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The most clinically fruitful manipulations of the cholinergic system have involved inhibition of the enzyme acetylcholinesterase (AChE), which results in increased acetylcholine levels (32, 33, 34). The first-generation drugs, such as physostigmine and tacrine, suffered from the drawbacks of non-selectivity and short duration of action; in addition, tacrine is hepatotoxic. The third-generation drugs are selective (no effect on butyrlcholinesterase) and long-acting. Examples are donepezil and phenserine (a physostigmine derivative). The only two drugs approved for treating Alzheimer’s disease in the U.S. are tacrine and donepezil. Their use results in modest benefits which are lost when the drug is discontinued. Recently, an alkaloid from Huperzia serrata with potent anti-AChE activity has successfully undergone clinical tests in China in patients with disorders ranging from forgetfulness to Alzheimer’s disease (35).
With respect to the catecholamine system, these neurotransmitters are formed by the stepwise conversion of tyrosine into dopa and then to dopamine, noradrenaline, and adrenaline. Because the enzymatic step following tyrosine is rate-limiting, it is not therapeutically very useful to administer large amounts of tyrosine in the expectation of achieving high levels of catecholamine neurotransmitters. The use of L-dopa is altogether another story; precursor therapy (a politically-correct term for orthomolecular therapy) with this substance has been quite successful in Parkinson’s disease. The therapeutic use of selegiline, a monamine oxidase-B inhibitor, is generally preferred nowadays. Catacholamine agonists include bromocriptine, a well-known dopamine D2 receptor agonist, and adrafanil, a central alpha adrenergic agonist which, although not extensively researched, has been promoted as a new category of drug, "eugregoric".
In view of the NMDA receptor’s role in excitotoxic neuronal death, strategies involving its stimulation (29) might invoke visions of mad doctors and therapeutic nihilism. However, the NMDA receptor is involved in learning. Blocking the receptor’s calcium channel with dizocilpine impairs learning, at least in rats. Presumably receptor agonists such as glutamate, glycine, polyamines (e.g., spermidine), D-cycloserine, and milacemide might have a role in enhancing memory. Ingram (29) suggests possible combined use with AChE inhibitors. On the other hand, calcium channel blockers, such as nimodipine, might prove useful in the event of overstimulation of NMDA receptors; they also have the beneficial effect of raising DHEA.
Nitric oxide in the nervous system is derived from the action of neuronal nitric oxide synthase on arginine. As mentioned above, NO may be involved in neuronal damage when intracellular calcium is high. It is also evidently involved in learning, as the antagonist N-nitro-L-arginine is able to block learning. Nitric oxide may function as a common signal transduction pathway between NMDA and muscarinic Ach receptors (36).
CIRCULATORY DRUGS AND HERBS. Among agents that enhance circulation, Ginkgo biloba has probably received the most attention. Werbach and Murray (37) list a dozen relevant human studies in their reference book. Recently, LeBars et al. (38) conducted a placebo-controlled, double blind, randomized study on the use of a ginkgo extract in dementia due to Alzheimer’s disease or stroke. Twice as many subjects improved, and half as many deteriorated, in the treatment group. The results, which took 6 months to become apparent, were enhanced cognitive performance and social function for 6 months to 1 year in a substantial number of those on ginkgo.
Another botanical circulatory aid is vinpocetine, a derivative of vincamine, extracted from the periwinkle and now available in the United States as a dietary supplement. It has been found useful in stroke, inner ear disorders and deafness, space-motion sickness, eye disorders, and memory enhancement.
Other agents that help circulation include piracetam, picamilon, and a procaine-hematoporphyrin mixture sold under the name KH3. The former two are GABA derivatives, although piracetam is devoid of GABAergic activity. Picamilon, which is the sodium salt of N-nicotinoyl-GABA, has been demonstrated to increase cerebral blood flow in cats.
