PKC activators enhance GABAergic neurotransmission and paired-pulse facilitation in hippocampal CA1 pyramidal neurons

Xu, Changqing; Liu, Q.-Y.; Alkon, Daniel L.

doi:10.1016/j.neuroscience.2014.03.008

Cited by 17 publications

(9 citation statements)

References 40 publications

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“…Although PKC modulation has not been extensively studied in TBI models, in an Alzheimer’s disease model it increased PKCε, which facilitated amyloid β plaque degradation by increasing the enzyme neprilysin [25]. It also enhanced gabaergic signaling improving learning and memory through PKCα modulation and decreased synaptic loss [26, 27]. Following ischemic stroke, bryostatin-1 modulated PKCα and PKCε to enhance survival and reduce edema in aged Sprague–Dawley rats [28].…”

Section: Introductionmentioning

confidence: 99%

Bryostatin-1 Restores Blood Brain Barrier Integrity following Blast-Induced Traumatic Brain Injury

et al. 2014

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Recent wars in Iraq and Afghanistan have accounted for an estimated 270,000 blast exposures among military personnel. Blast traumatic brain injury (TBI) is the ‘signature injury’ of modern warfare. Blood brain barrier (BBB) disruption following blast TBI can lead to long-term and diffuse neuroinflammation. In this study, we investigate for the first time the role of bryostatin-1, a specific protein kinase C (PKC) modulator, in ameliorating BBB breakdown. Thirty seven Sprague–Dawley rats were used for this study. We utilized a clinically relevant and validated blast model to expose animals to moderate blast exposure. Groups included: control, single blast exposure, and single blast exposure + bryostatin-1. Bryostatin-1 was administered i.p. 2.5 mg/kg after blast exposure. Evan’s blue, immunohistochemistry, and western blot analysis were performed to assess injury. Evan’s blue binds to albumin and is a marker for BBB disruption. The single blast exposure caused an increase in permeability compared to control (t=4.808, p<0.05), and a reduction back toward control levels when bryostatin-1 was administered (t=5.113, p<0.01). Three important PKC isozymes, PKCα, PKCδ, and PKCε, were co-localized primarily with endothelial cells but not astrocytes. Bryostatin-1 administration reduced toxic PKCα levels back toward control levels (t=4.559, p<0.01) and increased the neuroprotective isozyme PKCε (t=6.102, p<0.01). Bryostatin-1 caused a significant increase in the tight junction proteins VE-cadherin, ZO-1, and occludin through modulation of PKC activity. Bryostatin-1 ultimately decreased BBB breakdown potentially due to modulation of PKC isozymes. Future work will examine the role of bryostatin-1 in preventing chronic neurodegeneration following repetitive neurotrauma.

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Section: Introductionmentioning

confidence: 99%

Bryostatin-1 Restores Blood Brain Barrier Integrity following Blast-Induced Traumatic Brain Injury

et al. 2014

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“… 3 Indeed, preliminary data on the properties of bryostatin 1 for cancer therapy showed such promise that a Good Manufacturing Processes campaign was undertaken, wherein 18 g of bryostatin 1 was isolated from a collection of 10,000 gallons of wet bryozoan. 4 This supply of material has supported dozens of phase I and phase II clinical trials against diverse cancers, 3f and in addition has led to the identification of bryostatin 1 as a promising candidate for the treatment of Alzheimer’s disease 5 and HIV. 6 …”

Section: Introductionmentioning

confidence: 99%

Synthesis of seco-B-Ring Bryostatin Analogue WN-1 via C–C Bond-Forming Hydrogenation: Critical Contribution of the B-Ring in Determining Bryostatin-like and Phorbol 12-Myristate 13-Acetate-like Properties

