Targeting the Endocannabinoid System to Treat Sepsis

From Signa Vitae:

ABSTRACT

The endocannabinoid system represents a potential therapeutic target in sepsis due to the presence of cannabinoid receptors (CB2) on immune cells. In this review we discuss how various targets within the endocannabinoid system can be manipulated to treat the immune consequences of sepsis. One of the targets outlined are the endocannabinoid receptors and modulation of their activity through pharmacological agonists and antagonists. Another therapeutic target covered in this review is the modulation of the endocannabinoid degradative enzyme’s activity. Modulation of degradative enzyme activity can change the levels of endogenous cannabinoids thereby altering immune activity. Overall, activation of the CB2 receptors causes immunosuppression and can be beneficial during the hyperactivated immune state of sepsis, while suppression of the CB2 receptors may be beneficial during a hypoimmune septic state.

From the beginning of the paper:

Sepsis is a complex immune disorder that can affect the function of almost all organ systems in the body. This disorder is characterised by a malfunctioning immune response to an infection that involves both pro-inflammatory and immunosuppressive mediators. This leads to severe damage and failure of vital organs, resulting in patient death (figures 1,2). Sepsis, septic shock, and systemic inflammatory response syndrome are the leading causes of mortality in surgical intensive care unit patients internationally. (1) Within the United States alone, the incidence of sepsis is around 750,000 annually, (2)resulting in more than 200,000 deaths.(3)

Older individuals with fragile immune systems are at a higher risk of developing sepsis after invasive surgical procedures. Concurrently, the proportion of our ageing population has been increasing steadily over the years with 8% of the population being over 60 years old in 1950, 11% in 2009, and predicted to be 22% in 2050. (4) As a result, the incidence of sepsis in North America is projected to rise along with the risk of patient mortality. (2) Unfortunately, current management of sepsis is limited to supportive care, and therapeutic intervention is mainly hindered by the complex pathophysiology and heterogeneous immuno-inflammatory nature of the disease. (5) Although supportive care is beneficial to septic patients, there are no specific therapeutic options available that target the immune system to eliminate septic related mortality. All of these facets have resulted in a significant cost to the heath care system. (2)

The current lack of viable therapeutic treatment options for sepsis underscores our insufficient understanding of this complex disease. The endocannabinoid system, a key regulator of essential physiological functions including the immune system, has recently emerged as a potential therapeutic target for sepsis treatment. The endocannabinoid system acquires its name from the plant Cannabis Sativa, which has been used medically to treat a variety of ailments, as well as recreationally for centuries. Cannabis Sativa contains more than 60 active phytocannabinoids with the primary phytocannabinoid 9-tetrahydrocannabinol (THC), (6) activating both endogenous endocannabinoid receptors. (7)

The conclusion:

Conclusion
The endocannabinoid system modulates the immune response in experimental sepsis. Manipulating the endocannabinoid system may have potential therapeutic benefit in clinical sepsis where immune and inflammatory dysfunction can be detrimental. Multiple targets exist within the endocannabinoid system, e.g. the system can be targeted at the level of receptors by administration of synthetic compounds, similar to the endocannabinoids, which either increase or inhibit receptor activation to provide the desired therapeutic effect. Alternatively, the endogenous enzymes that degrade endocannabinoids or cannabinoid like lipids can also be targeted in order to manipulate the levels of endocannabinoids. Proper identification of the septic stage is crucial to determine the adequate therapeutic response that will be most beneficial. Due to the biphasic nature of sepsis immunopathology, immune suppression through endocannabinoid modulation can help mitigate the hyper-immune response during the early septic state, while immune activation may be beneficial in later stages.

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