Table 2.
Therapeutic trial for inflammation and its interaction with αSyn in PD
| Category | Compound | Description | Findings | Status |
|---|---|---|---|---|
| Microglia | CSF1R inhibitor (PPLX3397-Pexidartinib) | Inhibits microglia/macrophage | Depletion of microglia suppressed αSyn aggregation and transmission in mice [17, 94] | Preclinical |
| Minocycline (Mino) | Reduces the proliferation/activation of resting microglia | Prevention of the dopaminergic neurons loss, increased the dopamine level, decreased the Lewy body pathology in mice [104] | Phase 2 | |
| NINDS NET-PD | ||||
| Fingolimod | Blocks T cell egress from lymph nodes (prevents T-cell entry to the brain) | Decreased αSyn pathology in enteric nervous system of A53T transgenic mice [105] | Preclinical | |
| Rosiglitazone | PPARγ, inhibits microglial release of TNFα | Reduced αSyn pathology and prevented loss of dopaminergic neurons [106] | Preclinical | |
| Pioglitazone | PPARγ agonists, inhibits microglia activation | Modifies progression in early PD [107] | Phase 2 | |
| Astrocyte | NLY01 (GLP-1R agonist) | Blocks A1 neurotoxic astrocyte generation by microglia | Reduced αSyn pathology in A53T transgenic mice [99] | Preclinical |
| Phase 1, the drug was found to be safe and well-tolerated | Phase 2 | |||
| NCT03672604 | ||||
| SGK1 inhibitor | SGK1 is negatively regulated by Nurr and Fox2 in glial cells | Ameliorated neuronal αSyn aggregation and protected dopaminergic neuron loss [108] | Preclinical | |
| TLR2 | T2.5 antibodies | Blocks TLR2 | Decreased αSyn pathology and inflammation in mice [109] | Preclinical |
| LAG3 receptor | LAG3 antibodies (C9B7W and 410C9) | Blocks LAG3 receptor | Reduced αSyn transmission [77] | Preclinical |
| T lymphocytes | GA | Attenuates the activation of CD4+T cells and the pro-inflammatory response | Improved the motor function and restored the αSyn level in the midbrain and striatum of MPTP-treated mice [110] | Preclinical |
| Sargramostim (Leukine) | Human recombinant granulocyte-macrophage colony-stimulating factor affects myeloid recovery | Sargramostim treatment in PD is well-tolerated [111] | Phase 1 | |
| NCT010882010 | ||||
| Inflammasome | MCC950 | Blocks ATP and nigericin dependent NLRP3 activation | Prevented inflammasome activation by fibrillar αSyn, and led to less neuron loss and better dopaminergic signaling [112] | Preclinical |
| PAP | Selective inhibitor of phosphodiesterase 10A activity | Inhibited αSyn aggregation and neuronal cell death results from MPTP/P mice model [113] | Preclinical | |
| VX-765 (caspase-1 inhibitor) | Inhibits proteolytic processing of IL-1β and IL-18 to secreted forms | Inhibition of caspase-1 rescued BE(2)-M17 human dopaminergic neuroblastoma cells from the toxic effects of αSyn [114] | Preclinical | |
| Reduced αSyn pathology in transgenic mouse model of MSA [115] | ||||
| Inzomelid (IZD174) (NLRP3 inhibitor) | Inhibitor of inflammasomes containing NLRP3, or nod-like receptor family, pyrin domain-containing protein 3 | The treatment was well tolerated in double-blind evaluations in healthy volunteers | Phase 1 | |
| NCT04338997 | ||||
| Cytokines | XPro1595 (TNF inhibitor) | Targeted soluble TNF | Reduced the αSyn protein level [116] | Preclinical |
| Neuroprotective effects in rat model [117] |
αSyn, alpha-synuclein; PD, Parkinson’s disease; NINDS NET-PD, National Institute of Neurological Disorders and Stroke Neuroprotection Exploratory Trials in Parkinson’s Disease; PPARγ, peroxisome proliferator activated receptor gamma; GLP-1R, glucagon-like peptide-1 receptor; SGK1, serum and glucocorticoid-regulated kinase 1 inhibitor; TLR, toll-like receptor; GA, glatiramer acetate; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; ATP, adenosine triphosphate; PAP, papaverine; IL, interleukin; MSA, multiple system atrophy; TNF, tumor necrosis factor.