Postischemic PKC activation rescues retrograde and anterograde long-term memory

Abstract

Therapeutics for cerebral ischemia/hypoxia, which often results in ischemic stroke in humans, are a global unmet medical need. Here, we report that bryostatin-1, a highly potent protein kinase C (PKC) activator, interrupts pathophysiological molecular cascades and apoptosis triggered by cerebral ischemia/hypoxia, enhances neurotrophic activity, and induces synaptogenesis in rats. This postischemic therapeutic approach is further shown to preserve learning and memory capacity even 4 months later as well as long-term memory induced before the ischemic event. Our results of electromicroscopic and immunohistochemical analyses of neuronal and synaptic ultra-structure are consistent with a PKC-mediated synaptic remodeling and repair process that confers long-lasting preservation of spatial learning and memory before and after the cerebral ischemic/hypoxic event, suggesting a previously undescribed therapeutic modality for cerebral ischemia/hypoxia and ischemic stroke.bryostatin ͉ protein kinase C ͉ stroke therapy ͉ synaptogenesis C erebral ischemia/hypoxia, which often results in stroke, is the third leading cause of death and the most common cause of long-term disability in the developed countries. Decades of intensive searching for neuroprotective drugs against cerebral ischemia/ischemic stroke have met many preclinical but not clinical successes (1-8). The only option currently available for the treatment of ischemic stroke is the thrombolytic therapy (such as, the recombinant tissue plasminogen activator), which must be administered within 3 h after the episode to achieve early arterial recanalization. Several factors most likely contribute the translational failures. Targeting mainly the pathological cascades induced by ischemia/hypoxia (arresting the pathological pathway), such as extracellular build up of excitatory aminio acids and intracellular Ca 2ϩ elevation, is most effective when the blockers are given at or immediately before an ischemic event. Furthermore, the targeted neurotransmitters, Ca 2ϩ , and many enzymes involved in the ischemic/hypoxic responses are also critical for neuronal functions so that their effective blockade cannot be maintained without producing serious adverse effects or toxicity. In addition, the short-term effectiveness of agents arresting the pathological pathway as determined in most preclinical studies, does not guarantee a cure, because such drug candidates may delay but not prevent the pathological impact (9).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. ResultsHere, we investigated therapeutic effects of postischemic bryostatin-1 in two paradigms: one involving long-term anterograde, and the other retrogra...

Current Status and Future Prospects of C1 Domain Ligands as Drug Candidates

“…Global cerebral ischemia selectively injures the pyramidal neurons in the dorsal hippocampal CA1 area, causing dramatic and long-lasting impairment of spatial learning and memory [104,105]. In an animal model of experimental global ischemia, chronic bryostatin 1 administered for 5 weeks, with the first dose given 24 hours after the induced injury, restored the performance of the rats in memory and learning tasks [104].…”

PKC ε Activation Prevents Synaptic Loss, Aβ Elevation, and Cognitive Deficits in Alzheimer's Disease Transgenic Mice

“…The high abundance of PKC in presynaptic nerve fibers suggests a role in neurite outgrowth, synapse formation, and neurotransmitter release (Shirai et al, 2008). Nontoxic drugs activating PKC ␣ and ) can promote synaptogenesis under nonpathological conditions and prevent synaptic loss under pathological conditions (Hongpaisan and Alkon, 2007;Sun et al, 2008Sun et al, , 2009. PKC activity and expression levels are lower in the cerebral cortex of AD patients (Saitoh et al, 1989;Matsushima et al, 1996).…”

Design, synthesis, and evaluation of potent bryostatin analogs that modulate PKC translocation selectivity

“…(36) and other neurodegenerative disorders (37). Bryostatin also exhibits neuroprotective capabilities in animal models of cerebral ischemia, indicating its potential use for minimizing the destructive neurological effects of stroke (38). Of special recent significance, bryostatin, not unlike prostratin (39), has been found to activate latent HIV reservoirs, providing a potential strategy for the eradication of HIV (40).…”