Metabolic Brain Disease

, Volume 33, Issue 4, pp 1293–1306 | Cite as

Phosphodiesterase 4 and 7 inhibitors produce protective effects against high glucose-induced neurotoxicity in PC12 cells via modulation of the oxidative stress, apoptosis and inflammation pathways

  • Nazanin Namazi Sarvestani
  • Saeedeh Saberi Firouzi
  • Reza Falak
  • Mohammad Yahya Karimi
  • Mohammad Davoodzadeh Gholami
  • Akram Rangbar
  • Asieh HosseiniEmail author
Original Article


Diabetic neuropathy (DN) is the most common diabetic complication. It is estimated diabetic population will increase to 592 million by the year 2035. This is while at least 50–60% of all diabetic patients will suffer from neuropathy in their lifetime. Oxidative stress, mitochondrial dysfunction, apoptosis, and inflammation are crucial pathways in development and progression of DN. Since there is also no selective and effective therapeutic agent to prevent or treat high glucose (HG)-induced neuronal cell injury, it is crucial to explore tools by which one can reduce factors related to these pathways. Phosphodiesterase 4 and 7 (PDE 4 and 7) regulate oxidative damage, neurodegenaration, and inflammatory responses through modulation of cyclic adenosine monophosphate (cAMP) level, and thus can be as important drug targets for regulating DN. The aim of this study was to evaluate the protective effects of inhibitors of PDE 4 and 7, named rolipram and BRL5048, on HG-induced neurotoxicity in PC12 cells as an in vitro cellular model for DN and determine the possible mechanisms for theirs effects. We report that the PC12 cells pre-treatment with rolipram (2 μM) and/or BRL5048 (0.2 μM) for 60 min and then exposing the cells to HG (4.5 g/L for 72 h) or normal glucose (NG) (1 g/L for 72 h) condition show: (1) significant attenuation in ROS, MDA and TNF-a levels, Bax/Bcl-2 ratio, expression of caspase 3 and UCP2 proteins; (2) significant increase in viability, GSH/GSSG ratio, MMP and ATP levels. All these data together led us to propose PDE 4 and 7 inhibitors, and specifically, rolipram and BRL5048, as potential drugs candidate to be further studied for the prevention and treatment of DN.


Diabetic neuropathy Phosphodiesterase 4 and 7 inhibitors High glucose PC12 cells, Neurotoxicity Oxidative damage Apoptosis Inflammation 



This study was supported by a grant from Iran University of Medical Sciences.

Compliance with ethical standards

Conflicts of interest

The authors declare no conflict of interest.


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Authors and Affiliations

  1. 1.Department of Animal Biology, School of Biology, Department of ScienceUniversity of TehranTehranIran
  2. 2.Department of Pharmacology, Faculty of MedicineTehran University of Medical SciencesTehranIran
  3. 3.Department of Immunology, School of MedicineIran University of Medical SciencesTehranIran
  4. 4.Razi Drug Research CenterIran University of Medical SciencesTehranIran
  5. 5.Department of Toxicology and Pharmacology, School of PharmacyHamadan University of Medical SciencesHamadanIran

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