bryostatin-1 and Stroke

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

Global cerebral ischemia/hypoxia, as can occur during human stroke, damages brain neural networks and synaptic functions. The recently demonstrated protein kinase C (PKC) activation-induced synaptogenesis in rat hippocampus suggested the potential of PKC-mediated antiapoptosis and synaptogenesis during conditions of neurodegeneration. Consequently, we examined the effects of chronic bryostatin-1, a PKC activator, on the cerebral ischemia/hypoxia-induced impairment of synapses and neurotrophic activity in the hippocampal CA1 area and on hippocampus-dependent spatial learning and memory. Postischemic/hypoxic bryostatin-1 treatment effectively rescued ischemia-induced deficits in synaptogenesis, neurotrophic activity, and spatial learning and memory. These results highlight a neuroprotective signaling pathway, as well as a therapeutic strategy with an extended time window for reducing brain damage due to stroke by activating particular PKC isozymes.

Topics: Aging; Animals; Behavior, Animal; Bryostatins; Cell Differentiation; Cell Survival; Enzyme Activation; Hypoxia; Isoenzymes; Learning; Male; Memory; Microscopy, Electron; Neurons; Protein Kinase C; Rats; Rats, Wistar; Stroke; Synapses