Effects of early rolipram treatment on histopathological outcome after controlled cortical impact injury in mice

Atkins, Coleen M.; Cepero, Maria L.; Kang, Yuan; Liebl, Daniel J.; Dietrich, W. Dalton

doi:10.1016/j.neulet.2012.10.019

Cited by 32 publications

(31 citation statements)

References 44 publications

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“…Thus, it is possible that treatments that selectively increase cAMP levels may not be useful in all brain injury models, since they could effectively decrease cGMP levels as an unintended consequence. This may explain some of the reported discrepancies in the use of PDE4 inhibitors in brain injury [114, 115]. …”

Section: Role Of Cgmp-pdes and Tbimentioning

confidence: 99%

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Phosphodiesterase Inhibitors as Therapeutics for Traumatic Brain Injury

Titus¹,

Oliva²,

Wilson³

et al. 2014

CPD

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Developing therapeutics for traumatic brain injury remains a challenge for all stages of recovery. The pathological features of traumatic brain injury are diverse, and it remains an obstacle to be able to target the wide range of pathologies that vary between traumatic brain injured patients and that evolve during recovery. One promising therapeutic avenue is to target the second messengers cAMP and cGMP with phosphodiesterase inhibitors due to their broad effects within the nervous system. Phosphodiesterase inhibitors have the capability to target different injury mechanisms throughout the time course of recovery after brain injury. Inflammation and neuronal death are early targets of phosphodiesterase inhibitors, and synaptic dysfunction and circuitry remodeling are late potential targets of phosphodiesterase inhibitors. This review will discuss how signaling through cyclic nucleotides contributes to the pathology of traumatic brain injury in the acute and chronic stages of recovery. We will review our current knowledge of the successes and challenges of using phosphodiesterase inhibitors for the treatment of traumatic brain injury and conclude with important considerations in developing phosphodiesterase inhibitors as therapeutics for brain trauma.

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Section: Role Of Cgmp-pdes and Tbimentioning

confidence: 99%

“…This was not model-dependent, since this result was observed in two distinct brain injury models, fluid-percussion brain injury and controlled cortical impact [114, 115]. …”

Section: Pde4 Inhibitors As Anti-inflammtory Agents For Tbimentioning

confidence: 99%

Phosphodiesterase Inhibitors as Therapeutics for Traumatic Brain Injury

Titus¹,

Oliva²,

Wilson³

et al. 2014

CPD

View full text Add to dashboard Cite

show abstract

“…However, lack of subtype-selective PDE4 inhibitors has hampered the development of this therapeutic approach for TBI [21, 22]. In this study, we characterized the effect of a PDE4B-selective inhibitor, A33, on inflammation, pathology and behavioral deficits after TBI.…”

Section: Introductionmentioning

confidence: 99%

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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“…This finding agrees with other reports that have shown that rolipram treatment exacerbated neuronal injury in experimental stroke (27-29). In addition to cerebral ischemia, reports have shown exacerbation of brain injury by rolipram treatment in other models of CNS disease (30, 31). One possible mechanism for exacerbation of brain injury by cAMP-stimulating agents such as rolipram is induction of compensatory upregulation of certain PDE4 isoforms (32-34) to accelerate cAMP degradation (35, 36).…”

Section: Discussionmentioning

confidence: 99%

Effects of PDE4 Pathway Inhibition in Rat Experimental Stroke

et al. 2014

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PURPOSE The first genomewide association study indicated that variations in the phosphodiesterase 4D (PDE4D) gene confer risk for ischemic stroke. However, inconsistencies among the studies designed to replicate the findings indicated the need for further investigation to elucidate the role of the PDE4 pathway in stroke pathogenesis. Hence, we studied the effect of global inhibition of the PDE4 pathway in two rat experimental stroke models, using the PDE4 inhibitor rolipram. Further, the specific role of the PDE4D isoform in ischemic stroke pathogenesis was studied using PDE4D knockout rats in experimental stroke. METHODS Rats were subjected to either the ligation or embolic stroke model and treated with rolipram (3mg/kg; i.p.) prior to the ischemic insult. Similarly, the PDE4D knockout rats were subjected to experimental stroke using the embolic model. RESULTS Global inhibition of the PDE4 pathway using rolipram produced infarcts that were 225% (p<0.01) and 138% (p<0.05) of control in the ligation and embolic models, respectively. PDE4D knockout rats subjected to embolic stroke showed no change in infarct size compared to wild-type control. CONCLUSIONS Despite increase in infarct size after global inhibition of the PDE4 pathway with rolipram, specific inhibition of the PDE4D isoform had no effect on experimental stroke. These findings support a role for the PDE4 pathway, independent of the PDE4D isoform, in ischemic stroke pathogenesis.

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Effects of early rolipram treatment on histopathological outcome after controlled cortical impact injury in mice

Cited by 32 publications

References 44 publications

Phosphodiesterase Inhibitors as Therapeutics for Traumatic Brain Injury

Phosphodiesterase Inhibitors as Therapeutics for Traumatic Brain Injury

Therapeutic benefits of phosphodiesterase 4B inhibition after traumatic brain injury

Effects of PDE4 Pathway Inhibition in Rat Experimental Stroke

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