The Phosphodiesterase 9 Inhibitor PF‐04449613 Promotes Dendritic Spine Formation and Performance Improvement after Motor Learning

Lai, Baoling; Li, Miao; Hu, Wanling; Li, Wei; Gan, Wen‐Biao

doi:10.1002/dneu.22623

Cited by 4 publications

(2 citation statements)

References 75 publications

(135 reference statements)

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“…Conversion of early LTP signaling to late LTP supported by cGMP might explain the improvement in episodic memory performance 24 hours after a single dose of BI 409306 in the present study. This might also indicate that BI 409306 improves long-term memory performance through cGMP-mediated promotion of synaptic plasticity, including structural changes such as enhanced development of dendritic spines and synapses, which has been demonstrated in cultured hippocampal neurons and in cortical pyramidal neurons in mice following PDE9A inhibition (Hutson et al, 2011;Lai et al, 2018).…”

Section: Discussionmentioning

confidence: 84%

The Novel Phosphodiesterase 9A Inhibitor BI 409306 Increases Cyclic Guanosine Monophosphate Levels in the Brain, Promotes Synaptic Plasticity, and Enhances Memory Function in Rodents

Rosenbrock

Giovannini

Schänzle

et al. 2019

J Pharmacol Exp Ther

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N-methyl-D-aspartate (NMDA) receptor-dependent long-term potentiation (LTP) is an established cellular model underlying learning and memory, and involves intracellular signaling mediated by the second messenger cyclic guanosine monophosphate (cGMP). As phosphodiesterase (PDE)9A selectively hydrolyses cGMP in areas of the brain related to cognition, PDE9A inhibitors may improve cognitive function by enhancing NMDA receptor-dependent LTP. This study aimed to pharmacologically characterize BI 409306, a novel PDE9A inhibitor, using in vitro assays and in vivo determination of cGMP levels in the brain. Further, the effects of BI 409306 on synaptic plasticity evaluated by LTP in ex vivo hippocampal slices and on cognitive performance in rodents were also investigated. In vitro assays demonstrated that BI 409306 is a potent and selective inhibitor of human and rat PDE9A with mean concentrations at half-maximal inhibition (IC 50) of 65 and 168 nM. BI 409306 increased cGMP levels in rat prefrontal cortex and cerebrospinal fluid and attenuated a reduction in mouse striatum cGMP induced by the NMDA-receptor antagonist MK-801. In ex vivo rat brain slices, BI 409306 enhanced LTP induced by both weak and strong tetanic stimulation. Treatment of mice with BI 409306 reversed MK-801-induced working memory deficits in a T-maze spontaneous-alternation task and improved long-term memory in an object recognition task. These findings suggest that BI 409306 is a potent and selective inhibitor of PDE9A. BI 409306 shows target engagement by increasing cGMP levels in brain, facilitates synaptic plasticity as demonstrated by enhancement of hippocampal LTP, and improves episodic and working memory function in rodents. SIGNIFICANCE STATEMENT This preclinical study demonstrates that BI 409306 is a potent and selective PDE9A inhibitor in rodents. Treatment with BI 409306 increased brain cGMP levels, promoted long-term potentiation, and improved episodic and working memory performance in rodents. These findings support a role for PDE9A in synaptic plasticity and cognition. The potential benefits of BI 409306 are currently being investigated in clinical trials.

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Section: Discussionmentioning

confidence: 84%

The Novel Phosphodiesterase 9A Inhibitor BI 409306 Increases Cyclic Guanosine Monophosphate Levels in the Brain, Promotes Synaptic Plasticity, and Enhances Memory Function in Rodents

Rosenbrock

Giovannini

Schänzle

et al. 2019

J Pharmacol Exp Ther

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“…Lgr5-EGFP-IRES-CreERT2 mice (Stock #008875, Jackson Laboratory) [4,70,71], Sox2-CreER mice (Stock #017593, Jackson Laboratory) [14], and Rosa26-tdTomato reporter mice (Stock #007914, Jackson Laboratory) [4,72] of both sexes were used in the experiments. The mouse breeding strategy is shown in Fig.…”

Section: Animalsmentioning

confidence: 99%

Knockdown of Foxg1 in supporting cells increases the trans-differentiation of supporting cells into hair cells in the neonatal mouse cochlea

Zhang

Dong

et al. 2019

Cell. Mol. Life Sci.

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Foxg1 is one of the forkhead box genes that are involved in morphogenesis, cell fate determination, and proliferation, and Foxg1 was previously reported to be required for morphogenesis of the mammalian inner ear. However, Foxg1 knock-out mice die at birth, and thus the role of Foxg1 in regulating hair cell (HC) regeneration after birth remains unclear. Here we used Sox2 CreER/+ Foxg1 loxp/loxp mice and Lgr5-EGFP CreER/+ Foxg1 loxp/loxp mice to conditionally knock down Foxg1 specifically in Sox2+ SCs and Lgr5+ progenitors, respectively, in neonatal mice. We found that Foxg1 conditional knockdown (cKD) in Sox2+ SCs and Lgr5+ progenitors at postnatal day (P)1 both led to large numbers of extra HCs, especially extra inner HCs (IHCs) at P7, and these extra IHCs with normal hair bundles and synapses could survive at least to P30. The EdU assay failed to detect any EdU+ SCs, while the SC number was significantly decreased in Foxg1 cKD mice, and lineage tracing data showed that much more tdTomato+ HCs originated from Sox2+ SCs in Foxg1 cKD mice compared to the control mice. Moreover, the sphere-forming assay showed that Foxg1 cKD in Lgr5+ progenitors did not significantly change their sphereforming ability. All these results suggest that Foxg1 cKD promotes HC regeneration and leads to large numbers of extra HCs probably by inducing direct trans-differentiation of SCs and progenitors to HCs. Real-time qPCR showed that cell cycle and Notch signaling pathways were significantly down-regulated in Foxg1 cKD mice cochlear SCs. Together, this study provides new evidence for the role of Foxg1 in regulating HC regeneration from SCs and progenitors in the neonatal mouse cochlea.

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Phosphodiesterase-5 inhibitors: Shedding new light on the darkness of depression?

Duarte-Silva

Filho

Barichello

et al. 2020

Journal of Affective Disorders

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The Phosphodiesterase 9 Inhibitor PF‐04449613 Promotes Dendritic Spine Formation and Performance Improvement after Motor Learning

Cited by 4 publications

References 75 publications

The Novel Phosphodiesterase 9A Inhibitor BI 409306 Increases Cyclic Guanosine Monophosphate Levels in the Brain, Promotes Synaptic Plasticity, and Enhances Memory Function in Rodents

The Novel Phosphodiesterase 9A Inhibitor BI 409306 Increases Cyclic Guanosine Monophosphate Levels in the Brain, Promotes Synaptic Plasticity, and Enhances Memory Function in Rodents

Knockdown of Foxg1 in supporting cells increases the trans-differentiation of supporting cells into hair cells in the neonatal mouse cochlea

Phosphodiesterase-5 inhibitors: Shedding new light on the darkness of depression?

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