Breaching The Brain To Treat Septic Shock

A neuropeptide called orexin has been shown to prevent mice from dying from septic shock.

AsianScientist (Feb. 15, 2017) – Scientists in Japan have identified a protein that could treat sepsis, a disease that kills an estimated 30 million people each year. Their findings have been published in eLife.

Sepsis is a life-threatening condition caused by an excessive immune response to infection that damages the patient’s own tissues and organs. In septic shock, the most severe stage of sepsis, blood pressure drops to a dangerously low level, often leading to multiple organ failure and death. To date, there is no effective therapy available for septic shock.

Now, a research team led by Professor Masashi Yanagisawa of the International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, has found that subcutaneous injection of the neuropeptide orexin can markedly improve the survival rate of mice suffering from endotoxin shock (sepsis model mice).

Orexin, first discovered by Yanagisawa and his colleagues in 1998, plays a critical role in controlling sleep and wakefulness, and is also known to alter heart rate and body temperature in rats, suggesting that it may potentially be a therapeutic agent for circulatory shock.

However, the clinical application of orexin is technically difficult because it works in the brain, and delivery of orexin to the brain is hampered by the blood-brain barrier (BBB), an interface that selectively transports essential molecules to the brain and separates the brain from the circulatory system in order to protect the central nervous system (CNS) from hazardous substances.

“We exploited the leakiness of the BBB, a hallmark pathophysiology of the systemic inflammatory syndrome, in order to deliver orexin into the CNS,” Irukayama-Tomobe says.

The researchers confirmed that peripherally injected orexin can enter the brain because of the enhanced BBB permeability caused by septic shock, which subsequently helps mice to survive and recover from septic shock by restoring body temperature and increasing the heart rate. They further found that orexin is likely to regulate immune responses through multiple signaling pathways in the brain.

Future studies include elucidation of the precise mechanism through which CNS orexin regulates the responses of the immune system. They are validating the effect of peripherally administered orexin in primates with septic shock, aiming at clinical applications in the future.

The article can be found at: Ogawa et al. (2016) Peripherally Administered Orexin Improves Survival of Mice with Endotoxin Shock.


Source: University of Tsukuba.
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