Highlights: 

  • NMN mitigates cellular defects brought about by the chemotherapy drug cisplatin — used to treat cancers like lung, testicular, ovarian, and breast cancer.
  • Treatment with NMN prevents cisplatin-induced disruptions in mitochondrial function, such as reduced production of ATP — cellular energy. 
  • NMN prevents cisplatin-induced mitochondrial swelling, a phenomenon that occurs in response to neural injury.

“Chemobrain” is a term used to describe chemotherapy-induced cognitive impairment, which includes impaired memory, attention, and information processing. Up to 60% of chemotherapy patients experience chemobrain years following treatment. Still, there remain no effective treatments due to an unclear understanding of the processes that underlie chemobrain. 

Now, researchers from the Mayo Clinic present in Brain Plasticity evidence suggesting NMN can prevent chemobrain by restoring mitochondrial function. In human neurons, Rashid and colleagues show that NMN mitigates cisplatin-induced cellular defects like DNA damage. Furthermore, NMN prevents cisplatin-induced disruptions in mitochondrial function and structure. The findings elucidate the cellular underpinnings of previous findings showing that NMN alleviates chemo-induced memory loss. 

NMN Prevents Chemo-Induced Mitochondrial Defects in Neurons 

Cisplatin is capable of binding to mitochondrial DNA, the DNA found in mitochondria important not only for mitochondrial function but cellular function as well. Cisplatin binding to DNA causes DNA damage and increases the generation of mitochondrial reactive oxygen species (mROS). mROS are highly reactive molecules that, in excessively high concentrations, cause damage to cells — oxidative stress. 

To study the effect of NMN on cisplatin-exposed human neurons, Rashid and colleagues took stem cells from a 16-year-old male and chemically transformed them into cortical neurons. The neurons were pretreated with NMN for thirty minutes before being exposed to cisplatin for twenty-four hours. The results showed that with NMN pretreatment, cisplatin-induced DNA damage and increases in mROS were greatly reduced. 

(Rashid et al., 2023 | Brain Plasticity) NMN Reduces DNA Damage and Mitochondrial Reactive Oxygen Species (mROS). In neurons treated with cisplatin (CIS) and saline (orange), DNA damage (𝛾-H2AX foci formation) and mROS (MitoSOX intensity) are greatly increased. However, NMN (blue) largely prevents these cellular defects.

Mitochondria convert oxygen and nutrients into adenosine triphosphate (ATP), a chemical cells use for energy. As impaired mitochondria generate excessive mROS, the resulting oxidative stress dissipates the electrochemical gradient that allows mitochondria to produce ATP, leading to reduced ATP production. 

To assess the health of the mitochondrial electrochemical gradient, Rashid and colleagues measured the mitochondrial membrane potential, essentially the voltage of mitochondria. They found that cisplatin reduced both the membrane potential and level of ATP in human neurons. However, this was prevented by NMN pretreatment. 

(Rashid et al., 2023 | Brain Plasticity) NMN Prevents Mitochondrial Dysfunction. In neurons treated with cisplatin (CIS) and saline (orange), the mitochondrial membrane potential (A) and ATP levels (B) are reduced. However, NMN (blue) prevents these measures of mitochondrial dysfunction.

A structural feature of mitochondria in response to neural injury is their swelling. Rashid and colleagues measured mitochondrial swelling by assessing the size of mitochondria under a powerful (transmission electron) microscope. Cisplatin caused an increase in mitochondrial area, which was prevented by NMN, suggesting the prevention of swelling.

(Rashid et al., 2023 | Brain Plasticity) NMN Prevents Mitochondrial Structural Changes. In neurons treated with cisplatin (CIS) and saline (orange), the mitochondrial area is increased, indicative of mitochondrial swelling and neural injury.  However, NMN (blue) prevents this increase in mitochondrial size.

NMN Protects Against Cancer Therapy Side Effects 

Mitochondrial impairments are prominent features of brain aging and neurodegeneration that underlie cognitive impairment. Thus, the findings of Rashid and colleagues suggest that NMN can potentially aid in preventing brain aging and neurodegeneration, especially in response to chemotherapies like cisplatin. 

NMN has also been shown to prevent heart damage in response to doxorubicin, a chemotherapy for cancers like leukemia, and protect against intestinal wall injury in response to radiation therapy, commonly used to treat abdominal and pelvic tumors in older individuals. Thus, with more studies, we may see more evidence showing that NMN can prevent the side effects of various cancer therapies.