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Table 1 Drugs proposed for repositioning in PD with suggested new mechanisms of action

From: Repositioning of drugs for Parkinson’s disease and pharmaceutical nanotechnology tools for their optimization

Drugs Initial therapeutic indication Initial mechanism of action Novel therapeutic indication suggested Novel mechanism of action suggested Model of evaluation References
Exenatide Type II diabetes mellitus GLP-1 receptor agonist that promotes glucose-dependent insulin secretion Neuroprotective in PD Exerts neuroprotective effects through GLP-1 receptors, resulting in motor performance improvements, behavior, learning, and memory Clinical trial, single-center, randomized, double-blind, placebo-controlled. The trial included 60 patients [7]
Levetiracetam Partial and generalized epilepsy The mechanism is unclear. It is suggested that the binding to synaptic vesicle 2A is the key factor in its action Neuroprotective in PD Counteracts the effect of pathological mutant expression of LRRK2 G2019S. It is a specific neuroprotectant on the mutant pathological toxicity of LRRK2 Three cell models:
Primary cortical neurons obtained from C57BL/6 LRRK2 WT and LRRK2 G2019S BAC mice
PC12 cells expressing doxycycline (dox) inducible LRRK2 G2019S mutant
SH‐SY5Y cells expressing the dopamine D2 receptor-bearing a Flag epitope
[8]
Semaglutide Type II diabetes mellitus It binds selectively to the GLP-1 receptor and stimulates insulin synthesis, causing a decrease in blood glucose Neuroprotective in PD Improves motor disturbances, reduces the decrease in TH levels, the accumulation of α-syn, and increases the expression of GDNF that protects dopaminergic neurons in the substantia nigra and the striatum Mouse model of chronic PD with MPTP
Seventy-two male C57BL/6 mice of 8 weeks of age were used
[10]
Vitamin B12 Vitamin B12 deficiencies Cofactor for the enzyme methionine synthase, essential for synthesizing purines and pyrimidines Neuroprotective in PD AdoCbl modulates the activity of LRRK2, which leads to alterations of protein conformation and ATP binding in LRRK2 (inhibits kinase activity) Mouse model. BAC LRRK2 (R1441G) and BAC LRRK2 (G2019S) transgenic mice, male, 3 to 5 months of age, and their non-transgenic littermates for LRRK2 kinase inhibition in striatal brain slices [11]
Pomalidomide Multiple myeloma Antineoplastic activity, inhibits proliferation and induces apoptosis of various tumor cells Neuroprotective in PD TNF-α inhibitory activity. In Drosophila, inhibition of inflammatory pathways triggered by the Eiger ortholog may be the main mechanism LRRK2WD40 model of PD. Drosophila melanogaster, with LRRK2 loss-of-function mutation in the WD40 domain. Adult wild type and LRRKWD40 mutants males were used [47]
Dabrafenib Metastatic melanoma with the BRAF V600E mutation Inhibits B-Raf kinase activity and decreases the proliferation of tumor cells that contain a mutated BRAF gene Neuroprotective in PD It inhibits apoptosis and enhances the phosphorylation of ERK. There is a protein–protein interaction between B-Raf and Rit2 (RIT2, PD risk gene) Cellular model: SH-SY5Y human neuroblastoma cells and HEK293T cells were used
Animal model: C57BL/6 J mice, 8 to 12 weeks old, 20 to 25 g, were used
[56]
Ketoconazole Fungal infections Interacts with 14-α-sterol demethylase, inhibit the synthesis of ergosterol, increasing the permeability of fungal cells Neuroprotective in PD Mechanism not suggested. The increase in dopaminergic neuron death was stopped Drosophila transgenic model of PD. The UAS-alpha-synuclein transgenic strain was generated using an attp40 insertion site strain and the Drosophila PhiC31 system [57]
