Cholinesterase Inhibitors: New Findings/New Benefits

The Durk Pearson & Sandy Shaw®
Life Extension NewsTM
Volume 8 No. 2 • April 2005


Cholinesterase Inhibitors: New Findings/New Benefits

As you know, cholinesterase inhibitors are a new class of drugs used in the treatment of Alzheimer’s disease. Cerebral-selective cholinesterase inhibitors (these work primarily in the brain, rather than equally affecting cholinesterase throughout the body) include donepezil and galantamine. Clinical trials using donepezil (presumably as a monotherapy) show Alzheimer’s patients deriving long-lasting beneficial effects, for at least two years.1

Two new studies1,2 by two independent groups using donepezil reveal exciting new effects in humans. Donepezil was chosen for the first study1 because it is the most widely used selective cerebral cholinesterase inhibitor for Alzheimer’s, with a low rate of side effects. The first study1 was a randomized, controlled study of donepezil in 24 healthy elderly males 61–70 years of age. The effects of donepezil at 5 mg/day for 4 weeks and then 10 mg/day for another 4 weeks were determined for GH release and IGF-1 levels.

The authors cite an earlier study in which the cerebral-selective cholinesterase inhibitor rivastigmine powerfully enhanced GH release in response to repeated GHRH (growth hormone-releasing hormone) pulses in healthy elderly male and female subjects. The mechanism for this potentiation is probably via the inhibition of somatostatin, a hormone that inhibits growth hormone release from the pituitary.1 One benefit of using a selective cholinesterase inhibitor to increase GH release as compared to using GH itself is (aside from the cost and inconvenience of injections) that the GH release in response to the cholinesterase inhibitor is still subject to natural regulatory mechanisms, so that the GH is released when it normally would be, only more so, whereas GH treatments cause GH effects without control mechanisms in place to limit it to physiological functionality. As a consequence, human treatment with actual GH has been fraught with side effects, such as edema, arthralgia, myalgia, and nerve-compression syndromes,1 as well as increased blood sugar levels (reduced glucose tolerance).

The authors report that “The main finding of this study was that full-dose treatment with the cerebral-selective ChEI donepezil elevated basal GH and IGF-1 to a remarkably increased level in the elderly male.” In fact, they found an increase of total serum IGF-1 of 31%, resulting in levels that are seen in males 20 years younger. The authors note the correlation of IGF-1 with lean body mass, bone mineral density, and cognitive function.1 IGF-1 is an important neuroprotective growth factor. They also note that lower IGF-1 levels are correlated with an increased risk of cardiovascular disease. On the potential downside, higher levels of IGF-1 are correlated with increased risks of certain cancers, such as prostate, breast, colorectal, and lung, but (the authors state) the associations are “modest and vary between sites.”

The second study2 examined, in 21 Alzheimer’s patients, the effects of 10 mg/day of donepezil for a month on release of inflammatory cytokines by peripheral blood mononuclear cells (PBMC), immune cells in the periphery. The important negative effects of excess inflammatory cytokines (largely released by the brain’s resident immune cells, microglia) on brain function are well established. The authors note that PBMC from Alzheimer’s patients release more amyloid precursor protein (APP) as compared to normal individuals; hence, they suggest that PBMC could be a circulating factory of APP that can deliver abnormal amyloid for deposition in the brain and peripheral tissues. In fact, inflammatory cytokines have been shown to increase APP expression in Alzheimer’s.

One of the interesting effects of acetylcholine is that, acting through the vagus nerve, it acts as an anti-inflammatory.3 Hence we have long thought that it would help to reduce inflammatory processes by increasing cholinergic activity through a choline and vitamin B5 (required to convert choline to acetylcholine) supplement. Now we also take our galantamine supplement to increase acetylcholine further.

The results showed that the unstimulated PBMC of Alzheimer’s subjects in the study spontaneously produced higher amounts of the inflammatory cytokines IL-6 and IL-1beta, as well as more OSM (oncostatin-M), which has both pro-inflammatory and anti-inflammatory effects. The authors note that this means the patients’ PBMC were already partially activated, although unstimulated. The effects of the 1-month treatment with 10 mg/day of donepezil showed that both unstimulated (spontaneous) and PHA-stimulated PBMC in all subjects released lower levels of OSM, IL-1beta (57% reduction in spontaneous, 54% in stimulated conditions), and IL-6. The results indicate that, although Alzheimer’s is considered a brain disorder, it also has peripheral effects, in this case an increase in pro-inflammatory immune activity. Since increased inflammation promotes a variety of age-associated diseases, such as cancer, cardiovascular disease, and neurodegenerative diseases, a decrease in inflammation through increased acetylcholine could be a major health benefit of selective cerebral cholinesterase inhibitors.

References

  1. Obermayr et al. The age-related down-regulation of the growth hormone/insulin-like growth factor-1 axis in the elderly male is reversed considerably by donepezil, a drug for Alzheimer’s disease. Exp Gerontol 40:157-63 (2005).
  2. Reale et al. Acetylcholinesterase inhibitors effects on oncostatin-M, interleukin-1beta, and interleukin-6 release from lymphocytes of Alzheimer’s disease patients. Exp Gerontol 40:165-71 (2005).
  3. Borovikova et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 405:458-62 (2000).

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