Table 2.
Literature search for CsA-like compounds’ association with Alzheimer’s disease.
| Compound | Description | Effect | Link to Alzheimer’s Disease |
|---|---|---|---|
| Fluphenazine | D1/D2 Receptor Antagonist | - | |
| Perphenazine | D1/D2 Receptor Antagonist | ↑ | Suppressed tau-induced lethargy, tau aggregation, and neuron loss in C. elegans[84]. |
| Ziprasidone | D2 Receptor Antagonist | - | |
| Loxapine | D2 Receptor Antagonist | - | |
| Paliperidone | D2/D3 Receptor Antagonist | - | |
| Haloperidol | Non-selective Dopamine | ↑ | Reduced tau phosphorylation in a tau mouse model[68]. |
| Receptor Antagonist | Inhibited Aβ formation in cultured mammalian cells[48]. | ||
| Thioridazine | Non-selective Dopamine | - | |
| Receptor Antagonist | |||
| Droperidol | Non-selective Dopamine | ↑ | Inhibited Aβ formation in cultured mammalian cells[48]. |
| Receptor Antagonist | |||
| Asenapine | Non-selective Dopamine | - | |
| Receptor Antagonist | |||
| Bromocriptine | D2 Receptor Agonist | ↑ | Improved Aβ1–42 induced neuroinflammation, neuronal apoptosis, and memory deficits in mice[78]. |
| Reduced Aβ-42 in human iPSC-derived neurons[67]. | |||
| Inhibited the binding of Aβ oligomers to EphB2[123]. | |||
| Aripiprazole | D2 Receptor Agonist | ↑ | Decreased Aβ accumulation and inhibited neuroinflammation in the brains of 5xFAD mice[53]. |
| Inhibited Aβ and P-tau in N2a Swe cells[47]. | |||
| Disulfiram | Dopamine-β-hydroxylase inhibitor | ↑ | Prevented Aβ aggregation SH-SY5Y human neuronal cells; also reduced plaque-burden in the dentate gyrus and ameliorated behavioral deficits in 5xFAD mice[107]. |
| Ergoloid | Non-selective Dopamine | ↑ | FDA-approved drug to improve cognitive function in AD, with varying efficacy[115]. |
| Receptor Effector | |||
| Formoterol | β2-adrenergic Receptor Agonist | ↑ | Improved cognition and decreased oxidative stress, neuro-inflammation, and apoptotic parameters in streptozotocin-induced sporadic AD mouse model[3]. |
| Isoproterenol | β2-adrenergic receptor agonist | ↑ ↓ | Restored lysosomal proteolysis, calcium homeostasis, and normal autophagy flux in PSEN1 Knock-out cells and fibroblasts from PSEN1 familial AD patients[72]. |
| Injection into the basolateral amygdala rescues the memory deficit caused by Aβ in rats[51]. | |||
| Reduced intracellular Zn2 + level increased by Aβ in mouse brain[62]. | |||
| Bilateral injection into rat hippocampus results in hyper phosphorylation of tau and disturbance of spatial memory retention[121]. | |||
| Arformoterol | β2-adrenergic Receptor Agonist | - | |
| Salbutamol | β2-adrenergic Receptor Agonist | ↑ | Impeded the aggregation of tau in vitro[131]. |
| Dipivefrin | β2 adrenergic Receptor Agonist | - | |
| Epinephrine | α-adrenergic Receptor Agonist | - | |
| Trifluoperazine | α1A-adrenergic Receptor antagonist | ↑ | Inhibited H2O2-induced cell viability loss, intracellular reactive oxygen species (ROS) generation, and reduced cell apoptosis in H2O2 in PC12 cells[77]. |
| Doxazosin | α1A-adrenergic Receptor Antagonist | ↑ | Prevented GSK-3β activation and Tau hyper phosphorylation on an in vitro model of organotypic hippocampal cultures exposed to amyloid-β[20]. |
| Mirtazapine | α2-adrenergic Receptor | - | |
