Phosphodiesterase Inhibition Rescues Chronic Cognitive Deficits Induced by Traumatic Brain Injury

Abstract

Traumatic brain injury (TBI) modulates several cell signaling pathways in the hippocampus critical for memory formation. Previous studies have found that the cAMP-protein kinase A signaling pathway is downregulated after TBI and that treatment with a phosphodiesterase (PDE) 4 inhibitor rolipram rescues the decrease in cAMP. In the present study, we examined the effect of rolipram on TBI-induced cognitive impairments. At 2 weeks after moderate fluid-percussion brain injury or sham surgery, adult male Sprague Dawley rats received vehicle or rolipram (0.03 mg/kg) 30 min before water maze acquisition or cue and contextual fear conditioning. TBI animals treated with rolipram showed a significant improvement in water maze acquisition and retention of both cue and contextual fear conditioning compared with vehicle-treated TBI animals. Cue and contextual fear conditioning significantly increased phosphorylated CREB levels in the hippocampus of sham animals, but not in TBI animals. This deficit in CREB activation during learning was rescued in TBI animals treated with rolipram. Hippocampal long-term potentiation was reduced in TBI animals, and this was also rescued with rolipram treatment. These results indicate that the PDE4 inhibitor rolipram rescues cognitive impairments after TBI, and this may be mediated through increased CREB activation during learning.

Compartmentalized PDE4A5 Signaling Impairs Hippocampal Synaptic Plasticity and Long-Term Memory

“…Pharmacological suppression of PDE4 activity promotes synaptic plasticity and memory (Randt et al, 1982;Barad et al, 1998;Rutten et al, 2009;Werenicz et al, 2012). The PDE4 selective inhibitor, rolipram, prevents memory deficits associated with sleep loss (Vecsey et al, 2009), traumatic brain injury (Titus et al, 2013), aging (Wimmer et al, 2012), muscarinic or NMDA receptor blockade (Egawa et al, 1997;Wiescholleck and Manahan-Vaughan, 2012), and mouse models of Alzheimer's disease (Gong et al, 2004;Reneerkens et al, 2009;Richter et al, 2013). However, the clinical use of broad PDE4 inhibitors is limited due to undesirable side effects, including emesis and diarrhea (Zeller et al, 1984;Bertolino et al, 1988;Spina, 2008).…”

Inhibition of Eukaryotic Initiation Factor 2 Alpha Phosphatase Reduces Tissue Damage and Improves Learning and Memory after Experimental Traumatic Brain Injury

“…Both clinical and experimental studies have shown that hippocampal neurons are particularly vulnerable to TBI, and loss of these neurons can continue for weeks to months after moderate-to-severe TBI. 12,13 The link between hippocampal neuronal damage and memory impairments has been established both in human TBI patients and in rodent TBI models using hippocampal-dependent learning and memory tasks. [14][15][16] However, no clinically proven neuroprotective therapy to reduce neuronal damage and improve learning and memory has been identified.…”

CREB Signaling Is Involved in Rett Syndrome Pathogenesis

“…MeCP2 was initially characterized as a methyl-DNA binding protein (Lewis et al, 1992) and a suppressor of gene transcription (Nan et al, 1997). Consistent with this notion, the majority of RTT-causing mutations are found in either the methyl-CpG binding domain or the transcription repression domain (Samaco and Neul, 2011).…”

“…To further elucidate the molecular mechanism underlying the cellular phenotypes of abnormal neuronal morphology and mitochondrial deficit in MECP2 mutant neurons, we focused on CREB, a transcription factor known to indirectly regulate MeCP2 level (Klein et al, 2007), directly interact with MeCP2 (Chahrour et al, 2008), and control the expression of numerous genes that regulate dendritic growth (Redmond et al, 2002;Wayman et al, 2006) and mitochondrial function (Ryu et al, 2005). Western blot analysis revealed significantly reduced levels of both total CREB and phosphorylated CREB (pCREB, a signature of CREB activation) in MECP2 T158M/T158M and MECP2-KO neurons compared with H9 neurons (Fig.…”

“…Subsequently, RTT patient-specific induced pluripotent stem cell (iPSC) lines (Marchetto et al, 2010;Ananiev et al, 2011;Cheung et al, 2011;Kim et al, 2011) and human embryonic stem cell (hESC) line lacking MECP2 were generated to complement the mouse models. More recently, mouse lines carrying RTT disease-causing Mecp2 point mutations also became available (Goffin et al, 2011;Schaevitz et al, 2013;Wegener et al, 2014;Pitcher et al, 2015;Brown et al, 2016). While they offer better accessibility for studying molecular and cellular mechanisms, the hESCs, iPSCs, and their derivatives display highly variable biological characteristics among lines generated from different individuals due to differences in genetic background, thereby complicating their use in disease modeling (Soldner and Jaenisch, 2012).…”