Felodipine Mild to moderate essential hypertension Decreases vasoconstriction by inhibiting the entry of calcium ions through voltage-gated L-type calcium channels Neuroprotective in PD Eliminates mutant α-syn in the brain of mice Zebrafish model and murine. The atg7 mutant fish line (atg7sa14768) and two different neurodegenerative disease mouse models (HD-N171–82Q mice and SNCA (A53T) G2-3 mice) and an mRFP-GFP-LC3 reporter line were used [58]
Raloxifene Osteoporosis in postmenopausal women SERM, increases the expression of proteins in the bone matrix Neuroprotective in PD It prevents the loss of dopaminergic neurons in the myenteric plexus, avoiding the increase in pro-inflammatory macrophage density Mouse model of PD with MPTP. Male C57BL/6 mice, ten weeks old, divided into 6 groups of 8 to 9 mice [59]
Omarigliptin Type II diabetes mellitus Inhibitor of DPP-4 Neuroprotective in PD Increasing GLP-1 and other hormone levels by inhibiting the degrading enzyme DPP-4 Murine model. Twenty-four rats were used, weighing 200 g ± 25, randomly assigned into four groups (n = 6) [60]
Triflusal Prophylaxis of thromboembolic disorder Acetylation of the active group of COX-1 prevents the formation of thromboxane-B2 in platelets Neuroprotective in PD It increases endogenous FGF20 production both in the nigrostriatal tract and in the ventral mesencephalic 6-OHDA lesioned rat model. 120 adult male Sprague Dawley rats, 250 to 280 g [61]
Candesartan High blood pressure, heart failure AT1 receptor antagonist. The antihypertensive action is due to the decrease in systemic peripheral resistance Neuroprotective in PD AT1 blockers lead to a decrease in the number of OX6-ir microglial cells, expression of CD68 mRNA, NADPH activity, expression of markers of the M1 phenotype, and α-syn-induced dopaminergic neuronal death α-syn overexpression model, in AAV9-α-syn vector. Adult male Sprague–Dawley rats, 8 to 10 weeks old, n = 220. Subgroup B1 (n = 28) was treated with vehicle, subgroup B2 (n = 24) with candesartan, and subgroup B3 (n = 24) with telmisartan [62]
Telmisartan Hypertension AT1 receptor antagonist. It binds selectively, blocking their effects and decreasing systemic vascular resistance Neuroprotective in PD AT1 blockers lead to a decrease in the number of OX6-ir microglial cells, expression of CD68 mRNA, NADPH activity, expression of markers of the M1 phenotype, and α-syn-induced dopaminergic neuronal death α-syn overexpression model, in AAV9-α-syn vector. Adult male Sprague–Dawley rats, 8 to 10 weeks old, n = 220. Subgroup B1 (n = 28) was treated with vehicle, subgroup B2 (n = 24) with candesartan, and subgroup B3 (n = 24) with telmisartan [62]
Nitazoxanide Gastrointestinal infections Cell membrane injury in parasites and depolarizes the mitochondrial membrane Neuroprotective in PD Loss in OCR and ATP production are improved. It confers protection against the loss of TH-positive neurons of the SN Mouse model of acute PD with MPTP. Male C57BL-6 J mice, 6 to 8 weeks old, 22 to 25 g, in 6 groups of 6 animals [63]
Metformin Type II diabetes mellitus It inhibits the activity of mitochondrial complex I. Lowers blood glucose levels by decreasing gluconeogenesis and decreasing intestinal glucose absorption Neuroprotective in PD It rescued TH-positive neurons, restored DA depletion and behavioral disturbances. Neuroprotection could be mediated by inhibition of α-syn phosphorylation and induction of neurotrophic factors
Protects rotenone-induced dopaminergic neurodegeneration by reducing lipid peroxidation
Mouse model of subchronic PD with MPTP. Adult male C57BL/6 mice, 10 weeks old, 20 to 25 g, in 4 groups with 6 mice
Mouse model of PD with rotenone. C57BL/6 mice were given an injection of saline or rotenone (2.5 mg/kg/day, ip) for 10 days
[64]
[65]
