The Phosphodiesterase Inhibitor Rolipram Promotes Survival of Newborn Hippocampal Neurons After Ischemia

Sasaki, Tsutomu; Kitagawa, Kazuo; Omura-Matsuoka, Emi; Todo, Kenichi; Terasaki, Yasukazu; Sugiura, Shiro; Hatazawa, Jun; Yagita, Yoshiki; Hori, Masatsugu

doi:10.1161/strokeaha.106.476754

Cited by 64 publications

(43 citation statements)

References 30 publications

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“…These results are in accordance with previous results using rolipram as a therapeutic agent in spinal cord injury and transient global ischemia where lower doses were also more effective (Block et al, 1997, Nikulina et al, 2004. Rolipram has also been found to improve outcome in experimental allergic encephalomyelitis, Alzheimer disease, multiple sclerosis, ischemia, and striatal excitotoxicity (Genain et al, 1995, Navikas et al, 1998, Folcik et al, 1999, Gong et al, 2004, Demarch et al, 2007, Sasaki et al, 2007. Our results and the many studies assessing rolipram in models of neurological disorders suggest that use of a PDE IV antagonist may be a promising avenue of research as we search for a successful pharmacological therapy for TBI patients.…”

Section: Discussionsupporting

confidence: 89%

Modulation of the cAMP signaling pathway after traumatic brain injury

Atkins

Oliva

Alonso

et al. 2007

Experimental Neurology

132

150

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Traumatic brain injury (TBI) results in both focal and diffuse brain pathologies that are exacerbated by the inflammatory response and progress from hours to days after the initial injury. Using a clinically relevant model of TBI, the parasagittal fluid-percussion brain injury (FPI) model, we found injury-induced impairments in the cyclic AMP (cAMP) signaling pathway. Levels of cAMP were depressed in the ipsilateral parietal cortex and hippocampus, as well as activation of its downstream target, protein kinase A, from 15 min to 48 hr after moderate FPI. To determine if preventing hydrolysis of cAMP by administration of a phosphodiesterase (PDE) IV inhibitor would improve outcome after TBI, we treated animals intraperitoneally with rolipram (0.3 or 3.0 mg/kg) 30 min prior to TBI, and then once per day for three days. Rolipram treatment restored cAMP to sham levels and significantly reduced cortical contusion volume and improved neuronal cell survival in the parietal cortex and CA3 region of the hippocampus. Traumatic axonal injury, characterized by β-amyloid precursor protein deposits in the external capsule, was also significantly reduced in rolipramtreated animals. Furthermore, levels of the pro-inflammatory cytokines, interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), were significantly decreased with rolipram treatment. These results demonstrate that the cAMP-PKA signaling cascade is downregulated after TBI, and that treatment with a PDE IV inhibitor improves histopathological outcome and decreases inflammation after TBI. Keywordscamp; Fluid-percussion; Inflammation; Interleukin-1β; PKA; Phosphodiesterase; Rolipram; TNF-α; Traumatic brain injury; TBI Traumatic brain injury (TBI) is a prevalent, debilitating health problem, occurring in 1.4 million people each year and disabling 5 million people in the United States (Langlois et al., 2004). The subsequent progressive injury after brain trauma develops from hours to days after the initiating insult, providing an accessible time window for pharmacological therapies. Despite Address correspondence to: W. Dalton Dietrich, Scientific Director, The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, P.O. Box 016960, (R-48), Miami, FL 33101, E-mail: ddietrich@miami.edu, Phone: 305-243-2297, Fax: 305-243-3207. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Brain trauma results in contusion formation, neuronal apoptosis, and axonal tract damage. These pathologies are worsened by the inflammatory cascade set into motion by the initial injury (Morganti-Kossmann et al., 2002. Two pro-i...

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Section: Discussionsupporting

confidence: 89%

Modulation of the cAMP signaling pathway after traumatic brain injury

Atkins

Oliva

Alonso

et al. 2007

Experimental Neurology

132

150

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“…The treatment lasted three, seven and 14 consecutive days according to the group. The dosage and dosing frequency of rolipram were selected on the basis of previous studies (18). The rats were randomly divided into five groups according to the tMCAO insult, sham procedure and drug use: i) Sham group, rats underwent the surgical procedure but without tMCAO; ii) vehicle group, rats underwent tMCAO and received 0.9% saline treatments; iii) three days group, rats underwent tMCAO and received a three-day rolipram course; iv) seven days group, rats underwent tMCAO and received a seven-day rolipram course; v) 14 days group, rats underwent tMCAO and received a 14-day rolipram course.…”

Section: Transient Middle Cerebral Artery Occlusion (Tmcao)mentioning

confidence: 99%

Rolipram stimulates angiogenesis and attenuates neuronal apoptosis through the cAMP/cAMP-responsive element binding protein pathway following ischemic stroke in rats