ENERGY METABOLISM. The influence of orthomolecular substances on energy metabolism has been discussed previously. Pharmaceuticals also influence energy metabolism in various ways. Meclofenoxate enhances glucose uptake. Ergoloid mesylates ehnance ATP synthesis, as well as increasing synaptic contacts and stabilizing neuronal cyclic AMP (39). Vinpocetine, in addition to enhancing circulation, improves oxygen utilization. This makes it useful in altitude sickness and presumably other hypoxic situations. It also is claimed to improve brain glucose uptake and ATP production. Piracetam, in addition to its previously-stated benefits, also enhances ATP production and oxygen utilization.
ANTIOXIDANTS. One of the unpleasant paradoxes of life is that the cool oxidative fire that sustains it, also burns up the vessel that contains it. Fortunately Nature has provided a panoply of antioxidants for protection: endogenous ones like glutathione, melatonin, CoQ10, and lipoic acid, and exogenous ones such as carotenoids, tocopherols, proanthocyanidins, flavonoids, ascorbate, and so forth. To these the pharmaceutical chemists have added a few new ones: meclofenoxate, selegiline, ergoloid mesylates, thiodipropionic acid, and the preservatives BHA and BHT. Selegiline is noteworthy for upregulating antioxidant enzyme activities (40) while suppressing hydroxyl radical formation in the substantia nigra (41). Piracetam also participates in hydroxyl radical scavenging.
MISCELLANEOUS AGENTS. Flupirtine is an analgesic drug, sold in Europe under the name Katadolon®, that has been in clinical use about 10 years. Recently, it has been shown in nerve cell culture to possess activity against apoptotic inducers (including glutamate and an amyloid b-protein-precursor fragment), making it potentially of great value in Alzheimer’s disease. Flupirtine prevents glutamate (NMDA receptor) toxicity through restoring glutathione levels, by inducing bcl-2, a proto-oncogene whose upregulation improves cell survival, and by moderating intracellular calcium (42).
With the discovery that apolipoprotein E is a risk factor for Alzheimer’s disease (43), many pharmaceutical and orthomolecular methods to control lipids have entered the realm of "smart" substances. The orthomolecular ones would include diets, fiber, chromium, essential fatty acids, antioxidants, and niacin, among others.
Other anti-aging substances include anti-amyloid and anti-crosslinking agents, and hormones. A side benefit of AChE inhibitors is their anti-amyloid effect. Cross-linking of proteins is a feature of aging that aminoguanidine is able to influence. Hormones have anti-aging effects of such depth and diversity that they would properly be subjects of a separate review greater in length than this one. The more popular anti-aging hormones are somatotropin, DHEA, vasopressin and melatonin, but one should not underestimate the importance of the sex hormones and thyroxine.
CONCLUSION. In conclusion, it is probably worth-while to keep in mind the distinction between physiologic developmental processes and diseases. Aging is an example of the former. It is no more a disease than is puberty, although I suppose some adolescents’ parents might dispute the aptness of my metaphor. The occurrence of diseases is made more likely by the decreased vitality and slower repair rates in aging, but specific diseases are not universal physiological processes. To treat diseases, pharmacologic intervention is honored by long and mainly successful usage.
On the other hand, for physiologic processes, a pharmacologic strategy seems ill-conceived. The process of aging will more likely come under control through orthomolecular manipulation of cell and molecular biology, through such means as increasing the count of redundant DNA molecules, replenishing defective mitochondria, enhancing metabolic efficiency, upregulating receptors, extending telomeres, and so forth. We are unlikely to find a single "magic bullet" for aging. If we rely too heavily on pharmacology before understanding the fundamental physiologic process we wish to target, we will only be firing shots in the dark.
