Mild to moderate early exercise promotes recovery from cerebral ischemia in rats.

OBJECTIVE: We examined the effects of various exercise intensities on recovery from middle cerebral artery occlusion (MCAO) in rats. METHODS: First, we administered a 120-minute left MCAO to male Sprague-Dawley rats and randomly assigned them to one of four groups: no exercise (Group 1), mild exercise (Group 2), moderate exercise (Group 3), and severe exercise (Group 4). Then, we trained the rats for 30 min per day for one week or two weeks. We used a five-point neurological evaluation scale to measure neurological deficits 1-day, 4-days, 7-days, 10-days and 14-days after MCAO and measured infarct volume by use of 2% 2,3,4-triphenyltetrazolium chloride in exercised brains. We also performed immunohistochemistry analysis of the brain to observe reactive astrocytosis at the peri-infarct region. RESULTS: Neurological examination indicated that Group 2 and 3 recovered better than Group 1 after one week and two weeks (p < 0.05). Moreover, Group 2 and 3 had reduced brain infarct volume compared with Group 1 after one week (p < 0.05). There were no significant differences between Group 4 and Group 1. The thickness of the peri-infarct astrocytosis was significantly reduced in Group 4 relative to Group 1 after one week. There was a significant negative correlation between the extent of reactive astrocytosis and neurological recovery (r = -0.648, p < 0.01). CONCLUSION: This study demonstrates that mild to moderate exercise that begins soon after induced cerebral ischemia promotes recovery and that astrocytes may have an important role in the recovery process.

Expression of L-serine biosynthetic enzyme 3-phosphoglycerate dehydrogenase (Phgdh) and neutral amino acid transporter ASCT1 following an excitotoxic lesion in the mouse hippocampus.

The nonessential amino acid L-serine functions as a glia-derived trophic factor and strongly promotes the survival and differentiation of cultured neurons. The L-serine biosynthetic enzyme 3-phosphoglycerate dehydrogenase (Phgdh) and the small neutral amino acid transporter ASCT1 are preferentially expressed in specific glial cells in the brain. However, their roles in pathological progression remain unclear. We examined the expression of Phgdh and ASCT1 in kainic acid (KA)-induced neurodegeneration of the mouse hippocampus using immunohistochemistry and Western blots. Our quantitative analysis revealed that Phgdh and ASCT1 were constitutively expressed in the normal brain and transiently upregulated by KA-treatment. At the cellular level, Phgdh was expressed in astrocytes in control and in KA-treated mice while ASCT1 that was expressed primarily in the neurons of the normal brain appeared also in activated astrocytes in KA treated mouse brain. The preferential glial expression of ASCT1 was consistent with that of Phgdh. These results demonstrate injury-induced changes in Phgdh and ASCT1 expression. It is hypothesized that the secretion of L-serine is regulated by astrocytes in response to toxic molecules such as glutamate and free radicals that promote neurodegeneration, and may correspond to the level of L-serine needed for neuronal survival and glial activation during brain insults.

Effect of human embryonic stem cell-derived neuronal precursor cell transplantation into the cerebral infarct model of rat with exercise.

We analyzed the therapeutic effect of the transplantation of the human embryonic stem cell (NIH Code: MB01)-derived neuronal precursor (hES-NP) cell and post-ischemic exercise in rats with the middle cerebral artery (MCA) infarct model. A cortical infarct was induced in 20 adult Sprague-Dawley rats by occlusion and reperfusion of the MCA. The rats were divided into four groups: hES-NP cell transplantation and exercise, transplantation only, exercise only, and Sham-operated with no exercise. In the cell-transplanted group, hES-NP cells were transplanted by stereotactic inoculation into the ipsilateral basal ganglia 7 days after infarct. We evaluated the clinical recovery of deficit, the size of infarct and the survival, migration, and differentiation of the transplanted cells. The transplanted hES-NP cells survived robustly in the ischemic brains 3 weeks post transplant. The majority of migrating cells in the ischemic rats had a neuronal phenotype. The clinical scores of all of the experimental groups were better than those of the Sham-operated group. Whereas the exercise-only group showed continuous clinical improvement, the cell-transplanted groups manifested less improvement than the exercise-only group. Moreover, the cell-transplanted groups did not differ in clinical improvement according to postinfarct-exercise or not. The infarct size was significantly reduced in both the cell-transplanted groups and the post-ischemic exercise group, compared with the Sham-operated group; however, the reduction of infarct size was most prominent in the exercise-only group. In our study, the inoculated site of the basal ganglia showed some damage induced by inoculation, such as loss of neuroglial cells, reactive gliosis and microcalcification, which was found in the Sham-operated group as well, and yet no inoculation-site injury has ever been reported. Our study revealed that stem cell transplantation can have a positive effect on behavioral recovery and reduction of infarct size, but the effect shown was no better than the effect of the exercise, which finding reconfirmed the importance of post-infarct rehabilitation. In addition, it was found that cell inoculation should be replaced by a noninvasive procedure.