Could An Injection One Day Protect You From Stress and Stress-Related Depression?

Posted on May 09, 2022

Stress Image

Stress – most of us experience it in some way every day. Some stress is good. It often drives us to face challenges or prepares us for dangerous situations. But really the definition of “good” stress is stress that doesn’t last very long. It comes around to help you meet the moment and then disappears. Stress becomes detrimental to our health when it sticks around and becomes a chronic issue. The longer we experience stress, the more taxed our physiological stress response becomes until it is taxed beyond its capabilities (Cooper, 2021).

Chronic stress not only taxes our stress response but can also lead to other health problems such as depression. Depression and stress are often viewed as a “bidirectional” relationship meaning that either one can lead to the other. It is estimated that 5% of people globally suffer from depression, and stress is one of the leading causes for depression (WHO, 2021).

There are non-medicinal treatments for mild depression such as behavioral activation, cognitive behavioral therapy, and interpersonal psychotherapy, but medication is often the only treatment for more severe cases. Selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs) are the two most commonly used anti-depressants. SSRIs and TCAs come with the possibility of adverse side effects, and they only treat the disease symptoms rather than preventing the occurrence of depression from the source (WHO, 2021).

Research conducted in 2021 suggests that treating depression at the source is a viable treatment option. The innate immune system is a defense system that protects the body against environmental challenges. But overactivation can lead to overproduction of inflammatory cytokines. However, reports indicate that if the immune system is mildly stimulated via activation of the TRIF-interferon regulatory factor 3 cascade, neuroprotective effects can be seen (at least in rodents). This suggests that stimulating the innate immune system prior to progression of depressive symptoms could be an alternative, and pre-emptive strategy to treat depression.

Another study recently identified lipopolysaccharide (LPS) as a possible treatment for depression in chronically stressed mice. The mechanism of action was determined to transform the neuroinflammatory response into an anti-inflammatory phenotype. LPS, however, can be toxic especially at high doses. It has been noted to increase the production of neutrophils and induce fever and sickness. So, LPS may not itself be a viable treatment option but luckily, we have something very similar to LPS that lacks its undesirable effects while still capable of inducing a robust immune response.

Monophosphoryl lipid A (MPLA) is a detoxified lipid A moiety derived from Salmonella LPS, but Avanti offers a synthetic version of MPLA called PHAD – short for phosphorylated hexaacyl disaccharide. First, they looked at the dosage response of MPLA compared to LPS. They found that a relatively low dose of MPLA (200 µg/kg) had no effect on chronic social defeat stress (CSDS)-induced depression-like behaviors in mice. However, increasing the dosage to 400, 800, or 1600 µg/kg was capable of preventing CSDS-induced depression-like behaviors.

They also looked at how long post-MPLA injection the preventative effects were still present. Unfortunately, they found that post-injection the preventative effects dissipated after 10 days. With this information, they tested multiple MPLA injections spaced out ten days apart from one another. In total, they injected MPLA four times. The results were positive noting that the multiple injection experiment resulted in a stronger immune response and an increased time interval with protective effect between injection and stress exposure. The results are preliminary, but this does suggest that injections of MPLA or something similar could allow the body to develop a long-term ability to protect itself from stress-induced depression. This represents a promising step toward preventative treatments of stress-induced depression.

MPLA and PHAD are not exactly the same. Since PHAD is a synthetic structural analog of MPLA, PHAD is a single chemical species whereas MPLA is a distribution of multiple chemical species. However, the induced immune response of PHAD (and other PHAD derivatives) is similar to the immune response induced by MPLA (see figure below). If you are interested in using Avanti’s synthetic MPLA analogs, take a look at our full line of lipid-based PHAD adjuvants.

Please take the time to read the full research article “Monophosphoryl Lipid A Tolerance Against Chronic Stress-Induced Depression-Like Behaviors in Mice” by Fu Li, Xu Lu, Yaoying Ma, Yue Gu, Ting Ye, and Chao Huang from Nantong University, Department of Pharmacology.

Other Resources:

Depression. September 13, 2021. World Health Organization.

Cooper, Jon. Stress and Depression. July 12, 2021. WebMD.