Pulmonary Hypertension & Viagra: Researchers Discover Novel Mechanisms of Sildenafil for Disease.


A group of researchers from the University of Pécs, Hungary, have attempted to understand the mechanism by which pulmonary vascular remodeling initiates right ventricular failure and hypoxia, one of the leading causes behind the mortality rates associated with Pulmonary Hypertension (PH).

viagra and PH

Sildenafil, known more commonly by its brand name Viagra, is an inhibitor of phosphodiesterase type 5 (PDE-5), an enzyme found in various tissues and involved in the cardiovascular system, and is frequently used in the treatment of PH, since it can improve exercise capacity, PH symptoms, and haemodynamics. However, the molecular mechanisms behind the protective effect exerted by this drug are not fully understood.

In this study, entitled “Novel Mechanisms of Sildenafil in Pulmonary Hypertension Involving Cytokines/Chemokines, MAP Kinases and Akt”, published in the PLOS ONE journal, the team used a monocrotaline (MCT, a toxic metabolite of plant origin)-induced rat PH model to analyze lung morphology, expression of cytokines, mitogen-activated protein kinase (MAPK) phosphorylation, phosphatidylinositol 3-kinase-Akt (PI-3k-Akt) pathway and nuclear factor (NF)-kB activation, to understand the mechanisms by which sildenafil’s exerts its protective effects in PH.

The authors could observe that sildenafil not only protected lung morphology but it also suppressed several cytokines directly related with neutrophil and mononuclear cell recruitment, such as cytokine-induced neutrophil chemoattractant (CINC)-1, CINC-2a/b, tissue inhibitor of metalloproteinase (TIMP)-1, interleukin (IL)-1a, lipopolysaccharide induced CXC chemokine (LIX), monokine induced by gamma interferon (MIG), macrophage inflammatory protein (MIP)-1a, and MIP-3a.

All of these cytokines induced by MCT treatment are regulated by NF-kB, and as such, through immunoblotting and immunohistochemistry with specific antibodies targeted at this nuclear factor, the authors discovered that MCT treatment caused a massive activation and nuclear translocation of NF-kB, a process significantly decreased upon sildenafil treatment.

Furthermore, sildenafil reduced the amount of extracellular signal-regulated kinase (ERK)1/2 and p38 MAPK activation, enhancing the activation of the cytoprotective Akt pathway in these PH mice.

Based on the results of this study, the authors concluded that, in mice, sildenafil is able to overcome the pathologic remodeling processes induced by MCT treatment, thus decreasing the infiltration of inflammatory cells and reducing edema formation.

Altogether, these data can reveal important clues regarding the novel mechanisms responsible for the beneficial effects of Viagra use in PH patients to reduce inflammation and swelling, moving one step closer to the development of improved therapies targeted at this progressive and incurable disease.

Serotonin may not play major role in depression, new evidence suggests


New research in mice throws into question the long-standing belief that serotonin deficiency plays a key role in depression.

shutterstock_Brain

Image: Allison Herreid/Shutterstock

A study by scientists in the US has cast doubt on the belief that a deficiency in serotonin, a chemical messenger in the brain, is a major trigger for depression.

The team from the John D. Dingell VA Medical Centre and Wayne State University School of Medicine in Michigan developed mice that lacked the ability to produce serotonin in their brains, and found they did NOT show signs of depression-like symptoms.

The results are published in ACS Chemical Neuroscience, and suggest that the majority of today’s antidepressants, which target serotonin, may not be as effective as we had hoped.

According to the World Health Organisation, depression is the leading cause of disability across the globe, affecting more than 350 million people worldwide. Back in the late 1980s, the antidepressant Prozac was developed, which works mainly by increasing the amount of serotonin in the brain. It seemed to be effective, and so other depression treatments that acted on serotonin began to flood the market. However, scientists know that 60 to 70 percent of patients taking such drugs continue to feel depressed.

The team, led by Donald Kuhn, decided to investigate whether serotonin was as involved in the disorder as we expect – if at all.

To do this, they developed “knockout” mice that didn’t have the ability to make serotonin in their brains. According to the current dogma, these mice should have been depressed. But while the mice were compulsive and aggressive, they didn’t show signs of depression-like symptoms, the researchers report.

After running a range of behavioural tests, the scientists found that when the knockout mice were put under stress, they behaved in the same way as most normal mice. Most of them also responded to antidepressant medications in a similar way to normal mice.

A press release explains: “These findings further suggest that serotonin is not a major player in the condition, and different factors must be involved.”

The authors conclude in their paper that this research could dramatically alter the creation of antidepressants in the future.

If this research is verified, it could turn out to be quite embarrassing – especially when this seems like it should have been one of the first studies done before the development of antidepressants. But mostly it’s great news, as it’ll give scientists a better indication than ever before of where we should be targeting antidepressant treatments.