Table 4.
Therapeutics. New drug discovery/repurposing. A, B. Connectivity Map [40, 41] (CMAP) analysis. Query for signature is done using exact Affymetrix probesets and direction of change. Drugs that have same gene expression profile effects to our high memory retention biomarkers signatures. A score of 1 indicates the perfect match, i.e. the best potential therapeutic for increasing memory retention. C, D. NIH LINCS analysis using the L1000CDS2 (LINCS L1000 Characteristic Direction Signature Search Engine) tool. Query for signature is done using gene symbols and direction of change. Shown are compounds mimicking direction of change in high memory. A higher score indicates a better match
| Rank | CMAP name | Score | Description |
|---|---|---|---|
| A. Top biomarkers CFG ≥ 12 (n = 23 probesets; 7 increased and 6 decreased were present in HG-U133A array used by CMAP). | |||
| 1 | Verteporfin | 1 | A benzoporphyrin derivative, is a medication used as a photosensitizer for photodynamic therapy to eliminate the abnormal blood vessels in the eye associated with conditions such as the wet form of macular degeneration. |
| 2 | Pioglitazone | 0.987 | A drug of the thiazolidinedione (TZD) class with hypoglycemic (antihyperglycemic, antidiabetic) action, used to treat diabetes |
| 3 | Salsolidine | 0.972 | A tetrahydroisoquinoline isolated from plants of the genus Salsola. Tetrahydroisoquinolines are steroselective competitive inhibitors of the enzyme monoamine oxidase. They are also a competitive inhibitors of catechol-O-methyltransferase. |
| 4 | Sulfadimidine | 0.97 | A sulfonamide antibacterial. |
| 5 | SB-203580 | 0.968 | Specific inhibitor of p38MAPK |
| 6 | Ronidazole | 0.966 | An antiprotozoal agent used in veterinary medicine |
| 7 | Mesalazine | 0.961 | Anti-inflammatory salycilate derivative used to treat ulcerative colitis |
| 8 | Dioxybenzone | 0.946 | An organic compound used in sunscreen to block UVB and short-wave UVA rays. It is a derivative of benzophenone. |
| 9 | Metamizole | 0.942 | A nonsteroidal anti-inflammatory drug |
| 10 | 8-Azaguanine | 0.936 | A purine analog with antineoplastic activity |
| B. Top Biomarkers CFG ≥ 10 (n = 138 probesets; 45 increased and 38 decreased were present in HG-U133A array used by CMAP). | |||
| 1 | Levonorgestrel | 1 | Progesterone derivative used as contraceptive. Progesterone and its derivatives have some evidence for promoting brain cell growth, at least in adult rats, and some studies have shown that it can improve cognitive performance in the aging mouse. |
| 2 | Aminohippuric acid | 0.955 | Nontoxic diagnostic tool to measure effective renal plasma flow |
| 3 | Meglumine | 0.933 | Meglumine, also known as megluminum or methylglucamine, belongs to the class of organic compounds known as hexoses. Often used as an excipient in pharmaceuticals. Methylglucamine orotate is a memory-improving drug, altough the ortoate component was though to be the active compound. |
| 4 | mesalazine | 0.932 | Nonsteroidal antiinflamatory drug used to treat inflammatory bowel diseases |
| 5 | Lymecycline | 0.92 | Tetracycline antibiotic; tetracyclines have been shown to have beneficial effects in neurodegenerative diseases |
| 6 | Torasemide | 0.918 | diuretic |
| 7 | Dioxybenzone | 0.916 | Sunscreen compound |
