze testing showed increased latency to locate a hidden platform in a severity-dependent manner, suggesting that our model can also produce graded memory deficits. Furthermore, an adhesive removal test revealed significant increases in time-to-contact and time-to-remove the adhesive tape from the paw in a severity-dependent manner, indicating that our TBI model produced graded somatosensory and motor deficits. Histological analysis presented a clear gradation in brain tissue damage following graded brain injuries. These findings collectively suggest that the current model may offer a sensitive, reliable and clinically-relevant model for assessments of therapeutic strategies forTBI.