Chronic Cognitive Dysfunction after Traumatic Brain Injury Is Improved with a Phosphodiesterase 4B Inhibitor

Titus, David J.; Wilson, Nicole M.; Freund, Julie E.; Carballosa, Melissa M.; Sikah, Kevin E.; Furones, Concepción; Dietrich, W. Dalton; Gurney, Mark E.; Atkins, Coleen M.

doi:10.1523/jneurosci.3212-15.2016

Cited by 49 publications

(59 citation statements)

References 69 publications

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“…Furthermore, A33 levels were nearly 2-fold higher in the injured brain than in the uninjured. The increased distribution of A33 in the acutely injured brain are contrary to what was previously observed in chronic A33-treated animals, where there was no significant difference in brain A33 levels in sham versus TBI animals [50]. The increased levels of A33 in the injured brain are likely due to blood-brain barrier (BBB) breakdown at this early time point after TBI [71].…”

Section: Discussionmentioning

confidence: 90%

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Therapeutic benefits of phosphodiesterase 4B inhibition after traumatic brain injury

et al. 2017

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Traumatic brain injury (TBI) initiates a deleterious inflammatory response that exacerbates pathology and worsens outcome. This inflammatory response is partially mediated by a reduction in cAMP and a concomitant upregulation of cAMP-hydrolyzing phosphodiesterases (PDEs) acutely after TBI. The PDE4B subfamily, specifically PDE4B2, has been found to regulate cAMP in inflammatory cells, such as neutrophils, macrophages and microglia. To determine if PDE4B regulates inflammation and subsequent pathology after TBI, adult male Sprague Dawley rats received sham surgery or moderate parasagittal fluid-percussion brain injury (2 ± 0.2 atm) and were then treated with a PDE4B - selective inhibitor, A33, or vehicle for up to 3 days post-surgery. Treatment with A33 reduced markers of microglial activation and neutrophil infiltration at 3 and 24 hrs after TBI, respectively. A33 treatment also reduced cortical contusion volume at 3 days post-injury. To determine whether this treatment paradigm attenuated TBI-induced behavioral deficits, animals were evaluated over a period of 6 weeks after surgery for forelimb placement asymmetry, contextual fear conditioning, water maze performance and spatial working memory. A33 treatment significantly improved contextual fear conditioning and water maze retention at 24 hrs post-training. However, this treatment did not rescue sensorimotor or working memory deficits. At 2 months after surgery, atrophy and neuronal loss were measured. A33 treatment significantly reduced neuronal loss in the pericontusional cortex and hippocampal CA3 region. This treatment paradigm also reduced cortical, but not hippocampal, atrophy. Overall, these results suggest that acute PDE4B inhibition may be a viable treatment to reduce inflammation, pathology and memory deficits after TBI.

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Section: Discussionmentioning

confidence: 90%

“…A33 has a half-life of approximately 3.8–4.5 hrs in the mouse brain, and is over 50-fold more selective for PDE4B (IC 50 = 27 nM) over PDE4D (IC 50 = 1569 nM) and other PDEs (IC 50 > 10μM) [49, 50]. This selectivity is due to a single amino acid polymorphism in the C-terminus of PDE4B, termed CR3 (Control Region 3) [49, 51].…”

Section: Introductionmentioning

confidence: 99%

Therapeutic benefits of phosphodiesterase 4B inhibition after traumatic brain injury

et al. 2017

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“…Previous studies found that PDE4 inhibition at 2 weeks (Titus et al, 2013b) and 3 months (Titus et al, 2016) post-FPI improved both LTP in vitro and cognition in vivo . This contrasts with our observation that delayed PDE4 inhibition (23 h post-injury) did not prevent blast-induced LTP deficits.…”

Section: Discussionmentioning

confidence: 99%

“…Alternative PDE4 inhibitors (piclamilast, ibudilast) similarly preserved plasticity. Although no other study has investigated the therapeutic potential of PDE4 inhibition after blast, several studies have observed that PDE4 inhibition preserved LTP measured 2 weeks and 12 weeks following FPI in rats (Titus et al, 2013b; Titus et al, 2016). The effectiveness of either ibudilast or piclamilast following TBI is unknown; however, ibudilast prevented LTP-deficits in cortical cell cultures after microglia activation (Mizuno et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Phosphodiesterase-4 inhibition restored hippocampal long term potentiation after primary blast

