Table 2 Current therapeutic approaches targeting oxidative stress

Coenzyme Q₁₀ (CoQ₁₀), and derivatives (EPI-589, MK-7)

– Numerous studies have shown decreased levels of CoQ₁₀ in plasma, platelets and distinct brain regions of PD patients [189].

– Evidence points to the role of elevated oxidative stress in the pathophysiological process of PD [190, 191].

– CoQ₁₀ is thought to be a potent antioxidant [192].

– CoQ₁₀ reduced rotenone-induced apoptosis and mitochondrial depolarization of primary rat mesencephalic neurons [193].

– Intrastriatal administration of CoQ₁₀ showed neuroprotective effects in a 6-OHDA rat model of PD [194]. Oral administration of CoQ₁₀ showed similar effects in a rotenone-induced rat model [195] and an MPTP-induced mouse model of PD [196, 197].

– Observed cellular effects included decreased ROS levels, normalized mitochondrial membrane potential, restored ATP generation.

– CoQ₁₀ phase I trials revealed good safety and tolerability profile. Possible clinical benefit in a phase II trial [198]. However, phase III trial revealed no disease-modification potential [199, 200].

– EPI-589 exhibited a good tolerability profile in a recent phase I trial [201]. MK-7 is currently tested in a placebo-controlled pilot study [202].

MitoQ, MitoVitE, MitoApocynin, MitoTEMPOL

– Mitochondria targeted antioxidant approaches. These modified compounds are suggested to show enhanced mitochondrial target engagement compared to parent antioxidant [203].

– MitoQ has been shown to exert neuroprotective effects against MPTP induced neurotoxicity in primary mesencephalic neuronal cells and cultured dopaminergic cells as well as in the MPTP mouse model of PD [204].

– MitoApocynin has been shown to reduce dopaminergic neurodegeneration and neuroinflammation as well as ameliorate mitochondrial function in a MitoPark transgenic mouse model [205]. It also prevented hyposmia and motor symptoms in a LRRK2 (R1441G) transgenic mouse model. It has also been shown to protect against MPTP-induced neurotoxicity in vitro and in vivo [206].

– MitoQ failed to slow PD progression in de novo PD patients in a double-blind placebo-controlled trial [207].

– Robust clinical data for other mitochondria targeted compounds are lacking.

GPI1485

– Belongs to the group of neuroimmunophilins and is supposed to exhibit neurotrophic and antioxidative effects [208].

– No study exists investigating the neuroprotective efficacy of GPI1485 in in vitro or in vivo models of PD.

– Clinical trial data is inconclusive regarding a disease modifying effect [209].

Glutathione

– Robust evidence for reduced levels of glutathione in PD patients exists [210].

– Oxidative stress and ROS production are key pathophysiological events in PD [190]. Glutathione is a major cellular antioxidant [211]. It reduces cellular ROS and helps maintaining healthy neuronal redox state.

– Glutathione provided neuroprotection against paraquat plus maneb induced toxicity in rat mesencephalic mixed neuronal/glial cultures [212].

– Intranasal application of glutathione showed no disease modifying effects in a phase IIb study in manifest PD patients [213].

N-Acetyl-cysteine (NAC)

– NAC elevates cellular glutathione levels, thereby promoting antioxidant effects.

– Intraperitoneally administered NAC significantly ameliorated rotenone-induced motor dysfunction and dopaminergic neuronal cell loss in rats [214]. It has also been shown to exert neuroprotective effects in a 6-OHDA rat model of PD [215].

– Orally administered NAC attenuated the loss of striatal dopaminergic terminals in transgenic, wild-type aSYN overexpressing mice [216].

– NAC administration over 3 months in PD patients resulted in improvements in PD symptoms and dopaminergic imaging (DaTScan) [217].

Nicotinamide adenine dinucleotide (NAD)

– Broad evidence for NAD deficiency in PD [218].

– Injection in the striatum ameliorated 6-OHDA-induced dopaminergic neurodegeneration and motor deficits in a mouse model of PD [219]. Additionally, it prevented 6-OHDA-induced neuronal cell loss in vitro.

– Additional evidence for direct improvement of mitochondrial function in PD patient derived iPSCs [220].

– Oral NAD treatment has been deemed safe and was well-tolerated in several clinical phase I trials [221, 222].

– Recent phase I trial indicated elevated brain NAD levels under treatment going along with clinical improvement of de novo PD patients [223]. Additionally, it induces upregulation of mitochondrial, antioxidant and proteasomal genes [223].

Inosine

– Inosine represents a metabolic precursor of the naturally occurring antioxidant urate.

– Elevated serum urate levels in healthy individuals are associated with reduced risk for developing PD [224].

– Urate exerted antioxidative effects in primary midbrain dopaminergic and MES 23.5 cell cultures leading to long-term protection [225,226,227].

– Elevated brain urate levels attenuated toxic effects of intrastriatal 6-OHDA injection in mice [226].

– Oral inosine exerted neuroprotective effects and ameliorated motor deficits and dopaminergic neurodegeneration in the rotenone and the MPTP mouse and rat model of PD [228,229,230].

– Inosine was able to elevate patient urate levels, and deemed safe in a phase I trial [231].

– However, a recent randomized, double-blind, placebo-controlled, phase III trial of oral inosine treatment in early PD revealed no effect on disease progression [232].

Ursodeoxycholic acid (UDCA)

– UDCA possesses among anti-apoptotic, and anti-inflammatory characteristics, also the ability to stabilize mitochondrial integrity.

– In the rotenone and MPTP mouse models, UDCA treatment rescued mitochondrial integrity, normalized mitochondrial membrane potential and lead to increased levels of ATP and decreased levels of ROS [233,234,235,236].

– UDCA treatment of primary human fibroblast cultures of LRRK2G2019S mutations carriers ameliorated mitochondrial function and ATP production [234].

– UDCA exhibits a well-characterized safety profile and was able to increase brain ATP levels of PD patients in a pilot study [237].

– A phase II, placebo-controlled trial is currently ongoing, testing UDCA’s potential to slow PD progression and the ability to increase brain ATP levels (NCT03840005).

Minocycline and creatine

– Minocycline and creatine likely own anti-apoptotic, anti-inflammatory, antioxidant, and bioenergetic effects [238].

– Oral supplementation of creatine increases longevity in mice [238].

– Minocycline protected dopaminergic neurons in MPTP and 6-OHDA toxin rodent models of PD [239].

– Creatine rescued dopaminergic nigral neurons from MPTP toxicity in a rodent model of PD [240].

– Within a phase II trial neither minocycline nor creatine was deemed futile, but larger trials are needed [241].

– However, placebo-controlled trial in multiple system atrophy patients did not show disease modifying potential of minocycline [242].

Deferiprone

– Deferiprone is a well-established iron chelator.

– Intracellular iron is elevated in PD patients and linked to increased levels of oxidative stress, and chelation of iron might therefore possess neuroprotective potential [243, 244].

– Deferiprone attenuated 6-OHDA as well as MPTP induced dopaminergic neurodegeneration in rodent models of PD [245,246,247].

– Deferiprone ameliorated MPP⁺ induced cytotoxicity of SHSY-5Y cells [248].

– Initial clinical trials indicated that deferiprone was able to decrease brain iron content [249, 250].

– However, in a recent phase II trial (FAIRPARK-II), involving de novo PD patients, deferiprone treatment led to an increase in parkinsonian symptoms and was found unsuitable for PD treatment [251].