Nicotinamide (NAM) ameliorates neuron connection integrity in mice with reduced brain blood flow(Pikovit44 | iStock)
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.
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.
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.
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.
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.
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.
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.