Phosphodiesterase Inhibitors as Therapeutics for Traumatic Brain Injury

Titus, David J.; Oliva, Anthony A.; Wilson, Nicole M.; Atkins, Coleen M.

doi:10.2174/1381612820666140826113731

Cited by 27 publications

(15 citation statements)

References 168 publications

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“…Therefore, these results might be of relevance in clinical practice to optimize the conditions for promoting and preserving the quality of oocytes during handling and culture of COCs retrieved from patients enrolled in programs of assisted reproduction. In addition, it will be of interest to determine whether the dual action of cAMP in the cumulus is exerted also on other HA-rich tissues, particularly at the inflammation site, where hyaluronan is expressed (92) and the protective effect of cAMP elevation through phosphodiesterase inhibitors has been proven (93)(94)(95).…”

Section: Discussionmentioning

confidence: 99%

Cyclic AMP-elevating Agents Promote Cumulus Cell Survival and Hyaluronan Matrix Stability, Thereby Prolonging the Time of Mouse Oocyte Fertilizability

Giacomo

Camaioni

Klinger

et al. 2016

Journal of Biological Chemistry

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Cumulus cells sustain the development and fertilization of the mammalian oocyte. These cells are retained around the oocyte by a hyaluronan-rich extracellular matrix synthesized before ovulation, a process called cumulus cell-oocyte complex (COC) expansion. Hyaluronan release and dispersion of the cumulus cells progressively occur after ovulation, paralleling the decline of oocyte fertilization. We show here that, in mice, postovulatory changes of matrix are temporally correlated to cumulus cell death. Cumulus cell apoptosis and matrix disassembly also occurred in ovulated COCs cultured in vitro. COCs expanded in vitro with FSH or EGF underwent the same changes, whereas those expanded with 8-bromo-adenosine-3,5-cyclic monophosphate (8-Br-cAMP) maintained integrity for a longer time. It is noteworthy that 8-Br-cAMP treatment was also effective on ovulated COCs cultured in vitro, prolonging the vitality of the cumulus cells and the stability of the matrix from a few hours to >2 days. Stimulation of endogenous adenylate cyclase with forskolin or inhibition of phosphodiesterase with rolipram produced similar effects. The treatment with selective cAMP analogues suggests that the effects of cAMP elevation are exerted through an EPAC-independent, PKA type II-dependent signaling pathway, probably acting at the post-transcriptional level. Finally, overnight culture of ovulated COCs with 8-Br-cAMP significantly counteracted the decrease of fertilization rate, doubling the number of fertilized oocytes compared with control conditions. In conclusion, these studies suggest that cAMP-elevating agents prevent cumulus cell senescence and allow them to continue to exert beneficial effects on oocyte and sperm, thereby extending in vitro the time frame of oocyte fertilizability.

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Section: Discussionmentioning

confidence: 99%

Cyclic AMP-elevating Agents Promote Cumulus Cell Survival and Hyaluronan Matrix Stability, Thereby Prolonging the Time of Mouse Oocyte Fertilizability

Giacomo

Camaioni

Klinger

et al. 2016

Journal of Biological Chemistry

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“…Those results suggested that modulation of the cAMP pathway could have therapeutic potential in preventing memory deficits following primary bTBI. Intriguingly, increasing cAMP through phosphodiesterase-4 inhibition was effective in improving outcome in some experimental models of TBI and also reduced cognitive impairments associated with Alzhemer’s disease, schizophrenia and aging (Gong et al, 2004; Maxwell et al, 2004; Smith et al, 2009; Titus et al, 2014; Wiescholleck and Manahan-Vaughan, 2012). Currently, there are no clinically-approved treatments for TBI (Silverberg et al, 2016).…”

Section: Introductionmentioning

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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“…PDEs as PDE4 and PDE7 are mainly selective on hydrolysis of cAMP whereas, PDE5, PDE6 and PDE9 are selective on cGMP. Since cGMP accumulation inhibits inflammation, the selective PDE5 inhibitors as sildenafil, tadalafil and vardenafil may seem good candidates for targeting UC diseases in which inflammation plays a central role (Keravis and Lugnier, 2012;Titus et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the colo-protective effects of tadalafil in an experimental model of ulcerative colitis in rats

Labib¹,

Abdelzaher²,

Shaker³

et al. 2017

Afr. J. Pharm. Pharmacol.

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Ulcerative colitis is a serious premalignant condition with a confusing multifactorial pathogenesis. It should warrant all attention by researchers, for exploration of new prophylactic or therapeutic drugs targeting its pathophysiology. The current study was conducted to study the possible role of tadalafil and its potential actions in ulcerative colitis rat model, induced by acetic acid. Forty eight male Wistar albino rats were classified into 6 groups: control group, acetic acid (AA)-ulcerated group, AA-ulcerated + tadalafil (1 mg/kg/day), AA-ulcerated + tadalafil (5 mg/kg/day), AA-ulcerated + tadalafil (10 mg/kg/day) and AA-ulcerated + sulfasalazine 100 mg/kg/day groups. Tissue malondialdehyde (MDA), superoxide dismutase (SOD) and myeloperoxidase (MPO) were determined. Also, caspase-3 gene expression was measured as an indicator of apoptosis. Histopathological examination of the colonic tissue was also done. In addition, serum levels of interleukin (IL)-1β and tumour necrosis factor (TNF)-α were measured. In AA-ulcerated group, there was significant elevation in tissue MDA levels and MPO activity with upregulation of caspase 3 gene expression. Meanwhile, AA caused decreases in the SOD activities. Also, AA induced elevation in the serum IL-1β and TNF-α levels. Pretreatment with tadalafil in doses of 1, 5 and 10 mg/kg/days guarded against changes in these parameters. Its effects were dose-dependent. According to the results, pretreatment with tadalafil in doses of 1, 5 and 10 mg/kg/day exerted dosedependent beneficial effects against AA-induced damage of the colon, possibly by exerting antiinflammatory and antioxidant effects. Also, reduction of apoptosis proved to be one of the contributing protective mechanisms of actions.

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Phosphodiesterase Inhibitors as Therapeutics for Traumatic Brain Injury

Cited by 27 publications

References 168 publications

Cyclic AMP-elevating Agents Promote Cumulus Cell Survival and Hyaluronan Matrix Stability, Thereby Prolonging the Time of Mouse Oocyte Fertilizability

Cyclic AMP-elevating Agents Promote Cumulus Cell Survival and Hyaluronan Matrix Stability, Thereby Prolonging the Time of Mouse Oocyte Fertilizability

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

Evaluation of the colo-protective effects of tadalafil in an experimental model of ulcerative colitis in rats

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