Table 1.
Therapies administered at adult life stages in the Ts65Dn mouse model of DS.
| Phenotype | Treatment | Mechanism | Age (M) | Treatment duration | Outcome | Long-term effect | References |
|---|---|---|---|---|---|---|---|
| L/M (MWM) | Donepezil (Class A) | AChE inhibitor | 4 | 7 w | Failed | NA | Rueda et al., 2008a |
| L/M (SA) | Physostigmine (Class A) | AChE inhibitor | 4 10 16 |
Acute Acute Acute |
Rescued Failed Failed |
NA NA NA |
Chang and Gold, 2008 |
| Olfactory learning | Galantamine (Class A) | AChE inhibitor | 3–6 | Acute | Rescued | NA | de Souza et al., 2011 |
| L/M (NOR, TM) | Pentylentetrazole (Class A) | Antagonist of GABAA R | 3–4 | 17 d | Rescued | Yes (at 2 m) | Fernandez et al., 2007 |
| L/M (MWM) | Pentylentetrazole (Class A) | Antagonist of GABAA R | 4 | 7 w | Rescued | NA | Rueda et al., 2008a |
| L/M (NOR) | Pentylentetrazole (Class A) | Antagonist of GABAA R | 2–3 | 2 w | Rescued | Yes (at 8 d) | Colas et al., 2013 |
| L/M (NOR) | Pentylentetrazole (Class A) | Antagonist of GABAA R | 12–15 | 2 w | Rescued | Yes (at 8 d) | Colas et al., 2013 |
| L/M (MWM) | RO4938581 (Class A) | GABAA α5 negative allosteric modulator | 3–4 | 6 w | Rescued | NA | Martínez-Cué et al., 2013 |
| L/M (NOR, MWM, CFC) | CGP55845 (Class A) | Antagonist of GABAB R | 2–3 | 3 w | Rescued | NA | Kleschevnikov et al., 2012 |
| L/M (MWM, CFC) | Ethosuximide (Class A) | Inhibits KCNJ6/GIRK2 channel, a GABAB–coupled ion channel | 4.5–5 | 10 w | Failed | NA | Vidal et al., 2012 |
| L/M (MWM, CFC) | Gabapentin (Class A) | Modulator of GABA synthesis | 4.5–5 | 10 w | Failed | NA | Vidal et al., 2012 |
| L/M (CFC, nesting behavior) | L-DOPS (Class A) | NA pro-drug | 6 | Acute | Rescued | No (at 2 w) | Salehi et al., 2009 |
| L/M (NOR, CFC, TM) | Xamoterol (Class A) | β1 receptor agonist | 9–12 | Acute | Rescued | NA | Faizi et al., 2011 |
| L/M (NOR, SA) | Clozapine-N-oxide (agonist of hM3Dq, administered via adeno virus into Locus Coeruleus) (Class A) | DREADD design in order to stimulate NA neurons of Locus Coeruleus | 14 | Acute | Rescued | NA | Fortress et al., 2015 |
| L/M (SA) | L-DOPS (Class A) | NA pro-drug | 11 | 2 w | Rescued | NA | Fortress et al., 2015 |
| L/M (CFC) | Memantine (Class A) | Antagonist of NMDA R | 4–7 | Acute | Rescued | NA | Costa et al., 2008; Ahmed et al., 2015 |
| L/M (WRAM, NOR) | Memantine (Class A) | Antagonist of NMDA R | 4 | 6 m | Improved | No (at 1 w) | Lockrow et al., 2011 |
| L/M (MWM) | Memantine (Class A) | Antagonist of NMDA R | 9 | 8–9 w | Rescued | NA | Rueda et al., 2010 |
| L/M (YM) | RO25-6981 (Class A) | Antagonist of NMDA R (GluN2B) | 3–6 | Acute | Failed | NA | Hanson et al., 2013 |
| L/M (YM, BM) | RO25-6981 (Class A) | Antagonist of NMDA R (GluN2B) | 3–6 | 2 w | Failed | NA | Hanson et al., 2013 |
| L/M (NOR, YM) | Fluoxetine (Class A) | Inhibits serotonine reuptake | > 2 m | 8 w | Rescued | NA | Begenisic et al., 2014 |
