Table 3 Therapeutic approaches targeting metabolism or mitochondrial quality control
From: Mitochondrial dysfunction in Parkinson’s disease – a key disease hallmark with therapeutic potential
Substance | Scientific basis | Results from preclinical studies | Results from clinical trials |
|---|---|---|---|
Metabolic remodeling | |||
Glucagon-like peptide (GLP-1) agonists, e.g. exenatide, liraglutide | – Antidiabetic therapy with GLP-1 agonists (e.g., exenatide, liraglutide) is associated with reduced risk for developing PD. | – Preclinical studies in toxin-induced rodent models of PD (MPTP, rotenone, and 6-OHDA) suggested a neuroprotective potential for GLP-1 agonist treatment [257]. – The mechanism of action is still unclear. Currently, modulation of neuroinflammatory pathways, reduction of ROS, normalization of cellular Ca2+ levels, restoring mitophagy and improving overall bioenergetic efficiency is suggested [258]. – However, conflicting results exist, indicating exenatide may worsen aSYN accumulation [259]. | – In a placebo-controlled trial exenatide treatment over 48 weeks resulted in clinical improvement of motor symptoms [260]. – A phase III trial (Exenatide-PD3; NCT04232969) is currently investigating the effect of a two-year exenatide treatment on motor symptomatology in PD patients [261]. – In a small double-blind, placebo-controlled, trial 52 weeks of liraglutide treatment resulted in significant improvement of non-motor symptoms and activities of daily living, while severity of motor symptoms was unchanged [262]. |
Peroxisome proliferator- activated receptor- γ (PPARγ) agonists, e.g., pioglitazone | – Antidiabetic treatment with pioglitazone is associated with a reduced risk for developing PD [256]. | – Pioglitazone showed neuroprotective potential in a transgenic mitochondrial complex IV deficient mouse line of PD. – It also attenuated MPTP-induced dopaminergic neurodegeneration in a rodent model of PD [263]. – Mechanism of neuroprotection is unclear. Modulation of different cellular pathways including reduced neuroinflammation, suppressed nitric oxide synthase activity, improved proteasomal clearance, and enhanced mitochondrial biogenesis have been suggested [264]. | – A phase II clinical trial investigating pioglitazone treatment over 44 weeks revealed no modification of disease progression in early PD patients [265]. |
Enhancing mitochondrial quality control | |||
mdivi-1 | – Excessive Drp1-mediated mitochondrial fission has been identified as a pathomechanistic pathway in PD [266]. – mdivi-1 blocks Drp1. | – mdivi-1 reduced proteinase K resistant aggregates and mitochondrial ROS production as well as improved autophagy and ATP production in aSYN overexpressing or PFF exposed cells in vitro [267,268,269]. – mdivi-1 rescued the motor phenotype und exerted neuroprotective effects in A53T-aSYN overexpressing rats, the rotenone- or MPTP-induced rodent model of PD, [267, 269] as well as in the PINK-KO [270] mice. | – mdivi-1 has not been tested in clinical trials yet. |
Miro-targeting | – Prolonged retention of the outer mitochondrial membrane protein Miro on mitochondria disturbs mitophagy and thereby contributes to PD pathology [271]. | – Reduction of Miro rescued mitophagy in human fibroblast cultures of PD patients and Drosophila models of PD [272, 273]. | – Miro reducers have not been tested in clinical trials. |
Increasing PINK1/Parkin levels | – Deficits in PINK1 and/or Parkin signaling are known causes of genetic PD. | – Several preclinical studies indicated that increasing levels of PINK1 or Parkin can recue MPTP induced neurodegeneration [274,275,276] or ameliorate aSYN mediated toxicity [277, 278]. | – Compounds increasing PINK1/Parkin are currently not tested in clinical trials. |