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Dr. Bob is Robert Hsiung, MD,
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Posted by Tomatheus on March 14, 2016, at 22:38:46
Press release: Inflammation-modulating chemical has AD potential
By Kathy Keatley Garvey
University of California, DavisA chemical discovered in the Bruce Hammock laboratory at the University of California, Davis, may be a new, innovative tool to control depression, a sometimes severe and chronic mental health condition that affects an estimated 350 million people worldwide.
The research, published March 14 in the journal Proceedings of the National Academy of Sciences, involves studies of an inhibitor of soluble epoxide hydrolase in rodents. Soluble epoxide hydrolase, or sEH, is emerging as a therapeutic target that acts on a number of inflammatory or inflammation-linked diseases.
"The research in animal models of depression suggests that sEH plays a key role in modulating inflammation, which is involved in depression," said Hammock, a distinguished professor of entomology with a joint appointment at the UC Davis Comprehensive Cancer Center. "Inhibitors of sEH protect natural lipids in the brain that reduce inflammation and neuropathic pain. Thus, these inhibitors could be potential therapeutic drugs for depression."
Researchers from Hammock's laboratory, collaborating with depression expert Kenji Hashimoto and colleagues at the Chiba University Center for Forensic Mental Health, Japan, examined the role of the potent sEH inhibitor known as TPPU, in a rodent "social defeat" model of depression.
They found that TPPU displayed rapid effects in both inflammation and social-defeat-stress models of depression. Expression of sEH protein was higher in key brain regions of chronically stressed mice than in control mice, they found.
New therapeutic approach"Most drugs for psychiatric diseases target how neurons communicate; here we are targeting the wellness and environment of the neurons," said UC Davis researcher Christophe Morisseau.
In further explaining the significance of the findings, UC Davis researcher Karen Wagner said: "The rapid antidepressant action of the sEH inhibitor in these [mouse] models of depression is truly noteworthy because current antidepressants used in humans and animal models take weeks to have full effects."
The researchers also discovered that postmortem brain samples of patients with psychiatric diseases, including depression, bipolar disorder and schizophrenia, showed a higher expression of sEH than controls.
The researchers found that administering TPPU to mice before inducing inflammation or repeated social-defeat stress in the animals prevented the onset of depression-like behaviors. Mice lacking the sEH gene did not show depression-like behavior after repeated social-defeat stress.
"All these findings suggest that sEH plays a key role in the pathophysiology of depression and that epoxy fatty acids, and their mimics as well as sEH inhibitors, are potential therapeutic or prophylactic drugs for depression," Hashimoto said.
Addresses a pressing need
Robert E. Hales, distinguished professor of clinical psychiatry and the Joe P. Tupin Endowed Chair of the Department of Psychiatry and Behavioral Sciences at UC Davis School of Medicine, said new medication treatment approaches are needed to treat depression. Hales, who was not involved in the research, said the new paper represents "an important and novel approach to treating depression."
"With lifetime prevalence rates of major depressive disorder being in the range of 16 percent, and with nearly two-thirds of patients failing to respond to pharmacologic treatments, there is a pressing need to discover new medication treatment approaches," Hales said. "Their findings lend support to the potential use of TPPU, a sEH inhibitor, as a new therapeutic medication to prevent and treat depression."
Collaborators and funding
Other authors on the paper are: Qian Ren, Min Ma, Tamaki Ishima, Ji-chun Zhang, Chun Yang, Wei Yao, Chao Dong and Mei Han, Chiba University; and Jun Yang at UC Davis.
Morisseau, Yang and Wagner are inventors on University of California patents related to soluble epoxide hydrolase. EicOsis Human Health, a Davis company that Hammock has founded to develop pharmaceuticals to alleviate neuropathic and inflammatory pain, has licensed some of these UC patents.
The research was funded by Grant-in-Aid for Scientific Research on Innovative Areas of the Ministry of Education, Culture, Sports, Science and Technology, Japan, to Kenji Hashimoto, (#24116006); and a Research Fellowship for Young Scientists of the Japan Society for the Promotion of Science (Tokyo, Japan) to Qian Ren.