| 8 | Ginkgolide A | 0.915 | A natural compound with neuroprotective and possible AD preventing effects |
| 9 | Rimexolone | 0.907 | Rimexolone is a derivative of prednisolone, a synthetic glucocorticoid with anti-inflammatory and immunosuppressive property. |
| 10 | Ketanserin | 0.905 | Ketanserin is a selective serotonin receptor antagonist with weak adrenergic receptor blocking properties. The drug is effective in lowering blood pressure in essential hypertension. It also inhibits platelet aggregation. It is well tolerated and is particularly effective in older patients. |
| Rank | Score | Drug | Description |
|---|---|---|---|
| C. Top biomarkers CFG ≥ 12 (n = 23 probesets, 18 unique genes; 8 increased and 10 decreased). | |||
| 1 | 0.2941 | BRD-K03371390 | 7-fluoro-6-methoxy-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-one |
| 2 | 0.2941 | NCGC00185923-01 | 3-[[4-(2,6-Difluoro-4-methoxyphenyl)sulfonyl-1,4-diazepan-1-yl]sulfonyl]aniline |
| 3 | 0.2353 | BENZANTHRONE | dye that binds to amyloid fibrils |
| 4 | 0.2353 | SQ 22536 | adenylyl cyclase inhibitor |
| 5 | 0.2353 | ICARIIN | prenylated flavanol glycoside from Epimedium sagittatum |
| 6 | 0.2353 | YM 90709 | IL-5 receptor antagonist |
| 7 | 0.2353 | QUIPAZINE MALEATE | binds to serotonin receptors, particularly to 5HT2A and 5HT3 |
| 8 | 0.2353 | Cisapride | serotonin 5-HT4 receptor agonist |
| 9 | 0.2353 | LEUCINE ENKEPHALIN | enkephalin |
| 10 | 0.2353 | BRD-K15318909 | Prima-1, anticancer agent |
| D. Top biomarkers CFG ≥ 10 (n = 112 unique genes; 68 increased and 64 decreased). | |||
| 1 | 0.1048 | Proparacaine hydrochloride | Local anesthetic |
| 2 | 0.0952 | BRD-K00944562 | [(4S,5S)-5-(2-Azidophenyl)-4-[2-(benzenesulfonyl)ethyl]-2-[4-(3-hydroxypropoxy)phenyl]-5H-1,3-oxazol-4-yl]-piperidin-1-ylmethanone |
| 3 | 0.0952 | BRD-A80151636 | (6Ar)-5-bromo-N-[(1S,4R)-2-hydroxy-7-(2-methylpropyl)-5,8-dioxo-4-propan-2-yl-3-oxa-6,9-diazatricyclo[7.3.0.02,6]dodecan-4-yl]-7-methyl-6,6a,8,9-tetrahydro-4H-indolo[4,3-fg]quinoline-9-carboxamide |
| 4 | 0.0952 | BRD-K05361803 | 5-Chloro-N-heptylnaphthalene-1-sulfonamide PKC activator |
| 5 | 0.0952 | BRD-K82137294 | 1-[(2S,3S)-2-[[Benzenesulfonyl(methyl)amino]methyl]-5-[(2R)-1-hydroxypropan-2-yl]-3-methyl-6-oxo-3,4-dihydro-2H-1,5-benzoxazocin-8-yl]-3-[4-(trifluoromethyl)phenyl]urea |
| 6 | 0.0952 | BRD-K34206396 | N-[(2S,3S)-2-[[1,3-Benzodioxol-5-ylmethyl(methyl)amino]methyl]-5-[(2R)-1-hydroxypropan-2-yl]-3-methyl-6-oxo-3,4-dihydro-2H-1,5-benzoxazocin-8-yl]-2-(1-methylindol-3-yl)acetamide |
| 7 | 0.0952 | Pioglitazone | A drug of the thiazolidinedione (TZD) class with hypoglycemic (antihyperglycemic, antidiabetic) action, used to treat diabetes |
| 8 | 0.0857 | TENOXICAM | Nonsteroidal anti-inflammatory drug |
| 9 | 0.0857 | BRD-K64642496 | Tert-butyl 3-[(2S,5S,8S)-14-methoxy-2-(2-methylpropyl)-4,7-dioxo-3,6,17-triazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraen-5-yl]propanoate Inhibitor of breast cancer resistance protein |
| 10 | 0.0857 | BRD-K18364651 | N-[(3R,9S,10S)-9-[[Cyclohexanecarbonyl(methyl)amino]methyl]-12-[(2S)-1-hydroxypropan-2-yl]-3,10-dimethyl-13-oxo-2,8-dioxa-12-azabicyclo[12.4.0]octadeca-1(14),15,17-trien-16-yl]pyridine-4-carboxamide |
Bold—drugs known to have pro-cognitive effects, which thus serve as a de facto positive control for our approach. Italic—natural compounds.