Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. Sepsis-associated encephalopathy (SAE) is one of the common serious complications of sepsis.
Many previous studies have shown that NMN has a protective effect on the brain and can improve cognitive dysfunction.
A study published in "REDOX BIOLOGY" by Changhai Hospital of Naval Medical University in 2023 found that NMN can alleviate memory dysfunction and neuron damage caused by sepsis, and reduce the inflammatory response and oxidative stress in the hippocampus of mice. NAD+/SIRT1 Pathways may be one of the mechanisms involved in protection.
The exact mechanism of sepsis-related encephalopathy is not fully understood, but the inflammatory response and abnormal activity of the immune system are thought to be key factors. Since NAD+ plays a vital role in cellular energy metabolism, immune inflammation and oxidative stress response, the researchers focused on NMN, the precursor of NAD+.
1. Sepsis leads to NAD+/SRIT1 pathway depletion
The researchers established a mouse model of sepsis-associated encephalopathy (SAE) by cecal ligation and puncture (CLP), and conducted a control study with a sham operation group (SHAM). By measuring the levels of NAD+, SIRT1 and PGC-1α in the hippocampus of the mouse brain, it was found that the NAD+ in the hippocampus of the CLP-induced sepsis mice was significantly lower than that of the control (SHAM) mice, and the same SIRT1 and PGC- Expression of 1α was also significantly reduced in CLP mice. Also, inflammation was enhanced in the hippocampus of septic mice.
Figure: The level of NAD+ in the hippocampus of CLP mice was significantly lower than that of the control group
NAD+ (nicotinamide adenine dinucleotide) is an important coenzyme involved in various biochemical reactions, and the decrease of NAD+ level is related to problems such as aging, disease and metabolic disorders. SIRT1 is an important member of the Sirtuins family known as "longevity protein" and needs to rely on NAD+ to function. The SIRT1/PGC-1α pathway is an important pathway to maintain the normal function of mitochondria and regulate cell metabolism. This suggests that sepsis leads to depletion of the NAD+/SRIT1 pathway, which in turn affects mitochondrial function and cellular metabolism.
2. NMN relieves memory impairment caused by sepsis
The researchers further found that NMN supplementation could significantly enhance the level of NAD+ in the hippocampus of CLP-induced sepsis mice within 24 hours, and also restore the NAD+ level to a certain extent within 72 hours. NMN treatment increases the expression of SIRT1 and PGC-1α in the hippocampus of septic mice. Meanwhile, western blot showed that NMN decreased the phosphorylation levels of P65 and P38 in the hippocampus of septic mice, indicating that the inflammatory response was suppressed.
Figure: NMN enhanced NAD+ levels and reduced inflammatory responses in CLP mice
The researchers further used the Morris water maze and conditioned fear experiments to test whether NMN could alleviate memory impairment in septic mice. In the Morris water maze test, compared with the control group, the CLP-induced sepsis group needed to spend more escape time, while NMN treatment could restore them to some extent. In the conditioned fear experiment, NMN also restored the characteristic immobility state (Freezing) in the fear response of CLP-induced septic mice. Prove that NMN may play a role in improving CLP-induced memory impairment.
Figure: NMN improves memory impairment in CLP mice
3. NMN inhibits neuroinflammation and oxidative stress
The researchers assessed the effect of NAD+ on sepsis-induced apoptosis in the hippocampal region by TUNEL assessment. It was found that the apoptosis rate of the CLP group was significantly higher than that of the control group mice, while NMN significantly reduced the apoptotic cells.
Microglial activation is a hallmark of neuroinflammation in sepsis-associated encephalopathy (SAE). The activated microglia in the hippocampus of CLP mice significantly increased, while NMN treatment significantly decreased the number of activated microglia, suggesting that NMN may inhibit neuroinflammation by inhibiting the activity of microglia.
Figure: NMN attenuates apoptosis and inhibits microglial activation in the hippocampal region
Because inflammatory response and oxidative stress are closely related to the pathogenesis of SAE, the researchers detected the levels of inflammatory cytokines and oxidation levels in the hippocampus of septic mice, and the results showed that the plasma and hippocampus of septic mice included The levels of inflammatory cytokines including IL-6, IL-1β, and TNF-α were significantly increased, while NMN treatment significantly decreased the levels of inflammatory cytokines. Likewise, NMN also significantly reduced oxidative stress in the hippocampus.
Figure: NMN reduces levels of inflammatory factors in plasma and hippocampus and oxidative stress in hippocampus
Sepsis caused by bacterial infection is accompanied by a decrease in NAD+ levels, and is prone to serious complications - sepsis-associated encephalopathy (SAE). NMN can improve memory impairment, neuroinflammation and oxidative stress caused by sepsis to a certain extent. This protective effect of NMN may be related to its enhanced NAD+/SIRT1 activity.