The phosphodiesterase-4 inhibitor, FCPR16, attenuates ischemia-reperfusion injury in rats subjected to middle cerebral artery occlusion and reperfusion

Chen, Jiajia; Yu, Hui; Zhong, Jiahong; Feng, Hong-Fang; Wang, Haitao; Cheng, Yufang; Zou, Zhengqiang; Huang, Chang; Zhou, Zhong‐Zhen; Zheng, Wenhua

doi:10.1016/j.brainresbull.2017.11.010

Cited by 31 publications

(27 citation statements)

References 44 publications

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“…FCPR16 shows higher PDE4 inhibitory activity (IC 50 = 90 nM) compared with canonical PDE4 inhibitor rolipram (IC 50 = 550 nM). We also found that FCPR16 had protective effects against cerebral ischemia-reperfusion injury through inhibiting inflammation and neuronal apoptosis in the brain in rats [33] . Most importantly, FCPR16 has low emetogenic potential, Our previous studies showed that oral administration of FCPR16 (3 mg/kg) did not induce vomiting in beagle dogs [33] .…”

Section: Introductionmentioning

confidence: 53%

“…We also found that FCPR16 had protective effects against cerebral ischemia-reperfusion injury through inhibiting inflammation and neuronal apoptosis in the brain in rats [33] . Most importantly, FCPR16 has low emetogenic potential, Our previous studies showed that oral administration of FCPR16 (3 mg/kg) did not induce vomiting in beagle dogs [33] . FCPR16 displays at least 600-fold selectivity for PDE4B and 1111-fold selectivity for PDE4D over other PDEs (PDE1-3 and PDE5-11) [31] , while PDE4B is the most abundant isoform in the basal ganglia and PDE4D expression is also observed in the basal ganglia [34] .…”

Section: Introductionmentioning

confidence: 53%

“…Additionally, astrocytes play direct and critical roles in mediating neuronal survival and function in PD [58] , and astrocytes also mediates oxidative stress in the models of PD [59] . Interestingly, our previous study showed that FCPR16 suppressed the activation of astrocytes in the brain [33] . It is worth to study the role of FCPR16 or other PDE4 inhibitor in Redox regulation in astrocytes in both cellular and animal models of PD.…”

Section: Discussionmentioning

confidence: 92%

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Inhibition of phosphodiesterase 4 by FCPR16 protects SH-SY5Y cells against MPP+-induced decline of mitochondrial membrane potential and oxidative stress

Zhong

Huang

et al. 2018

Redox Biology

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Phosphodiesterase 4 (PDE4) is a promising target for the treatment of Parkinson's disease (PD). However, the underlying mechanism has not yet been well elucidated. Additionally, most of current PDE4 inhibitors produce severe nausea and vomiting response in patients, which limit their clinical application. FCPR16 is a novel PDE4 inhibitor with little emetic potential. In the present study, the neuroprotective effect and underlying mechanism of FCPR16 against cellular apoptosis induced by 1-methyl-4-phenylpyridinium (MPP+) were examined in SH-SY5Y cells. FCPR16 (12.5–50 μM) dose-dependently reduced MPP+-induced loss of cell viability, accompanied by reductions in nuclear condensation and lactate dehydrogenase release. The level of cleaved caspase 3 and the ratio of Bax/Bcl-2 were also decreased after treatment with FCPR16 in MPP+-treated cells. Furthermore, FCPR16 (25 μM) significantly suppressed the accumulation of reactive oxygen species (ROS), prevented the decline of mitochondrial membrane potential (Δψm) and attenuated the expression of malonaldehyde level. Further studies disclosed that FCPR16 enhanced the levels of cAMP and the exchange protein directly activated by cAMP (Epac) in SH-SY5Y cells. Western blotting analysis revealed that FCPR16 increased the phosphorylation of cAMP response element-binding protein (CREB) and protein kinase B (Akt) down-regulated by MPP+ in SH-SY5Y cells. Moreover, the inhibitory effects of FCPR16 on the production of ROS and Δψm loss could be blocked by PKA inhibitor H-89 and Akt inhibitor KRX-0401. Collectively, these results suggest that FCPR16 attenuates MPP+-induced dopaminergic degeneration via lowering ROS and preventing the loss of Δψm in SH-SY5Y cells. Mechanistically, cAMP/PKA/CREB and Epac/Akt signaling pathways are involved in these processes. Our findings indicate that FCPR16 is a promising pre-clinical candidate for the treatment of PD and possibly other oxidative stress-related neuronal diseases.