Partial support was provided by the National Institute of Environmental Health Sciences R01 ES002710, NIEHS Superfund Research Program grant P42 ES004699 and NIH U24 DK097154 West Coast Comprehensive Metabolomics Center.
Hammock and Professor Bruce German of UC Davis recently received a National Institutes of Health grant, in collaboration with Pei-an Shih of the UC San Diego Department of Psychiatry, to investigate the role of bio-active lipids in a related psychiatric disorder, anorexia nervosa.
Source: University of California, Davis
Press release URL: https://www.ucdavis.edu/news/chemical-discovered-uc-davis-may-be-new-tool-depression-therapy
Posted by SLS on March 15, 2016, at 6:51:27
In reply to Inflammation-modulating chemical has AD potential, posted by Tomatheus on March 14, 2016, at 22:38:46
I had taken minocycline for about a year - maybe more. I took it only for its anti-inflammatory effects in the brain. It helped a great deal. Unfortunately, I began to develop hyperpigmentation (a darkening) of my feet and shins. It has mostly faded.
My impression is that inflammation emerges after the onset of depression rather than before. However, it might then act to extend or perpetuate the depressive neurophysiology - a sort of self-reinforcing loop. I don't know this for sure, of course.
- Scott
Posted by Hugh on March 15, 2016, at 11:56:06
In reply to Inflammation-modulating chemical has AD potential, posted by Tomatheus on March 14, 2016, at 22:38:46
When I suffer from an inflammatory condition, such as bronchitis, I become much more depressed. As my inflammation improves, my depression improves.
Posted by SLS on March 15, 2016, at 13:54:44
In reply to Re: Inflammation-modulating chemical has AD potential, posted by Hugh on March 15, 2016, at 11:56:06
> When I suffer from an inflammatory condition, such as bronchitis, I become much more depressed. As my inflammation improves, my depression improves.
Me, too.
I had that experience this past month. My depression worsened significantly. I am only now starting to recapture the gains I had made previously. Just today, it occurred to me to take ibuprofen to move things along. There have been several studies sponsored by the NIH looking at the use of NSAID anti-inflammatories to help antidepressants work better. I don't know what the results have been.
A friend of mine had suffered from double-depression. She was doing fairly well, was employed, but was still somewhat dysthymic. When she contracted an infection, it precipitated a major depressive episode during which she had to fight suicidal feelings. It took a few weeks, but the episode resolved after the infection passed.
- Scott
Posted by Tomatheus on March 15, 2016, at 14:40:03
In reply to Re: Inflammation-modulating chemical has AD potential » Tomatheus, posted by SLS on March 15, 2016, at 6:51:27
> My impression is that inflammation emerges after the onset of depression rather than before.
Scott,
Based on what I've read, I'm inclined to agree with you, at least to an extent. One factor that I think might account for the reported tendencies toward increased levels of inflammatory markers in patients with depression is the low vitamin D status that's been found to be associated with depression (Parker & Brotchie, 2011). A study that examined the association between vitamin D deficiency and inflammation in older Irish adults (Laird et al., 2014) found that participants with deficient vitamin D levels had significantly higher concentrations of interleukin-6 and C-reactive protein, as well as significantly higher interleukin-6-to-interleukin-10 and C-reactive-protein-to-interleukin-10 ratios, than participants whose vitamin D levels were sufficient. This finding follows reports from "numerous" in vitro studies that have indicated that vitamin D can significantly reduce concentrations of tumor necrosis factor and interleukin-6 and also increase the secretion of interleukin-10 (Laird et al., 2014). Considering that Zhang et al. (2012) found that two forms of vitamin D dose-dependently inhibited lipopolysaccharide-induced increases in interleukin-6, tumor necrosis factor, and p38 phosphorylation in human blood monocytes, there is reason to think that vitamin D might play a causative role in reducing inflammatory markers. Factors other than hypovitaminosis D might account for the associations that have been found between inflammation and depression, but I think that the evidence that I've described here points toward the possibility that low vitamin D levels might play a role in mediating the increased levels of inflammatory markers that tend to be found in patients with depression. Perhaps hypovitaminosis D might play a role in both causing depressive symptoms and in increasing the concentrations of inflammatory markers, or maybe hypovitaminosis D occurs mainly as a consequence of depression and then also contributes to raising inflammatory markers that tend to be increased in depressed patients, but I tend to think that the low vitamin D levels that tend to occur in patients with depression might at least contribute to the increased levels of inflammatory markers that have been found in those with depression.
