A study published in Frontiers in Neurology has detailed how three well-known longevity-associated compounds affect vascular cognitive impairment (VCI) in a rat model.
A rat model of a common human disease
In bilateral common carotid artery occlusion (BCCAO), the arteries of rats are sutured to reduce blood flow. This mimics arterial occlusion in human beings [1], which frequently occurs in the elderly and leads to VCI. This disease is only slightly less common than Alzheimer’s disease, and its incidence is gradually increasing [2].
The researchers go into detail regarding nicotinamide mononucleotide (NMN), metformin, and rapamycin, citing previous studies that have shown positive effects. Metformin has been reported to potentially have effects against Alzheimer’s, Parkinson’s, and Huntington’s [3]. Rapamycin was reported to have effectiveness in a rat model of Alzheimer’s [4]. NMN was reported to have positive effects on Alzheimer’s by mediating one of the important activators involved [5].
With this prior research and well-known methodology in hand, the researchers began their own rat study, comparing these three compounds against one another along with an undrugged BCCAO group and a group given a sham surgery.
Pretreatment and behavior analysis
Instead of administering any of these compounds to the rats after their arteries were occluded, the researchers chose to administer them every day for two weeks beforehand. Rats in the BCCAO-only group and the rapamycin group had notably less body mass than the sham group, and rats given metformin and NMN had notably more.
The researchers performed two major cognitive tests on the rats. The novel object recognition test, which judges a rat’s ability to determine whether or not it has seen an object before, was conducted three weeks after the surgery. The BCCAO rats performed poorly on this test compared to the sham group. However, rats given BCCAO along with any of the three tested compounds performed almost as well as rats given the sham surgery.
The Morris water maze test focuses on rats’ ability to find and stay on a platform located underwater, and it was conducted a month after the surgery. Here, the story was similar; rats given BCCAO performed much more poorly than the sham group, although rapamycin seemed to be slightly but not significantly less effective than the other compounds.
Analysis under the microscope
After the cognitive tests, the researchers sacrificed the animals in order to examinine various regions of their brains. While none of the compounds yielded much benefit in the corpus callosum, BCCAO had much less effect on the internal capsule and the striatum in all three treatment groups. The effect of BCCAO on biomarkers for myelin were also greatly ameliorated in all three treatment groups as well.
The microglia were also substantially affected. Iba1+ microglia were dramatically increased after BCCAO but slightly reduced by any treatment. Iba1+ microglia that were also positive for CD68, a marker of the inflammatory M1 macrophage type, were also increased by BCCAO but halved by any treatment. Interestingly, Iba1+ and CD206+ proteins, markers for M2 healing-type macrophages, were not directly increased by BCCAO but were substantially increased by any of the treatments, with NMN doing the most good and rapamycin doing slightly less in this regard.
Conclusion
While strongly conclusive, this study leaves many questions unanswered. All three treatments had very similar effects despite having putatively different mechanisms of action. There was no non-BCCAO group given any of these treatments, which would have been potentially useful data. No combination therapy was given, so we do not know if multiple treatments might have been antagonistic, additive, or even synergistic.
Still, this research is strong enough to raise the question of whether it might be time to engage in human clinical trials of any or all of these compounds. If such trials are successful, the resulting treatment regimen could potentially reduce the incidence or severity of an all-too-common brain disease.
Literature
[1] Farkas, E., Luiten, P. G., & Bari, F. (2007). Permanent, bilateral common carotid artery occlusion in the rat: a model for chronic cerebral hypoperfusion-related neurodegenerative diseases. Brain research reviews, 54(1), 162-180.
[2] Gorelick, P. B., Scuteri, A., Black, S. E., DeCarli, C., Greenberg, S. M., Iadecola, C., … & Seshadri, S. (2011). Vascular contributions to cognitive impairment and dementia: a statement for healthcare professionals from the American Heart Association/American Stroke Association. stroke, 42(9), 2672-2713.
[3] Aliper, A., Jellen, L., Cortese, F., Artemov, A., Karpinsky-Semper, D., Moskalev, A., … & Zhavoronkov, A. (2017). Towards natural mimetics of metformin and rapamycin. Aging (Albany NY), 9(11), 2245.
[4] Saunders, R. N., Metcalfe, M. S., & Nicholson, M. L. (2001). Rapamycin in transplantation: a review of the evidence. Kidney international, 59(1), 3-16.
[5] Yao, Z., Yang, W., Gao, Z., & Jia, P. (2017). Nicotinamide mononucleotide inhibits JNK activation to reverse Alzheimer disease. Neuroscience letters, 647, 133-140.