Cao

et al. 2015

Experimental and Therapeutic Medicine

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Abstract. Rolipram, a phosphodiesterase-4 inhibitor, can activate the cyclic adenosine monophosphate (cAMP)/cAMP-responsive element binding protein (CREB) pathway to facilitate functional recovery following ischemic stroke. However, to date, the effects of rolipram on angiogenesis and cerebral ischemia-induced neuronal apoptosis are yet to be fully elucidated. In this study, the aim was to reveal the effect of rolipram on the angiogenesis and neuronal apoptosis following brain cerebral ischemia. Rat models of ischemic stroke were established following transient middle cerebral artery occlusion and rolipram was administered for three, seven and 14 days. The results were examined using behavioral tests, triphenyl tetrazolium chloride staining, immunostaining and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) to evaluate the effects of rolipram therapy on functional outcome, angiogenesis and apoptosis. Western blot analysis was used to show the phosphorylated-(p-)CREB protein level in the ischemic hemisphere. The rolipram treatment group exhibited a marked reduction in infarct size and modified neurological severity score compared with the vehicle group, and rolipram treatment significantly promoted the microvessel density in the ischemic boundary region and increased p-CREB protein levels in the ischemic hemisphere. Furthermore, a significant reduction in the number of TUNEL-positive cells was observed in the rolipram group compared with the vehicle group. These findings suggest that rolipram has the ability to attenuate cerebral ischemic injury, stimulate angiogenesis and reduce neuronal apoptosis though the cAMP/CREB pathway.

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“…with rolipram, a type IV phosphodiesterase that induces CREB phosphorylation (p-CREB) and confers neuroprotection from various types of stress (25,26) (Fig. 1A).…”

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confidence: 99%

NR4A orphan nuclear receptors as mediators of CREB-dependent neuroprotection

Volakakis

Kadkhodaei²,

Joodmardi³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

135

113

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Induced expression of neuroprotective genes is essential for maintaining neuronal integrity after stressful insults to the brain. Here we show that NR4A nuclear orphan receptors are induced after excitotoxic and oxidative stress in neurons, up-regulate neuroprotective genes, and increase neuronal survival. Moreover, we show that NR4A proteins are induced by cAMP response element binding protein (CREB) in neurons exposed to stressful insults and that they function as mediators of CREB-induced neuronal survival. Animals with null mutations in three of six NR4A alleles show increased oxidative damage, blunted induction of neuroprotective genes, and increased vulnerability in the hippocampus after treatment with kainic acid. We also demonstrate that NR4A and the transcriptional coactivator PGC-1α independently regulate distinct CREB-dependent neuroprotective gene programs. These data identify NR4A nuclear orphan receptors as essential mediators of neuroprotection after exposure to neuropathological stress.excitotoxicity | kainic acid | oxidative stress N europathological conditions including stroke, Alzheimer's disease, and Parkinson's disease are associated with excitotoxic and oxidative stress. Transcriptional increases of neuroprotective genes, including antiapoptotic factors and scavengers of reactive oxygen species (ROS), are an important strategy for neuroprotection. Thus, understanding how neuroprotective gene programs are controlled at the transcriptional level is of considerable importance and may contribute to the identification of therapeutic strategies of disorders associated with neurodegeneration. cAMP response element binding protein (CREB) is a transcription factor that is activated in response to stressful stimuli such as hypoxia, oxidative stress, excitotoxicity, and ischemia (1). Evidence from loss-of-function and other types of experiments shows that CREB plays an important role in neuronal survival (2-5) and neuroprotection (6). It is also well established that CREB is required for acquisition of ischemic tolerance, an endogenous neuroprotective mechanism whereby prior exposure to brief ischemia produces resilience to subsequent normally injurious ischemia (7,8).Despite the well-documented neuroprotective effect of CREB, only little is known of how CREB mediates this activity and only few directly regulated neuroprotective target genes have been identified (9-13). In addition to target genes that are directly neuroprotective, CREB-induced transcription factors or cofactors may also contribute to neuron survival by regulating downstream gene batteries controlled by elevated cAMP levels in a transcription factor cascade initiated by activated CREB. Indeed, CREB induces the expression of peroxisome proliferator-activated receptor gamma coactivator-1a (PGC-1α), an important regulator of ROS-detoxifying enzyme gene expression (14). However, how CREB mediates neuroprotective gene cascades via the induction of additional transcriptional regulators remains unexplored.The NR4A orphan nuclear receptor (NR...

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The Phosphodiesterase Inhibitor Rolipram Promotes Survival of Newborn Hippocampal Neurons After Ischemia

Cited by 64 publications

References 30 publications

Modulation of the cAMP signaling pathway after traumatic brain injury

Modulation of the cAMP signaling pathway after traumatic brain injury

Rolipram stimulates angiogenesis and attenuates neuronal apoptosis through the cAMP/cAMP-responsive element binding protein pathway following ischemic stroke in rats

NR4A orphan nuclear receptors as mediators of CREB-dependent neuroprotection

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