Silencing phosphodiesterase 7B gene by lentiviral-shRNA interference attenuates neurodegeneration and motor deficits in hemiparkinsonian mice

Abstract

Different studies have suggested that the nucleotide cyclic adenosine 3', 5'-monophosphate can actively play an important role as a neuroprotective and anti-inflammatory agent after a brain injury. The phosphodiesterase 7 (PDE7) enzyme is one of the enzymes responsible for controlling specifically the intracellular levels of cyclic adenosine 3', 5'-monophosphate in the immune and central nervous systems. Therefore, this enzyme could play an important role in brain inflammation and neurodegeneration. In this regard, using different chemical inhibitors of PDE7 we have demonstrated their neuroprotective and anti-inflammatory activity in different models of neurodegenerative disorders, including Parkinson's disease (PD). In the present study, we have used the toxin 6-hydroxydopamine and lipopolysaccharide to model PD and explore the protective effects of PDE7B deficiency in dopaminergic neurons cell death. Lentivirus-mediated PDE7B deprivation conferred marked in vitro and in vivo neuroprotection against 6-hydroxydopamine and lipopolysaccharide toxicity in dopaminergic neurons and preserved motor function involving the dopamine system in mouse. Our results substantiate previous data and provide a validation of PDE7B enzyme as a valuable new target for therapeutic development in the treatment of PD.

Phosphodiesterase7 Inhibition Activates Adult Neurogenesis in Hippocampus and Subventricular Zone In Vitro and In Vivo

“…Given the fact that alterations in the specialized niches of the adult brain underlay many different brain disorders including neurodegenerative disease, our work suggest that PDE inhibition could be a novel strategy for the treatment of these disorders. This idea is further substantiated by our previous work showing an important neuroprotective role of PDE7 inhibition in different brain disorders and by our previous report in which we demonstrated that PDE7 inhibition after S14 treatment in vivo induces a strong neurogenesis in the substantia nigra pars compacta of 6‐OHDA‐lesioned animals toward a dopaminergic phenotype .…”

“…Although our group has recently demonstrated that PDE7 inhibition plays an important role on neuroprotection in different animal models of neurodegenerative disorders , so far there is almost no information about the effect of PDE7 inhibition on neurogenesis in the adult brain. More recently, our group has reported for the first time that the PDE7 inhibitor S14, which is able to cross the blood brain barrier, induces neurogenesis toward a dopaminergic phenotype in the substantia nigra pars compacta of adult rats lesioned with 6‐OHDA .…”

“…Diverse studies from our group have shown that different inhibitors of PDE7 are potent neuroprotective and anti‐inflammatory agents in some animal models of neurodegenerative disorders, including PD . We have also shown that PDE7 depletion in the SNpc , using specific shRNAs for PDE7B significantly protects dopaminergic neurons and improves motor function in LPS and 6‐OHDA lesioned mice . Very recently, we have reported that, in addition to its neuroprotective effect, chemical inhibition of PDE7 induces endogenous neuroregenerative processes toward a dopaminergic phenotype in an animal model of PD .…”

“…Within the brain, PDE7 mRNA has been found in the cerebellum, olfactory bulb, dentate gyrus of the hippocampus and striatum, being PDE7B much more abundant than PDE7A . PDE7 inhibition has been recently reported to be as a good therapeutic option for the treatment of different neurodegenerative diseases . In this regard, cAMP signaling pathway has been involved in different functions in the central nervous system, such as cellular growth, neuronal proliferation, and long‐term memory formation .…”

Protective efficacy of phosphodiesterase-1 inhibition against alpha-synuclein toxicity revealed by compound screening in LUHMES cells

“…PDE inhibition has been previously discussed as therapeutic approach for Huntington’s disease 37 and Alzheimer’s disease 38 . It was also reported that inhibition of the cAMP-selective PDE7 protected dopaminergic neurons in a 6-hydroxydopamine model of PD in vivo 39 . Moreover, PDE1 inhibition was discussed as an approach to improve neuronal plasticity and to be neuroprotective as treatment option for neurodegenerative diseases 40 .…”