CREB: a multifaceted regulator of neuronal plasticity and protection

Sakamoto, Kensuke; Karelina, Kate; Obrietan, Karl

doi:10.1111/j.1471-4159.2010.07080.x

Cited by 434 publications

(294 citation statements)

References 121 publications

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“…20 Increased BDNF levels are associated with enhanced CREB activity. 21 Combined treatment with CX1837 and local hydrogel delivery of BDNF resulted in a phosphorylation of CREB.…”

Section: Combined Hydrogel Delivery Of Brain-derived Neurotrophic Facmentioning

confidence: 99%

Combined Ampakine and BDNF Treatments Enhance Poststroke Functional Recovery in Aged Mice via AKT-CREB Signaling

Clarkson

Parker

Nilsson

et al. 2015

J Cereb Blood Flow Metab

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Cerebral ischemia results in damage to neuronal circuits and lasting impairment in function. We have previously reported that stimulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors with the ampakine, CX1837, increases brainderived neurotrophic factor (BDNF) levels and affords significant motor recovery after stroke in young mice. Here, we investigated whether administration of CX1837 in aged (24 months old) mice was equally effective. In a model of focal ischemia, administration of CX1837 from 5 days after stroke resulted in a small gain of motor function by week 6 after stroke. Mice that received a local delivery of BDNF via hydrogel implanted into the stroke cavity also showed a small gain of function from 4 to 6 weeks after stroke. Combining both treatments, however, resulted in a marked improvement in motor function from 2 weeks after insult. Assessment of peri-infarct tissue 2 weeks after stroke revealed a significant increase in p-AKT and p-CREB after the combined drug treatment. Using the pan-AKT inhibitor, GSK-690693, or deletion of CREB from forebrain neurons using the CREB-flox/CAMKii-cre mice, we were able to block the recovery of motor function. These data suggest that combined CX1837 and local delivery of BDNF are required to achieve maximal functional recovery after stroke in aged mice, and is occurring via the AKT-GSK3-CREB signaling pathway.

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“…20 Increased BDNF levels are associated with enhanced CREB activity. 21 Combined treatment with CX1837 and local hydrogel delivery of BDNF resulted in a phosphorylation of CREB.…”

Section: Combined Hydrogel Delivery Of Brain-derived Neurotrophic Facmentioning

confidence: 99%

Combined Ampakine and BDNF Treatments Enhance Poststroke Functional Recovery in Aged Mice via AKT-CREB Signaling

Clarkson

Parker

Nilsson

et al. 2015

J Cereb Blood Flow Metab

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show abstract

“…123 Rolipram inhibits the high-affinity, cAMP-specific PDE4, and it was the first PDE inhibitor tested in an animal model of AD, improving synaptic and cognitive functions in the double transgenic APP/ PS1. 103 Further studies with rolipram 124 and cilostazol, a PDE3 inhibitor, 104,105 linked their efficacy to the pCREB-mediated reversal of amyloid-beta-induced cognitive deficits.…”

Section: Pde Inhibitors In Alzheimer's Diseasementioning

confidence: 99%

Phosphodiesterases as Therapeutic Targets for Alzheimer's Disease

García‐Osta¹,

Cuadrado‐Tejedor²,

García‐Barroso³

et al. 2012

ACS Chem. Neurosci.

233

179

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Alzheimer's disease (AD) is the most common form of dementia among the elderly. In AD patients, memory loss is accompanied by the formation of beta-amyloid plaques and the appearance of tau in a pathological form. Given the lack of effective treatments for AD, the development of new management strategies for these patients is critical. The continued failure to find effective therapies using molecules aimed at addressing the anti-beta amyloid pathology has led researchers to focus on other non-amyloid-based approaches to restore memory function. Promising non-amyloid related candidate targets include phosphosdiesterases (PDEs), and indeed, Rolipram, a specific PDE4 inhibitor, was the first compound found to effectively restore cognitive deficits in animal models of AD. More recently, PDE5 inhibitors have also been shown to effectively restore memory function. Accordingly, inhibitors of other members of the PDE family may also improve memory performance in AD and non-AD animal models. Hence, in this review, we will summarize the data supporting the use of PDE inhibitors as cognitive enhancers and we will discuss the possible mechanisms of action underlying these effects. We shall also adopt a medicinal chemistry perspective that leads us to propose the most promising PDE candidates on the basis of inhibitor selectivity, brain distribution, and mechanism of action.

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“…These mechanisms facilitate the adaptation of neuronal gene expression patterns according to experience, broadening the functions of neuronal networks. Indeed, transcriptional regulations are required in LTM formation in vivo [170,171], as in ex vivo models of synaptic plasticity (LTP) [172,173], and are highly dependent of CREB and NFκB activities [174,175]. Among these regulations, histone acetylation plays an important and well-characterized role, whereby both HATs and HDACs are key regulators of cognitive processes.…”

Section: Hat In Synaptic Plasticity and Memorymentioning

confidence: 99%

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

et al. 2013

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The acetylation of histone and non-histone proteins controls a great deal of cellular functions, thereby affecting the entire organism, including the brain. Acetylation modifications are mediated through histone acetyltransferases (HAT) and deacetylases (HDAC), and the balance of these enzymes regulates neuronal homeostasis, maintaining the pre-existing acetyl marks responsible for the global chromatin structure, as well as regulating specific dynamic acetyl marks that respond to changes and facilitate neurons to encode and strengthen longterm events in the brain circuitry (e.g., memory formation). Unfortunately, the dysfunction of these finely-tuned regulations might lead to pathological conditions, and the deregulation of the HAT/HDAC balance has been implicated in neurological disorders. During the last decade, research has focused on HDAC inhibitors that induce a histone hyperacetylated state to compensate acetylation deficits. The use of these inhibitors as a therapeutic option was efficient in several animal models of neurological disorders. The elaboration of new cell-permeant HAT activators opens a new era of research on acetylation regulation. Although pathological animal models have not been tested yet, HAT activator molecules have already proven to be beneficial in ameliorating brain functions associated with learning and memory, and adult neurogenesis in wild-type animals. Thus, HAT activator molecules contribute to an exciting area of research.

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CREB: a multifaceted regulator of neuronal plasticity and protection

Cited by 434 publications

References 121 publications

Combined Ampakine and BDNF Treatments Enhance Poststroke Functional Recovery in Aged Mice via AKT-CREB Signaling

Combined Ampakine and BDNF Treatments Enhance Poststroke Functional Recovery in Aged Mice via AKT-CREB Signaling

Phosphodiesterases as Therapeutic Targets for Alzheimer's Disease

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

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