| Pimecrolimus | Calcineurin Inhibitor | ↑ | Reduced Aβ secretion in AD model neurons[90]. |
| Tacrolimus | Calcineurin Inhibitor | ↑ | Prevented age- and AD-associated microstructural changes in the hippocampus, parahippocampal cortex, and prefrontal cortex of the middle-aged beagle brain[43]. |
| Reversed learning and memory impairment caused by Aβ accumulation in Tg2576 APP mouse model[24]. | |||
| Ameliorated plaque-associated synapse loss in plaque bearing mouse model[110]. | |||
| Nimodipine | L-type Calcium Channel | ↑ ↓ | Protected microglia from Aβ-dependent cytotoxicity and inhibited Aβ-stimulated IL-1β synthesis in vivo[114]. |
| Inhibitor | No effect on amyloid pathology of 5xFAD mice[111]. | ||
| Facilitated the clearance of Aβ across the BBB in an in vitro model[8]. | |||
| Amiodarone | L-type Calcium Channel Inhibitor | ↑ | Inhibited β-secretase cleavage of APP and Aβ generation in HEK293-APP cells[87]. |
| Nicardipine | L-type Calcium Channel Inhibitor | ↑ | Facilitated the clearance of Aβ across the BBB in an in vitro model[8]. |
| Dronedarone | L-type Calcium Channel Inhibitor | - | |
| Loperamide | Calmodulin Inhibitor | - | |
| Tamoxifen | Estrogen Modulator | ↑ | Enhanced spatial and contextual memory and increased ACh levels in Aβ1-42 injected-breeding-retired-female mice[97]. |
| Aβ induced cell death in a mouse HT-22 cell line[42]. | |||
| Long-term use of tamoxifen in patients with breast cancer is associated with a lower risk of dementia[122]. | |||
| Toremifene | Estrogen Modulator | ↑ | Reduced Aβ secretion in AD model neurons[90]. |
| Mitotane | Estrogen Activator | - | |
| Megestrol Acetate | Progesterone Activator | - | |
| Desogestrel | Progesterone Agonist | - | |
| Dihydroergotamine | 5-HT1B/5-HT1D Agonist | ↑ | Inhibited the binding of Aβ oligomers to EphB2[123]. |
| Clozapine | 5-HT2A Inhibitor | ↑ | Improved Aβ-induced memory impairment and suppressed Aβ levels and plaque deposition in the brain of a transgenic mouse model of AD[17]. |
| Amoxapine | 5-HT2A Inhibitor | ↑ | Suppressed the level of Aβ in HEK293-APPsw cells[75]. |
| Nefazodone | 5-HT2A Inhibitor | - | |
| Flibanserin | 5-HT1A/5-HT2A Inhibitor | - | |
| Brexpiprazole | 5-HT1A Inhibitor | - | |
| Treprostinil | PPARγ Agonist | - | |
| Rosiglitazone | PPARγ Agonist | ↑ | Attenuated learning and memory deficits, and reduced Aβ 42 levels in Tg2576 mice[99]. |
| (maleate) | |||
| Rosiglitazone | PPARγ Agonist | ↑ | Elicits neuroprotection on SH-SY5Y cells[54]. |
| Facilitated Aβ clearance in mice overexpressing mutant human APP[28]. | |||
| Reduced spatial memory impairment, Aβ oligomers and aggregates, and astrocytic and microglia activation in a double transgenic AD mouse model[129]. | |||
| Fenofibrate | PPARα Agonist | ↑ ↓ | Reduced the release of Aβ-42 in APP/PS1 transgenic mice[141]. |
| Inhibited the Aβ-induced phenotype in a C. elegans AD model[73]. | |||
| Raised Aβ-42 in APP transfected H4 cells[70]. | |||
| Celecoxib | COX-1/COX-2 Inhibitor | ↑ ↓ | Cleared Aβ in the neurons of APP/PS1 transgenic mice[41]. |
| Attenuated AlCl3-induced intellectual impairment and the associated neurodegenerative changes in rats[2]. | |||
| No beneficial effects found in randomized control trials[82,86]. | |||