et al. 2014

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The seco-B-ring bryostatin analogue, macrodiolide WN-1, was prepared in 17 steps (longest linear sequence) and 30 total steps with three bonds formed via hydrogen-mediated C–C coupling. This synthetic route features a palladium-catalyzed alkoxycarbonylation of a C2-symmetric diol to form the C9-deoxygenated bryostatin A-ring. WN-1 binds to PKCα (Ki = 16.1 nM) and inhibits the growth of multiple leukemia cell lines. Although structural features of the WN-1 A-ring and C-ring are shared by analogues that display bryostatin-like behavior, WN-1 displays PMA-like behavior in U937 cell attachment and proliferation assays, as well as in K562 and MV-4-11 proliferation assays. Molecular modeling studies suggest the pattern of internal hydrogen bonds evident in bryostatin 1 is preserved in WN-1, and that upon docking WN-1 into the crystal structure of the C1b domain of PKCδ, the binding mode of bryostatin 1 is reproduced. The collective data emphasize the critical contribution of the B-ring to the function of the upper portion of the molecule in conferring a bryostatin-like pattern of biological activity.

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“…Preclinical studies show that Bry-1 is able to: enhance spatial learning and long-term memory in rats, mice, rabbits and the nudibranch ( Hermissenda ) [ 52 , 53 ]; increase spinophilin (regulatory subunit of protein phosphatase-1 catalytic subunit highly enriched in dendritic spines) and synaptophysin (major synaptic vesicle protein p38), synaptic proteins levels causing synapses structural changes [ 52 ]; exert neuroprotective effects on AD transgenic mice [ 54 ]; improve memory (measured as reduction in latency to escape, after oral Bry-1) in APP/PS1 (mice containing human transgenes for both amyloid precursor protein (APP), bearing the Swedish KM670/671NL (rs63751263, rs63750445) mutation and PSEN1 containing an L166P mutation (rs63750265), both under the control of the Thy1 promoter) transgenic mouse [ 55 ]; reduce Aβ levels in monomeric Aβ-treated cells “ in vitro ” [ 56 ]; reduce Aβ levels in Tg2576 AD mouse (mice overexpressing a mutant form of APP (isoform 695)) and aged rat recovery [ 57 ]; recover neurotrophic activity and synapses loss [ 57 ]; prevent neuronal apoptosis [ 57 ]; inhibit τ phosphorylation by GSK-3β inhibition [ 57 ]; enhance synaptogenesis, leading cognitive deficits recovery [ 57 ]. …”

Section: Drugs From Marine Organismsmentioning

confidence: 99%

“…enhance spatial learning and long-term memory in rats, mice, rabbits and the nudibranch ( Hermissenda ) [ 52 , 53 ];…”

Section: Drugs From Marine Organismsmentioning

confidence: 99%

New Drugs from Marine Organisms in Alzheimer’s Disease

et al. 2015

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Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder. Current approved drugs may only ameliorate symptoms in a restricted number of patients and for a restricted period of time. Currently, there is a translational research challenge into identifying the new effective drugs and their respective new therapeutic targets in AD and other neurodegenerative disorders. In this review, selected examples of marine-derived compounds in neurodegeneration, specifically in AD field are reported. The emphasis has been done on compounds and their possible relevant biological activities. The proposed drug development paradigm and current hypotheses should be accurately investigated in the future of AD therapy directions although taking into account successful examples of such approach represented by Cytarabine, Trabectedin, Eribulin and Ziconotide. We review a complexity of the translational research for such a development of new therapies for AD. Bryostatin is a prominent candidate for the therapy of AD and other types of dementia in humans.

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PKC activators enhance GABAergic neurotransmission and paired-pulse facilitation in hippocampal CA1 pyramidal neurons

Cited by 17 publications

References 40 publications

Bryostatin-1 Restores Blood Brain Barrier Integrity following Blast-Induced Traumatic Brain Injury

Bryostatin-1 Restores Blood Brain Barrier Integrity following Blast-Induced Traumatic Brain Injury

Synthesis of seco-B-Ring Bryostatin Analogue WN-1 via C–C Bond-Forming Hydrogenation: Critical Contribution of the B-Ring in Determining Bryostatin-like and Phorbol 12-Myristate 13-Acetate-like Properties

New Drugs from Marine Organisms in Alzheimer’s Disease

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