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Section: Introductionmentioning

confidence: 53%

Section: Introductionmentioning

confidence: 53%

Section: Discussionmentioning

confidence: 92%

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Inhibition of phosphodiesterase 4 by FCPR16 protects SH-SY5Y cells against MPP+-induced decline of mitochondrial membrane potential and oxidative stress

Zhong

Huang

et al. 2018

Redox Biology

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“…). Other nervous system disorders for which preclinical evidence suggests a therapeutic potential of PDE4i's include ischemic stroke(132,(137)(138)(139)(140), traumatic brain injury(141), axon regeneration(142), and substance abuse disorders (both causes and consequences,(143)(144)(145)(146)). …”

mentioning

confidence: 99%

Therapeutic targeting of 3′,5′-cyclic nucleotide phosphodiesterases: inhibition and beyond

Baillie

Tejeda

Kelly

2019

Nat Rev Drug Discov

235

295

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“…Also, in stroke PDE4 inhibitors have been found to attenuate the impact of the lesion in animal models. For example, in an ischemic stroke model in rats the PDE4 inhibitor FCPR16 reduced the level of pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) [ 46 ]. Next to these effects on the inflammatory response, CREB phosphorylation was increased and infarct volume reduced.…”

Section: Neuroinflammation In Abimentioning

confidence: 99%

A Mechanistic Rationale for PDE-4 Inhibitors to Treat Residual Cognitive Deficits in Acquired Brain Injury

Schreiber

Hollands

Blokland

2020

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Patients with acquired brain injury (ABI) suffer from cognitive deficits that interfere significantly with their daily lives. These deficits are long-lasting and no treatment options are available. A better understanding of the mechanistic basis for these cognitive deficits is needed to develop novel treatments. Intracellular cyclic adenosine monophosphate (cAMP) levels are decreased in ABI. Herein, we focus on augmentation of cAMP by PDE4 inhibitors and the potentially synergistic mechanisms in traumatic brain injury. A major acute pathophysiological event in ABI is the breakdown of the blood-brain-barrier (BBB). Intracellular cAMP pathways are involved in the subsequent emergence of edema, inflammation and hyperexcitability. We propose that PDE4 inhibitors such as roflumilast can improve cognition by modulation of the activity in the cAMPPhosphokinase A-Ras-related C3 botulinum toxin substrate (RAC1) inflammation pathway. In addition, PDE4 inhibitors can also directly enhance network plasticity and attenuate degenerative processes and cognitive dysfunction by increasing activity of the canonical cAMP/phosphokinase- A/cAMP Responsive Element Binding protein (cAMP/PKA/CREB) plasticity pathway. Doublecourtin and microtubule-associated protein 2 are generated following activation of the cAMP/PKA/CREB pathway and are decreased or even absent after injury. Both proteins are involved in neuronal plasticity and may consist of viable markers to track these processes. It is concluded that PDE4 inhibitors may consist of a novel class of drugs for the treatment of residual symptoms in ABI attenuating the pathophysiological consequences of a BBB breakdown by their anti-inflammatory actions via the cAMP/PKA/RAC1 pathway and by increasing synaptic plasticity via the cAMP/PKA/CREB pathway. Roflumilast improves cognition in young and elderly humans and would be an excellent candidate for a proof of concept study in ABI patients.

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The phosphodiesterase-4 inhibitor, FCPR16, attenuates ischemia-reperfusion injury in rats subjected to middle cerebral artery occlusion and reperfusion

Cited by 31 publications

References 44 publications

Inhibition of phosphodiesterase 4 by FCPR16 protects SH-SY5Y cells against MPP+-induced decline of mitochondrial membrane potential and oxidative stress

Inhibition of phosphodiesterase 4 by FCPR16 protects SH-SY5Y cells against MPP+-induced decline of mitochondrial membrane potential and oxidative stress

Therapeutic targeting of 3′,5′-cyclic nucleotide phosphodiesterases: inhibition and beyond

A Mechanistic Rationale for PDE-4 Inhibitors to Treat Residual Cognitive Deficits in Acquired Brain Injury

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