Nilotinib Chronic myelogenous leukemia It inhibits the tyrosine kinase activity of the BCR-ABL protein (oncogene that causes myelogenous leukemia) Neuroprotective in PD Inhibits the enzyme c-Abl. In PD, this protein loses its original shape and forms aggregates that the brain cannot discard and damage neurons Clinical trial. Single-center, phase 2, randomized, double-blind, placebo-controlled trial with 75 patients randomized 1:1:1 to placebo; nilotinib 150 mg; or nilotinib 300 mg [9, 50]
Exemestane Advanced breast cancer in postmenopausal women It binds irreversibly to the aromatase active site, reduces estrogen concentrations. This delays tumor growth and disease progression Neuroprotective in PD It activates the Nrf2 signaling pathway, induces the gene expression of NQO1, HO-1, and GCL, and suppresses inflammatory responses. By elevating antioxidant enzymes, it appears to protect nigral dopaminergic neurons Cell cultures. BV-2 murine microglial cells and CATH. Murine dopaminergic neuronal cells were cultured
Murine model. Male C57BL/6 J mice, 23 to 25 g, 8 weeks old, four groups (n = 10); vehicle-treated; MPTP; MPTP plus 1 mg/kg exemestane; MPTP plus 10 mg/kg exemestane
[67]
Salbutamol Bronchospasm and other chronic bronchopulmonary disorders Activation of β2AR in airway smooth muscle leads from cAMP activation to muscle relaxation Neuroprotective in PD
Associated with a lower risk of PD
It increases endogenous FGF20 production in the nigrostriatal tract and can potentially impact the survival of dopaminergic neurons
The β2AR ligands modulate the α-syn gene’s transcription (SNCA) through the acetylation of histone 3 lysine 27 from its promoter
6-OHDA lesioned mouse model. 120 adult male Sprague Dawley rats, 250 to 280 g. 80 rats in the in vivo screening and 40 in the neuroprotection study with 6-OHDA
The effects of β2AR activation were evaluated in a mouse model of human parkinsonism induced by MPTP and in a neuronal culture system derived from induced pluripotent stem cells
[61]
[68]
Pentamidine Pneumocystis carinii pneumonia The exact mechanism is unclear. It is believed to interfere with nuclear metabolism Improves motor performance in PD It produces inhibition of S100B, which inhibits the RAGE/NF-κB pathway in the nigrostriatal circuit, giving an improvement in motor performance Mouse model of PD with MPTP. Male C57Bl/6 J mice, 8 weeks old [69]
Ceftriaxone Bacterial infections (antibiotic) The beta-lactam fraction binds to carboxypeptidases, endopeptidases, and transpeptidases in the bacterial cytoplasmic membrane; bacteria produce defective cell walls Anti- LID Can attenuate the loss of TH together with an increase in glutamate uptake and the expression of the glutamate transporter GLT-1, this increase could reach the threshold of the expression level of GLT- 1 needed to prevent or reduce LID Rat model of 6-OHDA. Male Sprague Dawley rats (N = 38), 4 to 9 months old. The study was carried out in replicas in the three participating institutions [12]
Vilazodone Antidepressant The exact mechanism is unclear. It is known to selectively inhibit serotonin reuptake and act as a partial agonist at 5HT-1A receptors Anti- LID It selectively inhibits L-DOPA-induced gene regulation in the direct pathway of the dopamine-depleted striatum Hemiparkinsonian rat model injured with 6-OHDA
Mice were randomly divided into four experimental groups (n = 8 each). A subacute model of MPTP toxicity induced experimental parkinsonism in mice
[54, 55]
Methylene blue Acquired methemoglobinemia It reacts within red blood cells, converts the ferric ion (Fe3+) to its oxygen-bearing ferrous state (Fe2+) Anti- LID Antidyskinetic effects are likely to occur through inhibition of sGC in the CNS 6-OHDA lesioned rat model. Adult male Wistar rats, 200 to 250 g [70]
