Biomedical Updates

Nicotinamide Protects
Alzheimer’s Neurons

By Will Block

NOTICE: A double-blind, placebo-controlled 7-month study to find out more about Nicotinamide and its effects on Alzheimer’s disease progression.

Nicotinamide belongs to a class of drugs known as HDAC inhibitors, dietary supplements that are being studied to determine whether chronic use is safe and effective in improving brain function in subjects with mild to moderate Alzheimer’s disease (AD).

This study is recruiting participants who:

  1. Have a diagnosis of probable AD
  2. Are 50 years of age or older
  3. Have a study partner—friend or relative who can accompany the participant to all clinic visits and answer questions about him/her
  4. There are 7 total visits to the UC Irvine campus. Visits are every 2–6 weeks

For more information on the clinical trial, contact Beatriz Yanez at 949-824-5733

remarkable paper published last November found that nicotinamide, a form of vitamin B3, could help restore memory loss in Alzheimer’s-diseased (AD) mice.1 In the words of researcher Dr. Kim Green, “Cognitively [the mice] were cured. … They performed as if they’d never developed the disease.”2 So astounding were the results that the same University of California, Irvine, researchers are currently conducting a clinical trial to determine if it can help to keep memory normal in humans (see above notice). Now, following on the heels of that encouraging paper, researchers at the National Institute on Aging (NIA) have not only confirmed the plausibility of those findings, they have also clarifying the underlying mechanisms.3

For Neurons Too Much Excitement is Deadly

Consider that neurons—the core components of our brains that transmit information—have a deep thirst for the high amounts of energy that are needed to support their function and survival. Oddly, in the process of satisfying their need to be excited, they are vulnerable to excitotoxicity, a type of cell death involving bioenergetic stress. This is the same type of stress that may occur in several neurological disorders including stroke and Alzheimer’s disease.

Also consider that nicotinamide, a water soluble member of the B vitamin group, is used by your cells to form the coenzyme nicotinamide adenine dinucleotide (NAD+). The NIA researchers studied the roles of the NAD+ bioenergetic state, and NAD+-dependent enzymes such as SIRT1 (the fabled sirtuin; see article page 4 in this issue), in excitotoxic neuronal death in cultured neurons and in a mouse model of ischemic stroke. Ischemia is the deficiency of blood supply produced by vasoconstriction or obstacles to the arterial flow in specific tissue of the body.

“Cognitively [the mice] were cured.
… They performed as if they’d never
developed [Alzheimer’s disease].”

Nicotinamide Advances Cultures

In cultured neurons, excitotoxic activation of specific neurotransmitter receptors induced a rapid decrease of cellular NAD phosphate levels and mitochondrial membrane potential. This in turn led to a series of biochemical events that resulted in the appearance of markers of premature cell death and DNA strand breakage, respectively.

Oddly, in the process of satisfying
their need to be excited, neurons
are vulnerable to excitotoxicity,
a type of cell death involving
bioenergetic stress.

While nicotinamide inhibited SIRT1 deacetylation—a sirtuin process (see article page 4 in this issue)—without affecting SIRT1 protein levels, NAD+ levels were preserved. Furthermore, cells treated by nicotinamide were found to advance two ways: There was a reduced accumulation of enzymes deadly to neurons, and a reduction in neuronal death induced by excitotoxic insults.

Nicotinamide Reduced Infarct Size in Mice

In a mouse model of cerebral ischemic stroke, NAD+ levels were decreased after the onset of ischemia. When stroke occurred, there were dynamic changes of SIRT1 protein and activity levels which varied depending on the brain regions. However, when nicotinamide was given (200 mg/kg, intraperitoneally; the equivalent of 1377 mg for a 187 lb person) up to 1 h after the onset of ischemia, it raised brain NAD+ levels and reduced the infarct size, the amount of tissue deadened by ischemia.

These findings demonstrate that the
NAD+ bioenergetic state is a major
determinant of whether neurons live
or die under conditions of
excitotoxicity and ischemia.

