Poststroke neuronal rescue and synaptogenesis mediated in vivo by protein kinase C in adult brains

Abstract

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.bryostatin ͉ ischemia ͉ neuroprotection ͉ protein kinase C ͉ rat T emporary or permanent restriction of cerebral blood flow and oxygen supply results in cerebral ischemia and ischemic stroke, the third-leading cause of death and the most common cause of long-term disability in developed countries. Thrombolytic therapy (eg, recombinant tissue plasminogen activator) to achieve early arterial recanalization is the only option currently available to treat ischemic stroke. But this therapy's time-dependent effect (within 3 h after the event) limits its clinical use to only 5% of candidate patients (1), and it carries an increased risk of intracranial hemorrhage, reperfusion injury, and diminishing cerebral artery reactivity (2-5). Neuronal death and injury after cerebral ischemia involve pathological changes associated with necrosis and delayed apoptosis (6, 7). Neurons in the infarction core of focal, severe stroke are immediately eliminated and cannot be saved once ischemia develops. The ischemic penumbra, (i.e, brain tissues surrounding the core in focal ischemic stroke) and the sensitive neurons/networks in global cerebral ischemia are still sustained by the diminished blood supply, however. Further damage in these ischemic brain tissues occurs in a delayed manner after cerebral ischemia/stroke (8-10), responsible for clinical deterioration. Thus, effective postischemic therapy with an extended time window remains one of the greatest challenges to modern medical practice.A consistent consequence of cerebral ischemia/hypoxia in humans and other mammals is central nervous system dysfunction, the nature of which depends on the location and extent of injury. It has been well established that global cerebral ischemia/hypoxia selectively injures or damages the pyramidal neurons in the dorsal hippocampal CA1 area (11-14), which are essential for episodic memory, providing a sensitive measure for monitoring ischemic damage and recovery functionally. Experimental cerebral ischemia is usually induced focally through, for example, occlusion of the middle cerebral artery, or globally...

Postischemic PKC activation rescues retrograde and anterograde long-term memory

“…Bryostatin-1 alone had no effect on the density of presynaptic vesicles. The EM results are consistent with our previous observation using immunohistochemistry of synaptophysin, a presynaptic vesicle membrane protein, visualized by a confocal microscope (14).…”

“…PKC␦, on the other hand, is possibly involved in ischemic/reperfusion injury (21). Thus, consistent with biochemical changes of preand postsynaptic neurotrophic and other proteins (14), including spinophilin, synaptophysin, and BDNF, bryostatin-1 prevents synaptic loss, induces synaptogenesis, produces an antiapoptotic effect, and increases cell survival and activity of brain-derived neurotrophic factor (BDNF) in the dorsal hippocampal CA1 area as shown in our previous study (14).…”

“…The global ischemia/hypoxia-induced impairment of spatial learning and memory results from a gradual loss of synapses, apoptotic cell death, and an insufficient synaptic repairing/ neurotrophic activity in the dorsal hippocampus CA1 area (14). All of these consequences were effectively rescued by the bryostatin-1 treatment.…”

“…First, we determined whether postischemic bryostatin-1 would produce a persistent (e.g., many months) functional recovery of the neural circuits and synapses. Bryostatin-1 was administered (15 g/m 2 , i.v., two doses/week for 5 weeks) with the first dose given 24 h after the end of the cerebral ischemic/hypoxic event in rats (14). Spatial learning and memory abilities were tested 4 months after the last bryostatin-1 dose.…”

“…We have recently found that, instead of only arresting the pathological cascades in cerebral ischemia, postischemic (24 h after) bryostatin-1, a relatively isoform-selective protein kinase C (PKC) activator with antiapoptotic and synaptogenesisfacilitating properties (10-13), rescues rats from ischemic/ hypoxic impairment of spatial learning and memory (14), evaluated about 2 weeks after the end of a 5-week treatment.…”