ABSTRACT
BACKGROUND: The transplantation of bone marrow stromal cells (MSCs) has proved to ameliorate ischemic brain injury in animals, but most transplanted MSCs undergo apoptosis in the ischemic penumbra, greatly compromising the therapeutic value of this treatment. Meanwhile, cell apoptosis can be inhibited by post-ischemia exercise which has been demonstrated to improve the expression of related anti-apoptotic proteins. The present study investigated whether treadmill exercise enhances the neuroprotective effects of transplanted MSCs in a rat experimental stroke model. RESULT: Rats were subjected to 2-h middle cerebral artery occlusion (MCAO). Twenty-four hours after reperfusion, they were assigned randomly to receive no MSCs treatment and no exercise (control group), intravenous transplantation of MSCs and treadmill exercise (MSCs + Ex group), MSCs transplantation only (MSCs group) and treadmill exercise only (Ex group). Neurological assessment, TUNEL staining and western blot were performed. Compared with the MSCs group and Ex group, the MSCs + Ex group reported markedly improved neurological function, significantly decreased apoptotic cells, and increased expressions of survivin and bcl-2 (p < 0.05 or p < 0.01, respectively). Interestingly, the treadmill exercise significantly inhibited the apoptosis of transplanted MSCs. As a result, the number of engrafted MSCs in the MSCs + Ex group was significantly higher than that in the MSC group (p < 0.01). CONCLUSIONS: Treadmill exercise enhances the therapeutic potency of MSCs by improving neurological function and possibly inhibiting the apoptosis of neuron cells and transplanted MSCs. These effects may involve an increased expression of survivin and bcl-2.
Subject(s)
Bone Marrow Transplantation/methods , Brain Ischemia/physiopathology , Brain Ischemia/therapy , Exercise Therapy/methods , Mesenchymal Stem Cell Transplantation/methods , Mesenchymal Stem Cells/physiology , Animals , Apoptosis/physiology , Brain/pathology , Brain/physiopathology , Brain/surgery , Brain Ischemia/pathology , Disease Models, Animal , Infarction, Middle Cerebral Artery , Locomotion/physiology , Male , Mesenchymal Stem Cells/pathology , Microtubule-Associated Proteins/metabolism , Neurons/pathology , Neurons/physiology , Random Allocation , Rats, Sprague-Dawley , SurvivinABSTRACT
In laboratory studies, counting the spinal motoneurons that survived axonal injury is a major method to estimate the severity and regenerative capacity of the injured motoneurons after the axonal injury and rehabilitation surgery. However, the typical motoneuron marker, the choline acetyltransferase (ChAT), could not be detected in the injured motoneurons within the first 3-4 weeks postinjury. It is necessary to explore the useful and reliable specific phenotypic markers to assess the fate of injured motoneurons in axonal injury. Here, we used the fluorogold to retrograde trace the injured motoneurons in the spinal cord and studied the expression patterns of the alpha-motoneuron marker, the neuronal nuclei DNA-binding protein (NeuN) and the peripheral nerve injury marker, the activating transcriptional factor (ATF-3), and the oxidative stress marker, the neuronal nitric oxide synthase (nNOS) within the first 4 weeks of the root avulsion of the right brachial plexus (BPRA) in the adult male Sprague-Dawley rats. Our results showed that ATF-3 was rapidly induced and sustained to express only in the nuclei of the fluorogold-labeled injured motoneurons but none in the unaffected motoneurons from the 24 h of the injury; meanwhile, the NeuN almost disappeared in the avulsion-affected motoneurons within the first 4 weeks. The nNOS was not detected in the motoneurons until the second week of the injury. On the basis of the present data, we suggest that ATF-3 labels avulsion-injured motoneurons while NeuN and nNOS are poor markers within the first 4 weeks of BPRA.