| L/M (MWM) | Fluoxetine (Class A) | Inhibits serotonine reuptake | 5–7 | 4 w | Failed | NA | Heinen et al., 2012 |
| L/M (YM, NPR, NOR) | JZL184 (Class A) | Inhibitor of monoacylglycerol lipase that increases levels of 2-arachidonoylglycerol | 11 | 4 w | Failed (YM, NPR) Rescued (NOR) | NA | Lysenko et al., 2014 |
| L/M (MWM) | NAPVSIPQ+SALLRSIPA (fragments of ADNP and ADNF) (Class B) | Neuroprotection against oxidative stress | 10 | 9 d | Rescued | No (at 10 d) | Incerti et al., 2011 |
| L/M (MWM) | Peptide six (fragment of CNTF) (Class B) | Neurotrophic factor | 11–15 | 30 d | Improved | NA | Blanchard et al., 2011 |
| L/M (TM) | Estrogen (Class B) | Protects basal forebrain cholinergic neurons | 11–15 | 2 m | Improved | NA | Granholm et al., 2002 |
| L/M (MWM, PM) | Melatonin (Class B) | Free radical scavenger | 5–6 | 5 m | Improved | NA | Corrales et al., 2013 |
| L/M (WRAM) | Vitamin E (Class B) | Antioxidant | 4 | 4–6 m | Improved | NA | Lockrow et al., 2009 |
| L/M (MWM) | Piracetam (Class B) | Nootropic | 1.3 | 4 w | Failed | NA | Moran et al., 2002 |
| L/M (MWM) | SGS-111 (Class B) | Analog of Piracetam. Nootropic | 4–6 | 6 w | Failed | NA | Rueda et al., 2008b |
| L/M (WRAM) | Minocycline (Class B) | Anti-inflammatory | 7 | 3 m | Improved | NA | Hunter et al., 2004 |
| L/M (MWM, NOR, CFC) | Lithium (Class C) | Mood stabilizer. Interferes with GSK3β signaling | 5–6 | 4 w | Rescued | NA | Contestabile et al., 2013 |
| L/M (MWM) | DAPT (Class D) | Gamma-secretase inhibitor | 4 | Acute | Rescued | NA | Netzer et al., 2010 |
| L/M (MWM, NOR) | Epigallocatechin-3-gallate (EGCG) (Class D) | Inhibitor of DYRK1A kinase | 3 | 1 m | Rescued | NA | De la Torre et al., 2014 |
| LTP | Pentylentetrazole (Class A) | GABAA R antagonist | 3–4 | 17 d | Rescued | Yes (at 2 m) | Fernandez et al., 2007 |
| LTP | RO4938581 (Class A) | GABAA α5 negative allosteric modulator | 3–4 | 6 w | Rescued | NA | Martínez-Cué et al., 2013 |
| LTP | CGP55845 (Class A) | Antagonist of GABAB R | 2–3 | 3 w | Rescued | NA | Kleschevnikov et al., 2012 |
| LTP | Picrotoxin (Class A) | Antagonist of GABAAR | 3–4 | Acute | Rescued | Acute (slices) | Kleschevnikov et al., 2004 |
| LTP | Picrotoxin (Class A) | Antagonist of GABAAR | 4–6 | Acute | Rescued | Acute (slices) | Costa and Grybko, 2005 |
| LTP | RO25-6981 (Class A) | Antagonist of NMDA R (GluN2B) | 3–6 | 2 w | Rescued | Yes (at 2–4.5 w) | Hanson et al., 2013 |
| LTP | Fluoxetine (Class A) | Inhibits serotonine reuptake | > 2 | 8 w | Rescued | NA | Begenisic et al., 2014 |
| LTP | JZL184 (Class A) | Inhibitor of monoacylglycerol lipase/Endocann System | 11 | 4 w | Improved | NA | Lysenko et al., 2014 |
| LTP | Melatonin (Class B) | Free radical scavenger | 6–6.5 | 5–5.5 m | Rescued | NA | Corrales et al., 2014 |
| LTP | Lithium (Class C) | Mood stabilizer. Interferes with GSK3β signaling | 5–6 | 4 w | Rescued | NA | Contestabile et al., 2013 |
| LTP | Epigallocatechin-3-gallate (EGCG) (Class D) | Inhibitor of DYRK1A kinase | 2–5 | Acute | Rescued | Acute (slices) | Xie et al., 2008 |
