Alternative Approaches to the Search for Alzheimer’s Disease Treatments
Abstract
:1. Introduction
2. Major Challenges for Alzheimer’s Disease (AD) Treatment
3. Alternative Natural Treatment of AD used in Folk Medicine
Acknowledgments
Author Contributions
Conflicts of Interest
References
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Agents | Possible Causative Factors in Negative Clinical Results |
---|---|
1 Simvastatin 2 Atorvastatin | All hydroxy-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) have serious side effects that make them unsuitable for long-term use, including type 2 diabetes, hemolytic anemia, thrombocytopenia, myopathy, rhabdomyolysis, leukopenia, cataracts, ophthalmoplegia, loss of libido, erectile dysfunction, fulminant hepatic necrosis, hepatoma, and peripheral neuropathy [9,10]. |
3 Aβ vaccine, AN1792 (Elan, Dublin, Ireland/Wyeth, Philadelphia, PA, USA) 4 Bapineuzumab (Elan; Johnson & Johnson, New Brunswick, NJ, USA; Pfizer, New York, NY, USA) 5 Solanezumab (LY 2062430, Lilly, Indianapolis, IN, USA) | Vaccines and antibodies are foreign proteins. After long-term use, the body makes antibodies against them, nullifying their intended effects [2,11,12]. |
6 Tarenflurbil (Myriad, Salt Lake City, UT, USA) (R-flurbiprofen) an arylpropionic acid nonsteroidal anti-inflammatory drugs (NSAID) | The R-enantiomer exerts almost no cyclooxygenase (COX) inhibitory activity. Only 1.5% of the R-enantiomer is converted into the S-form (inhibitor of COX) [13,14]. The R-enantiomer reduces the levels of β-amyloid which may not be the main cause of Alzheimer’s disease (AD). |
7 Semagacestat (LY450139, Lilly) | The agent blocks Υ-secretase which, along with β-secretase, is responsible for cleaving β-amyloid from amyloid precursor protein (APP) in rats and is presumed to be a causative agent in AD. The negative clinical finding suggests that the mechanism is not so straight forward in human long-term studies [15]. |
8 Scyllo-inositol (ELND005, Elan/Transition, Toronto, ON, Canada) hexa-hydroxycyclohexane | A simple organic, low molecular weight compound (180.16 g/mol). High doses (100–200 mg) were effective; unfortunately, severe adverse reactions—including nine deaths—occurred. A higher molecular weight may produce a better central nervous system (CNS) active drug [16]. |
9 Tramiprosate (Bellus, Laval, QC, Canada) homotaurine | A synthetic homolog of taurine [17], its N-acetyl analog was approved by the food and drug administration (FDA, 2004, acamprosate) to treat alcohol dependence. It was not effective in phase III clinical trials for AD for any primary endpoint. It is a partial γ-Aminobutyric acid type A (GABAA) agonist. Its dipolar (zwitterion) nature may prevent penetration across the blood brain barrier. |
10 Rosiglitazone (Avandia, GSK, Brentford, UK) | Antidiabetic agent [18] with a thiazolidinedione group and a tertiary amino group attached to a pyridine ring. It exists mainly as a cation under physiological pH. It has been withdrawn from the market in several European countries. It has been alleged to increase the risk of heart attack and death. |
11 Receptor for advanced glycation end products (RAGE) Inhibitor (Pfizer/Transtech, Oulu, Finland) | May cause inhibition of pro-inflammatory gene activation. RAGE is hypothesized to be involved in inflammatory diseases like diabetes, AD, and some tumors. A balance between pro-inflammatory and anti-inflammatory factors is needed for longevity [19]. |
12 Avagacestat (BMS-708163 (synthetic compound 520.88 g/mol with a heterocycle and two benzene rings attached to a sulfonamide) | A Υ-secretase inhibitor, decreases Aβ40 and Aβ42. Phase II trials did not support further development. The amyloid hypothesis of AD remains to be confirmed or refuted [20]. |
13 IVIG Gammagard (Baxter, Deerfield, IL, USA) | Immunoglobulin therapy is useful in some acute infectious diseases, but may not be suitable for long-term use against chronic diseases like AD [21]. |
Structure | Category | Biological activities | References |
---|---|---|---|
| A dihydro-benzofuran lignan | Anti-inflammatory activity due to inhibition of excessive NO production | [22] |
| A pentacyclic triterpene | Antitumor, antidiabetic, antioxidant, cardio-protective, neuroprotective, antiparasitic, growth simulating | [23] |
| A pentacyclic triterpene | Antineoplastic, causes apoptosis in tumor cells, decreases synthesis of cholesterol and fatty acids by inhibition of sterol regulatory element binding proteins, increases insulin sensitivity | [24,25] |
| Flavonoid (polyphenol) | Antioxidant, antibacterial, antiestrogenic | [26] |
| A flavonoid glycoside with functional groups similar to estradiol(polyphenol) | Estrogenic, stimulates egg laying in Papilio xuthus on citrus leaves | [24,27] |
| Flavonoid (polyphenol) | Antibacterial, antitussive (CNS) | [24] |
| A pentacyclic triterpene | Antineoplastic, hypoglycemic, antiarthritic | [24,28] |
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Lien, E.J.; Adams, J.D.; Lien, L.L.; Law, M. Alternative Approaches to the Search for Alzheimer’s Disease Treatments. J 2018, 1, 2-7. https://doi.org/10.3390/j1010002
Lien EJ, Adams JD, Lien LL, Law M. Alternative Approaches to the Search for Alzheimer’s Disease Treatments. J. 2018; 1(1):2-7. https://doi.org/10.3390/j1010002
Chicago/Turabian StyleLien, Eric J., James D. Adams, Linda L. Lien, and Meng Law. 2018. "Alternative Approaches to the Search for Alzheimer’s Disease Treatments" J 1, no. 1: 2-7. https://doi.org/10.3390/j1010002