Highlights

• Inflammation impairs mitochondria and mitophagy, worsening brain cell damage.

• Supplementing with NMN restores cellular energy but may overstimulate harmful pathways.

• Combining NMN with a PARP1 inhibitor restores mitochondrial health and supports brain resilience.

Bringing the brain’s energy and immune systems back into balance is a promising new way for scientists to fight neurodegenerative diseases. Researchers at Ningxia Medical University recently published a study that shows how nicotinamide mononucleotide (NMN), a compound that gives you energy, and PJ34, an anti-inflammatory compound, can work together to heal brain cells and make them able to survive inflammatory stress. According to the study published in the Journal of Translational Medicine, this two-pronged approach shows promise for creating new ways to treat neurodegenerative disorders linked to mitochondrial damage.

Fighting Inflammation to Support an Aging Brain

Neurodegenerative diseases like Alzheimer’s and Parkinson’s are characterized by neuroinflammation, which is the brain’s immune response to damage or illness. At first, this immune response is helpful, but it can become too strong and harmful, messing up the work of cells and speeding up the disease’s progression. At the level of cells, this inflammation wrecks mitochondria, which are the little power plants that make cells do everything. One big reason why our brains get worse as we age is that our mitochondria stop working properly.

Some important molecules, like NAD+, become less common as we age. When NAD+ levels drop, mitochondria have a harder time making the energy cells need to work. This makes it easier for stress and inflammation to hurt brain cells.

A building block for NAD+ called nicotinamide mononucleotide (NMN) has gotten a lot of attention because it might be able to raise NAD+ levels, speed up energy metabolism, and improve the health of mitochondria. Early research suggests that taking NMN supplements might help make up for energy losses that come with getting older and make brain cells stronger.

But increasing NAD+ is not always enough. As an example, PARP1 is an enzyme that helps fix DNA damage but, when overactive, lowers NAD+ levels and starts brain processes that are harmful. This scenario creates a paradox: while NMN replenishes NAD+, an overactive PARP1 could undermine these benefits.

Luckily, scientists have found a way to solve this problem: they can use a drug called PJ-34 to stop PARP1 from working. The new study looked at what happened when NMN and PJ-34 were mixed. It found that they worked together to reduce neuroinflammation and mitochondrial damage.

An Effective Anti-Inflammatory Mix: NMN and PJ-34

Researchers used lipopolysaccharide (LPS), a compound that acts like an infection, to make lab-grown brain immune cells (called BV2 cells) swell up like inflammation in the brain. This exposure set off a chain of bad events: NMNAT3 activity dropped, which is an important enzyme for making mitochondrial NAD+, and PARP1 activity went through the roof. It made mitochondria stop working, lowered the energy level of cells, and stopped the process of cleaning up damaged mitochondria, which is called mitophagy.

When the researchers used NMN and PJ-34 on the inflamed cells together, they saw amazing results:

  • NMNAT3 levels were raised again, which meant that the process restored the cells’ ability to make mitochondrial NAD+.

  • Parp1 activity was lowered, which kept NAD+ levels high and stopped harmful cellular processes.

  • Cellular ATP levels were raised again, which made sure that vital functions had the energy they needed.

  • It became easier to get rid of damaged mitochondria and stop the buildup of broken parts.

Under a microscope, the treated cells showed a remarkable improvement in the structure and function of their mitochondria.

Mitochondrial Dynamics: Fusion, Fission, and Function

The shape of mitochondria is always changing because of processes known as fusion and fission. Fission helps separate damaged parts so they can be taken out, while fusion lets mitochondria join together and share resources. For mitochondria to work and cells to stay strong, there needs to be a good balance between these processes.

The researchers saw a change in this balance in the cells that were exposed to LPS: too much fission caused mitochondria to break up, while fusion processes were slowed down. Cellular stress got worse because of this imbalance, which led to mitochondrial dysfunction. Using NMN and PJ-34 to treat the condition helped bring back balance. The mitochondria’s structural recovery was in line with better energy production and better cell function.

NMN and PJ-34 reverse deleterious effects in a model of brain inflammation.
(Li et al., 2025 | Journal of Translational Medicine) NMN and PJ-34 reverse deleterious effects in a model of brain inflammation. Lab-grown brain immune cells (called BV2 cells) were treated with lipopolysaccharide (LPS), a compound that simulates infection, to mimic inflammation in the brain, causing a decrease in cell viability (left), mitochondrial length (middle), and energy levels (center). Treatment with NMN alone reversed the effects of LPS. The combination of NMN and PJ-34 produced an even stronger reversal, increasing cell viability numbers beyond those of healthy, untreated control cells.

A New Avenue for Treating Neurodegeneration

These results strongly suggest that using NMN along with a PARP1 inhibitor like PJ-34 could improve the quality of mitochondria, balance energy metabolism, and lessen the damage to the brain caused by inflammation. This two-pronged approach targets both NAD+ metabolism and mitochondrial repair, two important factors in the development of neurodegenerative diseases.

This study suggests that NMN could have even more neuroprotective effects when combined with PARP1 inhibitors. NMN is already being tested in clinical trials for its effects on aging and metabolic health.

This combination therapy might be able to treat or even stop diseases like Alzheimer’s and Parkinson’s by working on both making energy and repairing damage caused by inflammation.

In addition, this study shows how important healthy mitochondria are for brain resilience. A lot of neurodegenerative diseases are caused by a cycle of inflammation and mitochondrial dysfunction, and breaking this cycle could have huge effects on older populations.

In summary, boosting cellular energy with NMN shows promise, but combining it with a PARP1 inhibitor may be the real key to defending the brain against inflammation and age-related decline. As research advances, the prospect of safeguarding the brain from the damaging effects of aging and disease becomes increasingly plausible.