But even though there is, from my perspective, some reason to think that the increased levels of inflammatory markers that have been found to be associated with depression might not necessarily contribute to the causation of depression, I do think it's interesting that the inflammation-modulating chemical (TPPU) that was the focus of the press release that I posted here seemed to prevent the onset of depression-related behaviors in mice when the chemical was administered to the animals before they were subjected to either inflammation or repeated social-defeat stress. Maybe some methods of reducing inflammation (such as soluble epoxide hydrolase inhibition) might have more antidepressant potential than other methods of reducing inflammation? I don't know. I do think that the findings that were reported in the press release that I posted are quite preliminary, but at the same time, I think that if sEH inhibitors do turn out to possess some antidepressant efficacy that they'd represent a rather unique way of treating depression that might potentially help some patients who aren't being helped by the treatment methods that are currently available.
Tomatheus
==
REFERENCES
Laird, E., McNulty, H., Ward, M., Hoey, L., McSorley, E., Wallace, J.M.W., et al. (2014). Vitamin D deficiency is associated with inflammation in older Irish adults. The Journal of Clinical Endocrinology & Metabolism, 99, 0000-0000. Article: http://press.endocrine.org/doi/full/10.1210/jc.2013-3507
Parker, G., & Brotchie, H. (2011). 'D' for depression: Any role for vitamin D? Acta Psychiatrica Scandinavica, 124, 243-249. Abstract: http://www.ncbi.nlm.nih.gov/pubmed/21480836
Zhang, Y., Leung, D.Y.M., Richers, B.N., Liu, Y., Remigio, L.K., Riches, D.W., et al. (2012). Vitamin D inhibits monocyte/macrophage proinflammatory cytokine production by targeting MAPK phosphatase-1. The Journal of Immunology, 188, 2127-2135. Article: http://www.jimmunol.org/content/188/5/2127.full
Posted by Tomatheus on March 15, 2016, at 15:05:26
In reply to Re: Inflammation-modulating chemical has AD potential, posted by Hugh on March 15, 2016, at 11:56:06
> When I suffer from an inflammatory condition, such as bronchitis, I become much more depressed. As my inflammation improves, my depression improves.
Thank you for sharing this observation with us, Hugh. I definitely find the association between inflammation and depression to be interesting. I'm not sure about the extent to which the increases in inflammation that tend occur in depression contribute to causing depressive symptoms, but I don't think that there's much question that increases in depressive symptoms and increases in inflammation tend to occur together. And considering the information in the press release that I posted indicating that the inflammation-modulating chemical TPPU prevented the onset of depression-like behaviors in mice when the chemical was administered prior to the induction of inflammation or repeated social-defeat stress, maybe it is indeed the case that reducing inflammation can have antidepressant benefits. It sure will be interesting to see if TPPU, or perhaps other soluble epoxide hydrolase inhibitors, will end up demonstrating clinically significant antidepressant properties when used in human trials.
Tomatheus
Posted by Horse on March 19, 2016, at 2:29:42
In reply to Re: Inflammation-modulating chemical has AD potential, posted by Hugh on March 15, 2016, at 11:56:06
> When I suffer from an inflammatory condition, such as bronchitis, I become much more depressed. As my inflammation improves, my depression improves.
Myself included. Sickness behavior.
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