These findings demonstrate that the NAD+ bioenergetic state is a major determinant of whether neurons live or die under conditions of excitotoxicity and ischemia. They suggest that by preserving cellular NAD+ levels nicotinamide may provide therapeutic benefit in stroke.

There has been criticism levied against nicotinamide because its use might deny the caloric-restriction type benefits of sirtuins—by the way, this is not embraced by sirtuin pioneer Dr. David Sinclair.* Nonetheless, the findings of this study also suggest that SIRT1 is associated to bioenergetic state and stress responses in neurons, and moreover that when cellular energy levels are reduced, SIRT1 enzyme activity may consume sufficient NAD+ to nullify any cell survival-promoting effects of its sirtuin activity. All the more reasons to keep cellular energy levels high, which is what nicotinamide can do by protecting against excitotoxicity and by topping off NAD+ levels.

*Dr. Sinclair recently cautioned against the widespread belief that nicotinamide is anti-sirtuin. “One must be careful when calling nicotinamide an ‘inhibitor’ in this experiment. While it is true that our lab showed that nicotinamide is a direct inhibitor of SIRT1 enzyme, it is also a precursor of NAD+, and NAD+ is a co-substrate (i.e., activator) of SIRT1.” Moreover, “ [W]e should entertain the possibility that nicotinamide is activating SIRT1 in vivo, not inhibiting it. This would fit with other papers showing that SIRT1 is neuroprotective.” — Sinclair D. Alzheimer’s Research Forum. Nov. 11, 2008.

†Because the NIA researchers’ findings show that cellular NAD+ bioenergetic state is a critical factor in determining neuronal survival in excitotoxic and ischemic conditions, other nutrients that support the neuroprotective and increase cellular energy levels should be considered. Creatine, also an important osmolyte able to help with proper protein folding, is one such nutrient. (See Matthews RT, Ferrante RJ, Klivenyi P, Yang L, Klein AM, Mueller G, et al. Creatine and cyclocreatine attenuate MPTP neurotoxicity. Exp Neurol 1999;157:142–149. doi:10.1006/exnr.1999.7049; Matthews RT, Yang L, Jenkins BG, Ferrante RJ, Rosen BR, Kaddurah-Daouk R, et al. Neuroprotective effects of creatine and cyclocreatine in animal models of Huntington’s disease. J Neurosci 1998;18:156–163.; Sullivan PG, Geiger JD, Mattson MP, Scheff SW. Dietary supplement creatine protects against traumatic brain injury. Ann Neurol 2000;48:723–729. [PubMed: 11079535]doi:10.1002/1531-8249 (200011)48:5<723::AID-ANA5>3.0.CO;2-W.

Back to Alzheimer’s disease, the NIA researchers found that nicotinamide protects neurons against excitotoxicity, a finding consistent with previous data demonstrating its neuroprotective effects in models of Alzheimer’s and Huntington’s diseases.1 The results of the new trial utilizing nicotinamide underway at UC Irvine are eagerly awaited.


  1. Green KN, Steffan JS, Martinez-Coria H, Sun X, Schreiber SS, Thompson LM, LaFerla FM. Nicotinamide restores cognition in Alzheimer’s disease transgenic mice via a mechanism involving sirtuin inhibition and selective reduction of Thr231-phosphotau. J Neurosci 2008 Nov 5;28(45):11500-10.
  2. Dotinga R. Vitamin holds promise for Alzheimer’s disease. Healthday Nov. 5, 2008.
  3. Liu D, Gharavi R, Pitta M, Gleichmann M, Mattson MP. Nicotinamide prevents NAD+ depletion and protects neurons against excitotoxicity and cerebral ischemia: NAD+ consumption by SIRT1 may endanger energetically compromised neurons. Neuromolecular Med 2009;11(1):28-42. Epub 2009 Mar 14.

Will Block is the publisher and editorial director of Life Enhancement magazine.

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