Inflammation in the body is often linked to feeling sick, tired, or feverish, but scientists have long suspected that its effects can reach much deeper, including into the brain.
Over many years, researchers have suggested that strong or repeated inflammation may help trigger brain diseases such as Alzheimer’s and Parkinson’s disease.
Now, a new study from Japan offers clearer evidence of how this process may begin, showing that inflammation can disturb brain chemistry in very specific ways, even before obvious brain damage appears.
The study was led by Professor Kei Zaitsu from Kindai University in Japan and was published online on November 30, 2025, in the Journal of Proteome Research.
The research focused on what happens inside the brain during acute systemic inflammation, which is a strong inflammatory reaction affecting the entire body. This type of inflammation can occur during severe infections, injuries, or major immune responses.
To better understand this process, the researchers used a well-established animal model. They gave mice a high dose of lipopolysaccharide, often called LPS. LPS is a substance found on the surface of certain bacteria and is commonly used in research to trigger a powerful immune response.
After the injection, the mice showed a sharp increase in a blood marker called interleukin-1 beta, which confirmed that the body-wide inflammatory response was successfully activated.
The researchers then examined four different parts of the brain: the cerebrum, hippocampus, cerebellum, and hypothalamus.
These regions play different roles, including thinking, memory, movement, and hormone control. Instead of looking at brain structure, the team focused on metabolism, meaning the chemical reactions that keep brain cells alive and functioning.
To do this, they used a fast and advanced technique called PiTMaP-based metabolomics. This method allows scientists to measure many small molecules directly from brain tissue with very little preparation.
Using this approach, the team measured more than 70 different metabolites from each brain region, giving them a detailed picture of how inflammation affects brain chemistry.
What they found was surprising. Only one brain region, the cerebrum, showed clear and significant metabolic disruption. The other areas remained mostly unchanged. This suggests that the cerebrum may be especially vulnerable to inflammation, even when the rest of the brain appears stable.
One of the most important findings involved a substance called N-acetylaspartic acid, or NAA. NAA is commonly used as a marker of neuron health. Lower levels of NAA are often seen when neurons are stressed or damaged.
In this study, NAA levels in the cerebrum dropped sharply after inflammation, and the drop closely matched the rise in inflammatory markers in the blood. This strongly suggests that inflammation in the body can directly place stress on brain cells.
The researchers also found lower levels of aspartic acid and malic acid in the cerebrum. These molecules are part of an important energy pathway called the malate–aspartate shuttle. This pathway helps brain cells move energy into mitochondria, which are the cell’s power plants.
When this shuttle does not work properly, cells struggle to produce enough energy. The tight link between these metabolites showed that inflammation interfered with energy flow inside brain cells.
Another key discovery was a rise in urea levels in the cerebrum. Urea is normally processed and removed by the body, but when it builds up in the brain, it may become harmful. Past studies have already linked excess urea to diseases like Alzheimer’s and Huntington’s disease.
In this research, urea appeared as a central player in the disrupted metabolic network, suggesting that inflammation may push brain support cells into abnormal waste-handling behavior.
Together, these changes paint a clear picture. Acute inflammation can quietly disrupt brain metabolism by lowering neuron-protective substances, weakening energy production, and increasing toxic waste buildup. Importantly, these changes appear before visible brain damage occurs, meaning they may represent very early warning signs.
At the end of the study, the researchers analyzed their findings using advanced computer tools, including machine learning. Their models were able to perfectly separate inflamed brains from healthy ones based on metabolic patterns alone. This highlights how powerful these chemical signals are as indicators of brain stress.
In reviewing these findings, the study strongly supports the idea that inflammation does not affect the brain evenly. Instead, it targets specific regions and specific chemical systems.
The cerebrum appears particularly sensitive, and the early breakdown of energy and waste pathways may help explain how long-term inflammation increases the risk of neurodegenerative disease.
While this research was done in mice, it opens the door to future human studies that may use similar markers to detect brain risk early. If these metabolic changes can be measured outside the brain, they could one day help doctors identify people at risk long before symptoms begin.
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