Nalbuphine Analgesic (moderate to severe pain) The exact mechanism of action is unknown, but it is believed to interact with an opiate receptor site in the CNS Anti- LID Striatum analyzes showed that nalbuphine co-therapy blocks several molecular pathways of LID Model of PD in non-human primates treated with MPTP. Macaques with advanced parkinsonism and reproducible LID received subcutaneous treatment as monotherapy, acute coadministration with levodopa, and chronic coadministration for 1 month [71]
Ketamine General anesthetic It interacts with N-methyl-D-aspartate (NMDA) receptors, opioid receptors, muscarinic, monoaminergic, and voltage-sensitive Ca ion channels Anti- LID The effect is mediated by the release of BDNF in the striatum, followed by activation of ERK1 / 2 and mTOR signaling. This leads to a reduction in the mushroom spines’ density, a phenotype highly correlated with LID LID rodent model
Two Sprague–Dawley rats, male, adult, and about 225 g
The severity of the LID was evaluated by an investigator blinded to the experimental conditions
[72]
Dimethyl fumarate Multiple sclerosis It is not very well known. It is believed to upregulate the Nrf2 pathway that is activated in response to oxidative stress PD-associated synucleinopathy Activates NRF2 in the basal ganglia, protects nigral dopaminergic neurons against α-syn toxicity, and decreases astrocytosis and microgliosis Nrf2 − / − and Nrf2 + / + mice. An adeno-associated pseudotype 6 (rAAV6) viral vector was used to express human α-SYN under the neuron-specific human Synapsin 1 promoter [73]
Kanamycin Bacterial infections (antibiotic) It binds to four nucleotides of the 16S rRNA, which interferes with the initiation complex PD-associated synucleinopathy It effectively inhibits the solution phase and lipid-induced aggregation of α-syn The effect of Kanamycin on the binding affinities of Α-Syn towards both the model and mimic SUVs was studied using a specific lipid-staining fluorescent probe DiIC-18 (DiD) [74]
Incyclinide o CMT-3 Reduced antibiotic activity They have been used in trials to treat HIV infection, among others, for which the specific mechanisms are not yet known PD-associated synucleinopathy Inhibits α-syn amyloid aggregation. Disassembles α-syn fibrils into smaller fragments that cannot be seeded in subsequent aggregation reactions (fibril extraction mechanism) Cell cultures in SH-SY5Y. SH-SY5Y cells were incubated with α-synuclein oligomers prepared in the absence or the presence of CMT-3, and an LDH assay measured cytotoxicity [75]
Doxycycline Bacterial infections (broad-spectrum antibiotic) It inhibits translation by binding to the 16S rRNA portion of ribosome 9, preventing the binding of tRNA to the 30S subunit PD-associated synucleinopathy It reforms the oligomers of α-syn and inhibits their aggregation, thus avoiding cytotoxicity in dopaminergic cells Human neuroblastoma cell culture. SH-SY5Y cells were grown in DMEM supplemented with fetal bovine serum [76]
  1. AdoCbl Adocobalamina, AT1 Angiotensin II type 1, BDNF Brain-derived neurotrophic factor, cAMP Cyclic adenosine monophosphate, CMT-3 Tetracycline 3 modified chemically, CNS Central nervous system, COX-1 Cyclooxygenase-1, DA Dopamine, DPP-4 Dipeptidyl peptidase-4, ERK Extracellular Signal–Regulated Kinase, FGF20 Fibroblast growth factor 20, GCL Ganglion cell layer, GDNF Glial cell line–derived neurotrophic factor, GLP-1 Glucagon-like peptide 1, HO-1 Heme oxygenase-1, LID L-DOPA-induced dyskinesia, LRRK2 Leucine-rich repeat kinase 2, mTOR Mammalian target of rapamycin, MPTP 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine, NF-kB Factor nuclear-kappa B, NQO1 NADPH: quinone oxidoreductase 1, OCR Oxygen consumption rate, PD Parkinson’s disease, RAGE Receptor for advanced glycation end products, SERM Selective estrogen receptor modulator, sGC Soluble guanylyl cyclase, TH Tyrosine hydroxylase, TNF-α Tumor necrosis factor α, α-syn α-Synuclein, 6-OHDA 6-Hydroxydopamine