Introduction
The neurotoxin approach
Intracerebral neurotoxin application
Systemic neurotoxin application
Transgenic approach
Overexpression of αSyn in oligodendrocytes
The CNP-αSyn model
The MBP-αSyn model
The PLP-αSyn model
Overexpression of α1B-adrenergic receptor
Application of the MSA animal models in preclinical target development
Intervention | Animal model | Preclinical results | Clinical trial design, number of participants, outcome measures | Clinical results |
---|---|---|---|---|
Riluzole (anti-glutamatergic drug) | 6-OHDA + QA rat model [48] | Borderline reduction of the striatal lesion volume | Phase II/III; randomized, placebo-controlled; 194 treated, 197 placebo; survival, different scales (e.g., UPDRS, NNIPPS-PPS) [49] | No evidence of beneficial effect on survival and progression |
MPTP + 3-NP mouse model [50] | Mild decrease of striatal neurodegeneration | |||
Minocycline (tetracycline derivative) | 6-OHDA + QA rat model [51] | No behavioral effects, no neuroprotection, reduced microglial and astroglial activation | Phase II, randomized, placebo-controlled; 31 treated, 31 placebo; UMSARS, UPDRS [52] | No change in disease progression |
PLP-α-syn mouse model [38] | Significant reduction of nigral neurodegeneration parallel to suppressed microglial activation | |||
Rasagiline (irreversible MAO-B inhibitor) | PLP-α-syn + 3NP mouse model [53] | Behavioral improvement, neuroprotection of olivopontocerebellar and striatonigral pathways | Phase II; randomized, placebo-controlled; 84 treated, 90 placebo; UMSARS DWI (Poewe et al.) | No difference between treatment groups |
Rifampicin (antibiotic) | MBP-α-syn mouse model [54] | Reduction of α-syn aggregation, neuroprotection | Phase II/III; randomized, placebo-controlled; 50 treated, 50 placebo; UMSARS [55] | Study termination as interim futility criteria met |
Fluoxetine (selective serotonin reuptake inhibitor) | MBP-α-syn mouse model [56] | Motor improvement, reduction of α-syn aggregation, increased GDNF and BDNF levels, neuroprotection | Phase II randomized, placebo-controlled; UMSARS | No difference between treatment groups (unpublished) |
Mesenchymal stem cells | PLP-α-syn mouse model [57] | Borderline preservation of nigral neurons, downregulation of IL-2 and IL-17 | Phase I/II open label, historical control group; 11 treated, 18 placebo; safety, UMSARS, FDG-PET [58] | Safe, improved UMSARS, increased FDG-uptake |
MPTP-3-NP double-toxin mouse model [59] | Neuroprotective effects in SNc and striatum, anti-neuroinflammatory, and anti-gliotic effects | Phase II; randomized placebo-controlled; 14 treated, 17 placebo; UMSARS [60] | Delayed progression in UMSARS I and II, less extensive decrease in glucose metabolism |