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

Abstract

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.

Moderate-Intensity Intermittent Training Alters the DNA Methylation Pattern of PDE4D Gene in Hippocampus to Improve the Ability of Spatial Learning and Memory in Aging Rats Reduced by D-Galactose

“…Inhibition of PDE4 is considered a potential target for the treatment of nervous system diseases. Several studies have shown that the inhibition of PDE4 can improve hippocampus long-term potentiation (LTP) and dendritic spine density by activating cAMP/protein kinase A (PKA)/cAMP response element binding protein (CREB)/brain-derived neurotrophic factor (BDNF) signaling, increase synaptic plasticity, and then improve cognitive function [ 7 , 8 , 9 ]. For example, inhibition of PDE4 by the first-generation inhibitor Rolipram increased the level of cAMP and p-CREB in the hippocampus, as well as the survival and proliferation of new neurons in the hippocampal dentate gyrus, significantly improving hippocampal long-term potentiation [ 10 , 11 , 12 ].…”

Targeting phosphodiesterase 4 as a potential therapeutic strategy for enhancing neuroplasticity following ischemic stroke

“…In the CNS, PDE4 plays a key role in both chronic neurodegenerative diseases and acute neurological insults, including stroke 14 , 15 . Recently, an increasing number of reports have shown that inhibition of PDE4 is beneficial for neuroplasticity 16 - 18 , making it a promising candidate target that has therapeutic potential for the recovery of stroke. Thus, this review provides a perspective for advancing our understanding of the role of PDE4 in neuroplasticity after stroke, supporting the possibility of exploiting PDE4 inhibitors as effective therapeutics against ischemic stroke.…”

ROSTMEMA: A Double-Blind Randomized Placebo-Controlled Trial with the PDE4 Inhibitor Roflumilast in Patients Suffering from Long-term Cognitive Sequela After Stroke

“…more dendrites and synapses) by inhibiting the degradation of cAMP. This positive effect of PDE4 inhibition on plasticity has been shown in two different brain injury models and one study actually demonstrated the effect with roflumilast (12,13).…”