Vogel

Morales

Meaney

et al. 2017

Experimental Neurology

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Due to recent military conflicts and terrorist attacks, blast-induced traumatic brain injury (bTBI) presents a health concern for military and civilian personnel alike. Although secondary blast (penetrating injury) and tertiary blast (inertia-driven brain deformation) are known to be injurious, the effects of primary blast caused by the supersonic shock wave interacting with the skull and brain remain debated. Our group previously reported that in vitro primary blast exposure reduced long-term potentiation (LTP), the electrophysiological correlate of learning and memory, in rat organotypic hippocampal slice cultures (OHSCs) and that primary blast affects key proteins governing LTP. Recent studies have investigated phosphodiesterase-4 (PDE4) inhibition as a therapeutic strategy for reducing LTP deficits following inertia-driven TBI. We investigated the therapeutic potential of PDE4 inhibitors, specifically roflumilast, to ameliorate primary blast-induced deficits in LTP. We found that roflumilast at concentrations of 1 nM or greater prevented deficits in neuronal plasticity measured 24 h post-injury. We also observed a therapeutic window of at least 6 h, but <23 h. Additionally, we investigated molecular mechanisms that could elucidate this therapeutic effect. Roflumilast treatment (1 nM delivered 6 h post-injury) significantly increased total AMPA glutamate receptor 1 (GluR1) subunit expression, phosphorylation of the GluR1 subunit at the serine-831 site, and phosphorylation of stargazin at the serine-239/240 site upon LTP induction, measured 24 h following injury. Roflumilast treatment significantly increased PSD-95 regardless of LTP induction. These findings indicate that further investigation into the translation of PDE4 inhibition as a therapy following bTBI is warranted.

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“…Regarding PDE4 subtypes, PDE4D is considered to be related to cognitive improvement [34,35] while PDE4B is also considered to be involved in the cognitive function [36]. It would be worth investigating in future the relationship among treatment with roflumilast, PDE4 occupancy, and effects on cognitive domains in preclinical and clinical settings.…”

Section: Discussionmentioning

confidence: 99%

A Nonhuman Primate PET Study: Measurement of Brain PDE4 Occupancy by Roflumilast Using (R)-[11C]Rolipram

Takano

Garcia‐Segovia

et al. 2018

Mol Imaging Biol

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Purpose: Phosphodiesterase 4 (PDE4) inhibition in the brain has been reported to improve cognitive function in animal models. Therefore, PDE4 inhibitors are one of key targets potential for drug development. Investigation of brain PDE4 occupancy would help to understand the effects of PDE4 inhibition to cognitive functions. Roflumilast is a selective phosphodiesterase type 4 (PDE4) inhibitor used clinically for severe chronic obstructive pulmonary disease, but the effects to the brain have not been well investigated. In this study, we aimed to investigate whether roflumilast entered the brain and occupied PDE4 in nonhuman primates. Procedures: Positron emission tomography (PET) measurements with (R)-[11 C]rolipram were performed at baseline and after intravenous (i.v.) administration of roflumilast (3.6 to 200 μg/kg) in three female rhesus monkeys. Arterial blood samples were taken to obtain the input function. Protein binding was measured to obtain the free fraction (fp) of the radioligand. Total distribution volume (V T ) and V T /fp were calculated as outcome measures from two tissue compartment model. Lassen plot approach was taken to estimate the target occupancy.Results: The brain uptake of (R)-[ 11 C]rolipram decreased after roflumilast administration. PDE 4 occupancy by roflumilast showed dose-and plasma concentration-dependent increase, although PDE4 occupancy did not reach 50 % even after the administration of up to 200 μg/ kg of roflumilast, regardless of outcome measures, V T or V T /fp. Conclusions: This PET study showed that the brain PDE4 binding was blocked to a certain extent after i.v. administration of clinical relevant doses of roflumilast in nonhuman primates.Further clinical PET evaluation is needed to understand the relationship between PDE4 inhibition and potential improvement of cognitive function in human subjects.

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Chronic Cognitive Dysfunction after Traumatic Brain Injury Is Improved with a Phosphodiesterase 4B Inhibitor

Cited by 49 publications

References 69 publications

Therapeutic benefits of phosphodiesterase 4B inhibition after traumatic brain injury

Therapeutic benefits of phosphodiesterase 4B inhibition after traumatic brain injury

Phosphodiesterase-4 inhibition restored hippocampal long term potentiation after primary blast

A Nonhuman Primate PET Study: Measurement of Brain PDE4 Occupancy by Roflumilast Using (R)-[11C]Rolipram

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