REFERENCES
1. Harman, D: The aging process. Chapter 5 in Huemer, RP (ed.), The Roots of Molecular Medicine, WH Freeman, New York, 1986, pp 75-87
2. Nohl H: Involvement of free radicals in ageing: a consequence or cause of senescence. Br Med Bull 1993; 49:653-667
3. Strehler BL: Genetic instability as the primary cause of human aging. Exp. Geront. 1986; 283-319.
4. Strehler BL, Chang MP, Johnson LK: Loss of hybridizable ribosomal DNA from human post-mitotic tissues during aging: I. Age-dependent loss in human myocardium. Mech. Age. Devel. 1979; 11:371-378
5. Huemer, RP, Lee, KD, Reeves, AE, Bickert, C: Mitochondrial studies in senescent mice—II. Specific activity, buoyant density, and turnover of mitochondrial DNA. Exp. Geront. 1971; 6:327-334
6. Miquel J: An update on the oxygen stress-mitochondrial mutation theory of aging: genetic and evolutionary implications. Exp. Geront. 1998; 33:113-126
7. Lestienne P: Mitochondrial DNA mutations in human diseases: a review. Biochimie 1992; 74:123-130
8. Hayashi J, Ohta S, Kagawa Y, et al: Nuclear but not mitochondrial genome involvement in human age-related mitochondrial dysfunction. Functional integrity of mitochondrial DNA from aged subjects. J Biol Chem 1994; 269:6878-6883
9. Wallace, DC: Mitochondrial DNA in aging and disease. Scient Amer 1997 Aug; 277(2):40-47
10. Swerdlow RH, Parks JK, Miller SW, et al: Origin and functional consequences of the complex I defect in Parkinson’s disease. Ann Neurol 1996; 40:663-671
11. Miyako K, Kai Y, Irie T, et al: The content of intracellular mitochondrial DNA is decreased by l-methyl- 4-phenylpyridinium ion (MPP+). J Biol Chem 1997; 272:9605-9608
12. Kuhn W, Muller T, Winkel R, et al.: Parenteral application of NADH in Parkinson’s disease: clinical improvement partially due to stimulation of endogenous levodopa biosynthesis. J. Neural Transm 1996; 103:1187-1193
13. Lin FH, Wisniewski HM, Hwang YW, et al.: Detection of point mutations in codon 331 of mitochondrial NADH dehydrogenase subunit 2 in Alzheimer’s brains. Biochem Biophys Res Commun 1992; 182:238-246
14. Schnopp NM, Kosel S, Egensperger R, Graeber MB: Regional heterogeneity of mtDNA heteroplasmy in Parkinsonian brain. Clin Neuropathol 1996; 15:348-342
15. Kosel S, Egensperger R, Mehracin P, Graeber MB: No association of mutations at nucleotide 5460 of mitochondrial NADH dehydrogenase with Alzheimer’s disease. Biochem Biophys Res Commun 1994; 745-749
16. Birkmayer JG: Coenzyme nicotinamide adenine dinucleotide: new therapeutic approach for improving dementia of the Alzheimer type. Ann Clin Lab Sci 1996; 26:1-9
17. Shults CW, Beal MF, Fontaine D, et al: Absorption, tolerability and effects on mitochondrial activity of oral coenzyme Q10 in parkinsonian patients. Neurology 1998; 50(3):793-795
18. Packer L, Tritschler HJ, Wessel K: Neuroprotection by the metabolic antioxidant alpha-lipoic acid. Free Rad Biol Med 1997; 22:359-378.
19. Wolz P, Krieglstein J: Neuroprotective effects of alpha-lipoic acid and its enantiomers demonstrated in rodent models of cerebral ischemia. Neuropharmacol 1996; 35:369-375.
