Effects of protein kinase A and G inhibitors on hippocampal cholinergic markers expressions in rolipram- and sildenafil-induced spatial memory improvement

Hosseini-Sharifabad, Ali; Ghahremani, Mohammad Hossein; Sabzevari, Omid; Naghdi, Naser; Abdollahi, Mohammad; Beyer, Cordian; Bollen, Eva; Prickaerts, Jos; Roghani, Ali; Sharifzadeh, Mohammad

doi:10.1016/j.pbb.2012.01.017

Cited by 29 publications

(19 citation statements)

References 54 publications

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“…These facts underscore the effectiveness of this reporter gene assay in identifying novel small molecules with memory enhancing activity (Xia et al, 2009), such as rolipram (e.g. Hosseini-Sharifabad et al, 2012). …”

Section: Resultsmentioning

confidence: 96%

Crebinostat: A novel cognitive enhancer that inhibits histone deacetylase activity and modulates chromatin-mediated neuroplasticity

et al. 2013

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Long-term memory formation is known to be critically dependent upon de novo gene expression in the brain. As a consequence, pharmacological enhancement of the transcriptional processes mediating long-term memory formation provides a potential therapeutic strategy for cognitive disorders involving aberrant neuroplasticity. Here we focus on the identification and characterization of small molecule inhibitors of histone deacetylases (HDACs) as enhancers of CREB (cAMP response element-binding protein)-regulated transcription and modulators of chromatin-mediated neuroplasticity. Using a CREB reporter gene cell line, we screened a library of small molecules structurally related to known HDAC inhibitors leading to the identification of a probe we termed crebinostat that produced robust activation of CREB-mediated transcription. Further characterization of crebinostat revealed its potent inhibition of the deacetylase activity of recombinant class I HDACs 1, 2, 3, and class IIb HDAC6, with weaker inhibition of the class I HDAC8 and no significant inhibition of the class IIa HDACs 4, 5, 7, and 9. In cultured mouse primary neurons, crebinostat potently induced acetylation of both histone H3 and histone H4 as well as enhanced the expression of the CREB target gene Egr1 (early growth response 1). Using a hippocampus-dependent, contextual fear conditioning paradigm, mice systemically administered crebinostat for a ten day time period exhibited enhanced memory. To gain insight into the molecular mechanisms of memory enhancement by HDAC inhibitors, whole genome transcriptome profiling of cultured mouse primary neurons treated with crebinostat, combined with bioinformatic analyses of CREB-target genes, was performed revealing a highly connected protein-protein interaction network reflecting modules of genes important to synaptic structure and plasticity. Consistent with these findings, crebinostat treatment increased the density of synapsin-1 punctae along dendrites in cultured neurons. Finally, crebinostat treatment of cultured mouse primary neurons was found to upregulate Bdnf (brain-derived neurotrophic factor) and Grn (granulin) and downregulate Mapt (tau) gene expression—genes implicated in aging-related cognitive decline and cognitive disorders. Taken together, these results demonstrate that crebinostat provides a novel probe to modulate chromatin-mediated neuroplasticity and further suggests that pharmacological optimization of selective of HDAC inhibitors may provide an effective therapeutic approach for human cognitive disorders.

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Section: Resultsmentioning

confidence: 96%

Crebinostat: A novel cognitive enhancer that inhibits histone deacetylase activity and modulates chromatin-mediated neuroplasticity

et al. 2013

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“…Likewise, previous studies have shown that administration of sildenafil, or other PDE5 inhibitors, improves object recognition both in normal subjects, and in models of impaired cognition (reviewed in 18), and ameliorates inhibitory avoidance response in mice showing deficits in this task [53,54]. In contrast, sildenafil-induced memory improvement is abolished in animals receiving an intra-hippocampal infusion of a cGK inhibitor [27,37]. The finding that sildenafil increases cGMP levels and improves novel object recognition memory and passive avoidance learning in R6/1 mice further supports the idea that decreased hippocampal cGMP levels contribute to cognitive dysfunction in these mice.…”

Section: Discussionmentioning

confidence: 96%

Regulation of Hippocampal cGMP Levels as a Candidate to Treat Cognitive Deficits in Huntington’s Disease

et al. 2013

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Huntington’s disease (HD) patients and mouse models show learning and memory impairment associated with hippocampal dysfunction. The neuronal nitric oxide synthase/3',5'-cyclic guanosine monophosphate (nNOS/cGMP) pathway is implicated in synaptic plasticity, and in learning and memory processes. Here, we examined the nNOS/cGMP pathway in the hippocampus of HD mice to determine whether it can be a good therapeutic target for cognitive improvement in HD. We analyzed hippocampal nNOS and phosphodiesterase (PDE) 5 and 9 levels in R6/1 mice, and cGMP levels in the hippocampus of R6/1, R6/2 and HdhQ7/Q111 mice, and of HD patients. We also investigated whether sildenafil, a PDE5 inhibitor, could improve cognitive deficits in R6/1 mice. We found that hippocampal cGMP levels were 3-fold lower in 12-week-old R6/1 mice, when they show deficits in object recognition memory and in passive avoidance learning. Consistent with hippocampal cGMP levels, nNOS levels were down-regulated, while there were no changes in the levels of PDE5 and PDE9 in R6/1 mice. A single intraperitoneal injection of sildenafil (3 mg/Kg) immediately after training increased cGMP levels, and improved memory in R6/1 mice, as assessed by using the novel object recognition and the passive avoidance test. Importantly, cGMP levels were also reduced in R6/2 mouse and human HD hippocampus. Therefore, the regulation of hippocampal cGMP levels can be a suitable treatment for cognitive impairment in HD.

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“…To assess the effects of PKA on acupuncture treatment in cerebral multi-infarction model rats, we administered the drug at a concentration of 5 μmol/l, 1 μl/side, i.h. injection 3 h before applying acupuncture treatment once per day in 24-h intervals over a period of 14 days, as described previously [29].…”

Section: Drug Administrationmentioning

confidence: 99%

Hippocampal cAMP/PKA/CREB is required for neuroprotective effect of acupuncture

Shi

Yang

et al. 2015

Physiology & Behavior

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Effects of protein kinase A and G inhibitors on hippocampal cholinergic markers expressions in rolipram- and sildenafil-induced spatial memory improvement

Cited by 29 publications

References 54 publications

Crebinostat: A novel cognitive enhancer that inhibits histone deacetylase activity and modulates chromatin-mediated neuroplasticity

Crebinostat: A novel cognitive enhancer that inhibits histone deacetylase activity and modulates chromatin-mediated neuroplasticity

Regulation of Hippocampal cGMP Levels as a Candidate to Treat Cognitive Deficits in Huntington’s Disease

Hippocampal cAMP/PKA/CREB is required for neuroprotective effect of acupuncture

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