Bryostatin Improves Survival and Reduces Ischemic Brain Injury in Aged Rats After Acute Ischemic Stroke

Abstract

Background and Purpose Bryostatin, a potent protein kinase C (PKC) activator, has demonstrated therapeutic efficacy in preclinical models of associative memory, Alzheimer's disease, global ischemia, and traumatic brain injury. In this study, we tested the hypothesis that administration of bryostatin provides a therapeutic benefit in reducing brain injury and improving stroke outcome using a clinically relevant model of cerebral ischemia with tissue plasminogen activator (tPA) reperfusion in aged rats. Methods Acute cerebral ischemia was produced by reversible occlusion of the right middle cerebral artery (MCAO) in 18-20 month old female Sprague-Dawley rats using an autologous blood clot with tPA-mediated reperfusion. Bryostatin was administered at 6 h post-MCAO then at 3, 6, 9, 12, 15, and 18 d after MCAO. Functional assessment was conducted at 2, 7, 14, and 21 d after MCAO. Lesion volume and hemispheric swelling/atrophy were performed at 2, 7, and 21 d post-MCAO. Histological assessment of PKC isozymes was performed at 24 h post-MCAO. Results Bryostatin-treated rats showed improved survival post-MCAO, especially during the first 4 d. Repeated administration of bryostatin post-MCAO resulted in reduced infarct volume, hemispheric swelling/atrophy, and improved neurological function at 21 d post-MCAO. Changes in PKC alpha expression and PKC epsilon expression in neurons were noted in bryostatin-treated rats at 24 h post-MCAO. Conclusions Repeated bryostatin administration post-MCAO protected the brain from severe neurological injury post-MCAO. Bryostatin treatment improved survival rate, reduced lesion volume, salvaged tissue in infarcted hemisphere by reducing necrosis and peri-infarct astrogliosis, and improved functional outcome following MCAO.

Treatment with Enriched Environment Reduces Neuronal Apoptosis in the Periinfarct Cortex after Cerebral Ischemia/Reperfusion Injury

“…As apoptosis is one of the major causes that lead to cell death after I/R injury especially in the periinfarct cortex [26], suppressing apoptosis may be an effective way to improve the survival rate of neurons and eventually benefit the prognosis after stroke. Previous studies have demonstrated that cellular apoptosis can be inhibited by medicines or stem cell transplantation in animal models of cerebral ischemia [27-29]. This study for the first time evaluated EE treatment-induced inhibition of neuronal apoptosis in the periinfarct cortex after cerebral I/R injury, which offered a new insight into the underlying mechanism of EE’s neuroprotective effect.…”

Traumatic Brain Injury Induces Alterations in Cortical Glutamate Uptake without a Reduction in Glutamate Transporter-1 Protein Expression

“…35 A third study found increased expression of PKC isoforms in the left prefrontal cortex 24 hours following blast exposure TBI, with an increase in PKC and a decrease in PKC protein levels after treatment with the PKC modulator bryostatin-1. [64][65][66] These data were interpreted as indicating increased blood brain barrier permeability. 64 Similar to AKT, the cellular specificity, subcellular localization, and temporal changes in This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction.…”

Common Mechanisms of Alzheimer's Disease and Ischemic Stroke: The Role of Protein Kinase C in the Progression of Age-Related Neurodegeneration

“…Curcumin inhibits neuroinflammation by mitigating PKC induced toll-like receptor activation [147]. Our laboratory has shown that the PKC modulator, bryostatin-1, given post-MCAO increased PKC ε in an aged-female rat model, improves survival, decreases infarct volume, and leads to an increase in salvageable tissue [148]. At low doses bryostatin activates PKC isoforms, but in excess it has an inhibitory effect.…”