| Neurogenesis (DG) | RO4938581 (Class A) | GABAA α5 negative allosteric modulator | 3–4 | 6 w | Rescued | NA | Martínez-Cué et al., 2013 |
| Neurogenesis (DG) | Farmoterol (Class A) | β2 Receptor agonist | 5–6 | 15 d | Failed | NA | Dang et al., 2014 |
| Neurogenesis (DG) | Fluoxetine (Class A) | Inhibits serotonin reuptake | 2–5 | 24 d | Rescued | NA | Clark et al., 2006 |
| Neurogenesis (DG) | Peptide six (fragment of CNTF) (Class B) | Neurotrophic factor | 11–15 | 30 d | Rescued | NA | Blanchard et al., 2011 |
| Neurogenesis (DG) | Melatonin (Class B) | Free radical scavenger | 6–6.5 | 5–5.5 m | Rescued | NA | Corrales et al., 2014 |
| Neurogenesis (DG) | Lithium (Class C) | Mood stabilizer. Interferes with GSK3β signaling | 5–6 | 4 w | Rescued | NA | Contestabile et al., 2013 |
| Neurogenesis (SVZ) | Lithium (Class C) | Mood stabilizer. Interferes with GSK3β signaling | 12 | 1 m | Rescued | NA | Bianchi et al., 2010a |
| Neurogenesis (DG) | P7C3 (Class E) | Proneurogenic drug | 1–2.5 | 3 m | Improved | NA | Latchney et al., 2015 |
| Dendritic hypotrophy | Farmoterol (Class A) | β2 Receptor agonist | 5–6 | 15 d | Rescued | NA | Dang et al., 2014 |
| Connectivity | Peptide six (fragment of CNTF) (Class B) | Neurotrophic factor | 11–15 | 30 d | Rescued | NA | Blanchard et al., 2011 |
| Neurodegeneration | Estrogen (Class B) | Protects basal forebrain cholinergic neurons | 11–15 | 2 m | Rescued | NA | Granholm et al., 2002 |
| Neurodegeneration | Estrogen (Class B) | Protects basal forebrain cholinergic neurons | 9–15 | 2 m | Rescued | NA | Granholm et al., 2003 |
| Neurodegeneration | Minocyclin (Class B) | Anti-inflammatory | 7 | 3 m | Prevented | NA | Hunter et al., 2004 |
| Neurodegeneration | Vitamin E (Class B) | Antioxidant | 4 | 4–6 m | Prevented | NA | Lockrow et al., 2009 |
The classes reported in the column “Treatment” correspond to those summarized in the Section “Numerous Therapies Have Been Attempted in Order to Improve the Phenotype of the Trisomic Brain.” The outcome “Rescued” means that in treated Ts65Dn mice the examined phenotype became similar to that of untreated euploid mice. The outcome “Improved” means that in Ts65Dn mice treatment ameliorated but did not rescue the examined phenotype. The text in bold in the column “Outcome” highlights treatments that were ineffective (Failed) and the text in bold in the column “Long-term effect” highlights treatments that either had (Yes) or did no had (No) a long-term effect. ADNF, Activity Dependent Neurotrophic Factor; ADNP, Activity Dependent Neuroprotective Protein; BM, Barnes Maze; CFC, Contextual Fear Conditioning; CNTF, Ciliary Neurotrophic Factor; d, day; DG, dentate gyrus; m, month; MWM, Morris Water Maze; NA, not available; NOR, Novel Object Recognition; NPR, Novel Place Recognition; PM, Plus Maze; SA, Spontaneous Alternation Task; SVZ, subventricular zone; TM, T Maze; w, week; WRAM, Water Radial Arm Maze; YM, Y Maze.