bryostatin-1 and Cerebral-Infarction

Strokes can cause a variety of sequelae, such as paralysis, particularly in the early stages after stroke onset. Rehabilitation therapy atthis time often provides some degree of paralysis recovery. Neuroplasticity in the peri-infarcted cerebral cortex induced by exercise training may contribute to recovery of paralysis after cerebral infarction. However, the molecular mechanism of this process remains unclear. This study focused on brain protein kinase C (PKC), which is speculated to be involved in neuroplasticity. We evaluated the functional recovery of cerebral infarction model rats, by using rotarod test after running wheel training and with/without administration of bryostatin, a PKC activator. In addition, the expression of phosphorylated and unphosphorylated PKC subtypes, glycogen synthase kinase 3β (GSK3β), and collapsin response-mediator proteins 2 (CRMP2) were analyzed by Western blotting. In the rotarod test, bryostatin administration alone had no effect on gait duration, but the combination of training and this drug significantly prolonged gait duration compared with training alone. In protein expression analysis, the combination of training and bryostatin significantly increased phosphorylation of PKCα and PKCε isoforms, increased phosphorylation of GSK3β, which acts downstream of PKC, and decreased phosphorylation of CRMP2. The effect of bryostatin in combination with training appears to be mediated via PKC phosphorylation, with effects on functional recovery occurring through the downstream regulation of GSK3β and CRMP2 phosphorylation.

Topics: Animals; Bryostatins; Cerebral Cortex; Cerebral Infarction; Glycogen Synthase Kinase 3 beta; Physical Conditioning, Animal; Protein Kinase C; Protein Processing, Post-Translational; Rats; Stroke

Although it has been suggested that the combination of exercise and bryostatin-1 administration may induce greater functional recovery than exercise alone, the detailed molecular mechanisms are not well known. Here, we examined the relationship between this combination treatment and monoamine dynamics in the cerebral cortex peri-infarction area to promote our understanding of these molecular mechanisms. Experimental cerebral cortex infarctions were produced by photothrombosis in rats. Voluntary exercise was initiated 2 days after surgery. Motor performance was then measured using the rotarod test. Monoamine concentrations in the perilesional cortex were analyzed by high-performance liquid chromatography. In behavioral evaluations, performance in the rotarod test was significantly increased by exercise. Moreover, performance in the rotarod test after the combination of exercise and bryostatin-1 administration was significantly greater than that after exercise alone. In the analysis of monoamines, serotonin (5-HT) concentrations were significantly higher in the groups treated with exercise and bryostatin-1. In addition, 5-HT turnover was significantly lower in the groups treated with exercise and bryostatin-1. Furthermore, the mean latency in the rotarod test showed a significant positive correlation with 5-HT levels. In immunohistochemical analysis, 5-HT immunoreactivity in the dorsal raphe nucleus was shown to be higher in the groups treated with exercise. In the present study, we detected changes in the levels of monoamines associated with the combined treatment of exercise and bryostatin-1 administration in the perilesional cortex. It has been suggested that this combination of therapies may affect 5-HT turnover and serve to increase local 5-HT concentrations in the perilesional area.

Topics: Adjuvants, Immunologic; Animals; Biogenic Monoamines; Bryostatins; Cerebral Cortex; Cerebral Infarction; Disease Models, Animal; Exercise Therapy; Male; Motor Activity; Rats; Rats, Sprague-Dawley; Reaction Time; Recovery of Function; Rotarod Performance Test; Serotonin

Recently, it has become widely known that neuronal reorganization in the perilesional cortex contributes to some improvement of hemiparesis after stroke. Here, the authors examined in vivo the effects of administration of bryostatin-1, an activator of protein kinase C, combined with voluntary exercise on functional recovery and on cortical phosphorylation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunit GluR1 after infarction.In behavioral evaluation, the mean latency until falling from a rotating rod in the group with exercise and administered agent at 8 days after infarction was significantly longer than that in the other groups. Although there were no significant changes in GluR1 phosphorylation between bryostatin-1 administration alone and the untreated groups, exercise induced an increase in phosphorylated-Ser845-GluR1. Moreover, combining exercise with administration led to increased phosphorylated-Ser831-GluR1.These results suggest that bryostatin-1 facilitated exercise-induced paralysis recovery, which is possibly mediated by synaptic plasticity related to an increase in synaptic transmission efficiency.

Topics: Animals; Blotting, Western; Bryostatins; Cerebral Infarction; Combined Modality Therapy; Enzyme Activation; Male; Phosphorylation; Physical Conditioning, Animal; Protein Kinase C; Rats, Sprague-Dawley; Receptors, AMPA