Phosphodiesterase-5 is a therapeutic target for peripheral neuropathy in diabetic mice

Abstract

Peripheral neuropathy is a common and major complication of diabetes, the underlying mechanisms of which are not fully understood. Using a mouse model of type II diabetes, the present study investigated the role of phosphodiesterase-5 (PDE5) in peripheral neuropathy. BKS.Cg-m+/+Leprdb/J (db/db) mice were treated with sildenafil, a specific inhibitor of PDE5, at doses of 2 and 10 mg/kg or saline. Levels of PDE5 and morphometric parameters in sciatic nerve tissue as well as the motor and sensory function were measured in these mice. In diabetic mice, PDE5 expression in sciatic nerve tissue was significantly upregulated, while the myelin sheath thickness, myelin basic protein (MBP), and subcutaneous nerve fibers were significantly reduced. Treatment with sildenafil, significantly improved neurological function, assayed by motor and sensory conducting velocities and thermal and mechanical noxious stimuli, concomitantly with increases in myelin sheath thickness, MBP levels, and subcutaneous nerve fibers. In vitro, hyperglycemia upregulated PDE5 in Schwann cells, and reduced Schwann cell proliferation, migration and expression of brain-derived neurotrophic factor (BDNF). Blockage of PDE5 with sildenafil, increased cGMP, and completely abolished the effect of hyperglycemia on Schwann cells. Sildenafil upregulated cGMP-dependent protein kinase G1 (PKG1), whereas inhibition of PKG1 with a PKG inhibitor, KT5823, suppressed the inhibitory effect of sildenafil on Schwann cells. These data indicate that hyperglycemia substantially upregulates PDE5 expression and that the cGMP/PKG signaling pathway activated by sildenafil mediates the beneficial effects of sildenafil on diabetic peripheral neuropathy.

Disrupted Pulmonary Artery Cyclic Guanosine Monophosphate Signaling in Mice with Hyperoxia-Induced Pulmonary Hypertension

“…Litters of control and CH pups received sildenafil (0.8 mg/ml sildenafil in 5% dextrose) (Revatio; Pfizer, New York, NY) or vehicle (5% dextrose) injections (3 mg/kg/ dose, subcutaneous) every other day starting from P0, for a total of seven injections (21). AHR litters received one injection of sildenafil/vehicle before O 2 exposure.…”

Seminal vesicles and diabetic neuropathy: ultrasound evaluation after prolonged treatment with a selective phosphodiesterase‐5 inhibitor

“…Several studies on the use of PDE5i data for the treatment of DN have been published (Wang et al, 2011;Patil et al, 2004;Ali & Rakkah, 2007;Kamenov, 2011); the effects of these molecules on some functional aspects of the SV have been described , 2011;Orhan et al, 2006;Uckert et al, 2007;Gajar et al, 2007;Uckert et al, 2009;Birowo et al, 2010). Moreover, there are some data on the effects of PDE5i administration on sperm parameters (Hellstrom et al, 2008;Pomara et al, 2007).…”

“…Another aspect to consider is that the decreased nNOS (neuronal nitric oxide synthase)-cGMP system may play a crucial role in the pathogenesis of DN and, therefore the use of PDE5i may find a rational for the treatment of this condition (Patil et al, 2004). Moreover, it is known that hyperglycaemia substantially upregulates PDE5 expression and that the cGMP/PKG (protein kinase GI) signalling pathway activated by PDE5i mediates the beneficial effects of these molecules on diabetic peripheral neuropathy (Wang et al, 2011). Finally, a recent study suggests a chronic neuro-physiological effect of sildenafil (the first selective PDE5i used in the clinical practice) administration on male fertility profile exclusively in DN.…”

“…Moreover, evidence is accumulating that type 5 phosphodiesterase inhibitors (PDE5i) may be used for the treatment of DN (Wang et al, 2011;Patil et al, 2004;Ali & Rakkah, 2007;Kamenov, 2011) and that these molecules can modify some functional features in the SV (Ü ckert et al, 2011;Orhan et al, 2006;Uckert et al, 2007;Gajar et al, 2007;Uckert et al, 2009;Birowo et al, 2010). Therefore, the aim of this study was to investigate possible changes in the ultrasound (US) characteristics of the SV of infertile patients with DM and DN, after prolonged administration of tadalafil, a specific PDE5i.…”

Diabetic Cardiovascular Neuropathy

“…Phosphodiesterase-5 (PDE5) is highly specific for hydrolysis of cyclic nucleotides monophosphate, such as cyclic guanosine monophosphate (cGMP), which is a molecular messenger involved in regulation of vascular function, axon guidance, the modulation of DPN and pain perception [234][235][236]. PDE5 inhibitors including sildenafil, tadalafil, and vardenafil, are primarily used as pharmacological agents for the treatment of erectile dysfunction, but they also have a potential therapeutic application for the treatment of neurovascular dysfunction, neuroinflammatory and neurodegenerative diseases by inducing accumulation of cGMP and activation of cGMP dependent protein kinase, e.g., protein kinase G, signaling pathways [236,237].…”