• Treatment with the NAD+ precursor nicotinamide reduces brain damage in a diminished brain blood flow condition called chronic cerebral hypoperfusion (CCH).
  • Nicotinamide administration also improves cognition in CCH mice.
(Liu et al., 2021 | Frontiers in Neurology) Treating chronic cerebral hypoperfusion (CCH) mice with nicotinamide facilitates white matter (myelin) recovery and improves cognition. Researchers used NAM to treat CCH mice with white matter damage. In turn, NAM facilitates the recovery of the fatty, insulating layer around nerves called myelin to alleviate white matter damage. NAM also conferred improved CCH mouse cognition, most likely resulting from the improved white matter structural integrity.

A constant supply of blood is needed to fuel the brain’s many essential functions. When we experience reduced brain blood supply over an extended time, a condition called chronic cerebral hypoperfusion (CCH), lesions form in brain regions with fatty sheaths surrounding nerves called white matter. A hallmark of this fairly common condition in aged individuals is cognitive impairment, and research has even shown that CCH-induced white matter lesions facilitate the onset of age-related neurological diseases like Alzheimer’s and Parkinson’s. For these reasons, finding ways to treat and slow CCH progression to prevent cognitive decline and neurodegenerative disease onset has significant medical value.

Liu and colleagues from Nanjing Medical University published a study in Frontiers in Neurology where they used a precursor called nicotinamide (NAM) to the physiologically vital molecule nicotinamide adenine dinucleotide (NAD+) to improve cognition in mice with experimentally-induced CCH. Their findings indicate that NAM treatment improves cognitive function, reduces depressive-like behaviors, and improves white matter integrity in CCH mice. If NAM treatment of CCH is translatable to humans, it could possibly slow or prevent the onset of age-related ailments like Alzheimer’s and Parkinson’s diseases.

Nicotinamide is a NAD+ Precursor

NAM, as a precursor to NAD+, can be used to boost NAD+ levels. NAD+ plays a key role in multiple cell energy-generating reactions, and enzymes promoting DNA repair and maintenance and overall cellular health rely on NAD+ to function. NAD+ levels diminish as humans and many other animals age, which has been linked to the onset of age-related neurodegenerative diseases. So, using NAM to boost NAD+ levels during aging may slow and mitigate human age-related cognitive decline.

Nicotinamide Treatment Restores CCH Mouse Cognitive Function

To show administering NAM to mice improves cognitive function in an experimental CCH model, Liu and colleagues tested spatial learning and memory using the Morris water maze. With this test, the research team measured the time that mice remained in an area of a circular pool with a platform located in the water that would allow them to take a break from swimming.  The more time mice spend searching for the platform, the greater the decline in spatial learning and memory. Mice with CCH took significantly longer finding the platform, but injections of 200 mg/kg NAM per day for 30 days substantially restored this amount of time. Administering NAM significantly restored learning and memory based on measurements of time spent in the pool region with a platform used to escape the water.

(Liu et al., 2021 | Frontiers in Neurology) Nicotinamide (NAM) substantially improved chronic cerebral hypoperfusion (CCH) mouse learning and memory. The amount of time it took for mice to find a platform in a pool of water to escape swimming (escape latency) over four training days was greatest in CCH mice, but NAM treatment partially restored performance (A). The duration of time spent in the region of the pool with the platform (time in target quadrant) significantly diminished in CCH mice, but NAM treatment restored it (B). The recorded swim trajectories show that non-CCH sham mice spent more time in the target quadrant with the escape platform than CCH mice. NAM-treated CCH mice spent significantly more time in the target quadrant than the CCH mice (C). These results indicate that NAM treatment restores learning and memory in CCH mice.

Nicotinamide Reduces Depressive and Anxiety-Like Behavior in Mice with Poor Brain Blood Flow

Using a battery of tests, Liu and colleagues also measured depressive and anxiety-like behaviors, which are manifestations of cognitive deficits, in CCH miceThe researchers used an open field test where mice could either huddle to a corner or run around toward the center of a square enclosure indicating exploratory, non-depressed behavior. They also used a sucrose preference test providing a choice between drinking sucrose-infused water or regular water where non-depressed mice seeking pleasure would prefer sucrose. The third depression and anxiety test given was the forced swim test where mice were placed in a pool of water; in this scenario, depressed and anxious mice don’t swim, rendering them immobile. In all three instances, CCH mice showed significant signs of depressive and anxiety-like behaviors, but NAM treatment rescued these behavioral attributes toward normal levels.

(Liu et al., 2021 | Frontiers in Neurology) NAM treatment reduced depressive and anxiety-like behavior in CCH mice. The open-field test measures exploratory behavior with lower distances traveled and less time spent in the center zone indicative of depressed behavior. The trajectories at the top show non-CCH shame mice ran substantially longer distances and spent more time in the center zone than the CCH mice. NAM treatment partially restored these measures in CCH mice (A). The open-field test graphs show that NAM partially restored CCH mouse running distance (B) and time spent in the center zone (C). The sucrose preference test indicated that NAM treatment partially restored CCH mouse preference for pleasure (D). The forced swim test shows that NAM-treated CCH mice spend less time in a state of immobility when placed in a pool of water indicative of less depressed behavior than non-treated CCH mice (E).

Nicotinamide Reduces White Matter Brain Damage

Structural abnormalities of the brain often precede functional problems, resulting in aberrant or dysfunctional cognition and behavior. Since NAM administration improves CCH mouse cognition and behavior, Liu and colleagues wanted to find out whether NAM also mitigates CCH mouse brain structure abnormalities, specifically as they relate to white matter integrity. They found NAM treatment diminished the presence of harmful small white matter cavities called vacuoles in CCH mouse white matter, which resulted in less overall white matter damage following NAM treatment of CCH mice. These findings suggest that cognitive function and behavioral improvements seen in NAM-treated CCH mice came from reduced damage to brain white matter.

(Liu et al., 2021 | Frontiers in Neurology) NAM treatment reduces CCH mouse white matter brain damage. The top images show hematoxylin and eosin staining of brain white matter. Hematoxylin stains the cell nuclei blue and eosin stains other cellular material pink. The images show that non-CCH sham mice have more structural integrity and fewer gaps called vacuoles in the pink cellular material compared to CCH mice. NAM treatment of CCH mice reduces the presence of vacuoles and white matter damage toward that of non-CCH sham mice. The graph on the right illustrates these findings (A). The bottom images show Klüver-Barrera staining of white matter which is used to detect loss of myelin, the fatty sheath that surrounds nerves and makes up white matter. Myelin fibers are blue and nerve cells appear purple. The images show that CCH mice have white matter damage but that NAM treatment partially restores the white matter myelination.

This study shows that NAM treatment reduces white matter damage and improves cognition in CCH mice. But how NAM confers these benefits remains unknown. “The mechanism of action of NAM was not investigated,” stated Liu and colleagues in the publication. They propose that NAM may protect neurons and prevent inflammation by promoting DNA stability.

The Long-Term Effects and Human Translatability of Nicotinamide Treatment

Liu and colleagues say that further research on NAM treatment of cognitive impairment is needed. They recommend administering NAM over longer periods to test its potentially toxic effects since they used a short treatment duration in the study. Researchers will need to eventually find whether NAM reduces human white matter damage to prevent cognitive decline in long-term reduced brain blood flow conditions like CCH. If so, boosting NAD+ levels with the NAM precursor may provide a means to prevent cognitive decline stemming from this condition.