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