| Flurbiprofen | COX-1/COX-2 Inhibitor | ↑ | Lowered Aβ in H4 cell lines and in APP mice[27]. |
| Reduced Aβ-42 in both Neuro-2a cells and rat primary cortical neurons[36]. | |||
| Oxaprozin | COX-2 Inhibitor | ↑ | Epidemiological studies found reduced AD incidence[101]. |
| Eprosartan | AT1 Antagonist | ↑ | Restored and beneficially affected cerebral blood flow and connectivity[137]. |
| Did not alter the level of Aβ or APP in the brains of 3xTg-AD mice[31]. | |||
| Telmisartan | AT1 Antagonist | ↑ | Attenuated STZ induced impaired learning and memory as well as biochemical changes in AD mouse model [116]. |
| Improved cognitive decline and attenuated the Aβ-induced increase in expression of cytokines in Aβ 1–40 ICV injected mice[132]. | |||
| Reduced amyloid burden in the cortex and hippocampus of 5XFAD mice[130]. | |||
| Reserpine | VMAT1/VMAT2 Inhibitor | ↑ | Demonstrated neuroprotective activity against Aβ toxicity and anti-oxidative stress in PC12 cell cultures[60]. |
| Alleviated AB proteotoxicity in AD C. elegans model[7,112]. | |||
| Tetrabenazine | VMAT2 Inhibitor | ||
| Acitretin | Non-selective RAR Agonist | ↑ | Reduced Aβ40 and Aβ42 in APP/PS1–21 transgenic mice [127]. |
| Increased CSF APPs-α levels compared with the placebo group in a clinical study on AD patients[26]. | |||
| Tazarotene | RARa, RARb, RARg Agonist | ||
| Meclizine | Ach Blocker | ↑ | Restored cognition and biochemical alterations in STZ-treated mice[117]. |
| Nicotine | nAChRs Agonist | ↑ ↓ | Attenuated icv-STZ-induced impairments in recognition memory and was associated with higher neuronal density in rats[30]. |
| Reduced the levels of Aβ and BACE1 peptides in hippocampal area CA1 and prevented Aβ-induced impairment of learning and short-term memory in rat AD model[119]. | |||
| Reduced Aβ 1–42 positive plaques in the brains of APPsw mice[92]. | |||
| Increased the aggregation and phosphorylation state of tau in 3x-TgAD mice[94]. | |||
| Exacerbated cognitive impairment and tau phosphorylation in Aβ25–35 injected rats[22]. | |||
| Trientine | Copper (II) Chelator | ↑ | Decreased Aβ deposition and synapse loss in the brains of APP/PS1 mice[135]. |
| Bacitracin | Copper (II) Chelator | ↑ | Reduced pathology in a transgenic C. elegans model of proteotoxicity associated with AD[80]. |
| Letermovir | DNA Terminase Complex Inhibitor | - | |
| L-Valacyclovir | Viral DNA Polymerase Inhibitor | - | |
| Eltrombopag | Thrombopoietin Receptor Agonist | - | |
| Cilostazol | PDE3A Inhibitor | ↑ | Attenuated learning and memory impairment induced by Aβ 25–35 in mice[49]. |
| Suppressed Aβ-induced Apoptosis and oxidative stress, and increased cell viability of SH-SY5Y cells[95]. | |||
| Decreased accumulation of Aβ1-42 in activated N2aSwe cells[98]. | |||
| Dutasteride | 5α-Reductase Inhibitor | ||
| Chlorambucil | DNA Alkylator | ||
| Calcifediol | Vitamin D3 Receptor Agonist | ↑ | Improved cognitive function in a randomized controlled trial targeting elderly subjects with mild cognitive impairment[138]. Reduced total AB levels in SH-SY5Y cells transfected with human APP695[40]. |
↑:
Drug demonstrates a potentially beneficial effect on Alzheimer’s disease treatment.
↓:
Drug demonstrates a potentially exacerbating effect on Alzheimer’s disease pathologies.