20. Sano M, Ernesto C, Thomas RG: A controlled trial of selegiline, alpha tocopherol, or both as treatment for Alzheimer’s disease. The Alzheimer’s Disease Cooperative Study. New Engl J Med 1997; 336: 1216-1222
21. Thal LJ, Carta A, Clarke WR, et al: A 1-year multicenter placebo-controlled study of acetyl-L-carnitine in patients with Alzheimer’s disease. Neurol 1996; 47:705-711
22. Gadaleta MN, Petruzzella V, Daddabbo L, et al.: Mitochondrial DNA transcription and translation in aged rat. Ann NY Acad Sci 1994; 717:150-159
23. Schulz JB, Matthews RT, Klockgether T, et al.: The role of mitochondrial dysfunction and neuronal nitric oxide in animal models of neurodegenerative diseases. Mol Cell Biochem 1997; 174:193-197
24. Koh J, Yang LL, Cotman CW: [b]-Amyloid protein increases the vulnerability of cultured cortical neurons to excitotoxic damage. Brain Res 1990; 533: 315-320
25. Zs.Nagy I: On the possible role of nootropica in geriatric prevention and therapy. Ann NY Acad Sci 1996; 786:444-451
26. Dean W, Morgenthaler J, Fowkes SW: Smart Drugs II. The next generation. Smart Publications, Petaluma, California, 1993.
27. The Physician’s Guide to Life Extension Drugs. Life Extension Foundation, P.O. Box 229120, Hollywood, Florida 33022, 1998.
28. The Merck Index of Chemicals and Drugs, 8th edition. Merck & Co., Rahway, New Jersey, 1968
29. Ingram DK, Shimada A, Spangler EL, et al.: Cognitive enhancement: new strategies for stimulating cholinergic, glutamatergic, and nitric oxide systems. Ann NY Acad Sci 1996; 786:348-357
30. Petkov VV, Vuglenova Y: Pharmacological restoration of scopolamine-impaired memory. Acta Physiol Pharmacol Bulg 1985; 11(3):37-43
31. Popova JS, Petkov VD: Effect of the combination of the benzodiazepine tranquilizer medazepam and the nootropic agent meclofenoxate on the activity of rat brain muscarinic receptors. Gen Pharmacol 1990; 21(6):927-930
32. Pelagarza V.W.: New Drugs for Alzheimer’s disease. Am Fam Phys 1998; 58(5):1175-1182
33. Knopman DS: Current pharmacotherapies for Alzheimer’s disease. Geriatrics 1998; 53Suppl1:531-534
34. Tune LE, Sunderland T: New cholinergic therapies: treatment tools for the psychiatrist. J. Clin. Psychiat 1998; 59Suppl13:31-35
35. Ma YX, Zhu Y, Gu YD, et al: Double-blind trial of Huperzine-A (HUP) on cognitive deterioration in 314 cases of benign senescent forgetfulness, vascular dementia, and Alzheimer’s disease. Ann NY Acad Sci 1998; 854:506-507.
36. Meyer RC, Spangler, EL, Kametani H: Age-associated memory impairment: assessing the role of nitric oxide. Ann NY Acad Sci 1998; 854:307-317
37. Werbach MR, Murray MT: Botanical Influences on Illness. Third Line Press, Tarzana, California, 1994
38. LeBars PL, Katz MM, Berman N, et al.: A placebo-controlled, double-blind randomized trial of an extract of Ginkgo biloba for dementia. JAMA 1997; 278:1327-1332
39. Bertoni-Freddari C, Fattoretti P, Casoli T, et al.: Morphological alterations of synaptic mitochondria during aging: the effect of Hydergine treatment. Ann NY Acad Sci 1994; 717:137-149
40. Kitani K, Miyasaka K, Kanai S, et al: Upregulation of antioxidant enzyme activities by Deprenyl. Ann NY Acad Sci 1996; 786:391-409
41. Wu RM, Murphy DL, Chiueh CC: Suppression of hydroxyl radical formation and protection of nigral neurons by l-Deprenyl (selegiline). Ann NY Acad Sci 1996; 786:379-390
42. Perovic S, Böhm M, Meesters E, et al.: Pharmacological intervention in age-associated brain disorders by Flupirtine: Alzheimer’s and prion diseases. Mech Age Devel 1998; 101:1-19
43. Roses, AD: Apolipoprotein E and Alzheimer’s disease. Proc Nat Acad Sci USA 1995; 92:4725-4727
