Insights Into The Pathogenesis Of Neurodegenerative Diseases: Focus On Mitochondrial Dysfunction And Oxidative Stress Part 5

7.2. Targeting Oxidative Stress and Mitochondrial Dysfunction in Parkinson's Disease

Currently prescribed treatments for PD are levodopa with 1-amino acid decarboxylase inhibitors, dopamine agonists (pramipexole, ropinirole, rotigotine), MAO-B inhibitors (selegiline, rasagiline), catechol-O-methyltransferase inhibitors (entacapone), and anticholinergic drugs [415], while refractory cases may undergo surgical deep brain stimulation procedures. 

Catechol is a powerful neurotransmitter that promotes nerve signal transmission, which plays a vital role in human cognitive functions such as memory, learning, and thinking. Many studies have shown that catechol and memory are closely related.

According to research, catechol mainly appears in the cerebral cortex, hippocampus, and cingulate gyrus in the human brain, which are the core areas of human cognition. Therefore, the lack and deficiency of catechol will lead to a decline in people's cognitive and memory abilities.

In addition, catechol can also promote the generation and storage of long-term memory, which can help us better remember learning content, experiences, and feelings, thereby deepening our understanding of the world, improving our thinking ability and creativity, and promoting success in our careers and lives.

In addition, some studies in recent years have found that catechol not only has a significant impact on human memory function but may also help people prevent and treat some neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. Therefore, we should eat more foods rich in catechols, such as tea, cocoa, raisins, etc., and maintain good living habits and eating habits to protect our brains and promote cognitive and memory abilities.

In summary, catechols and memory are inextricably linked. We should maintain an optimistic attitude and actively explore ways to improve self-cognition and memory, which can not only help us better face life challenges but also help protect our mental and physical health. It can be seen that we need to improve our memory. Cistanche can significantly improve memory because it has antioxidant, anti-inflammatory, and anti-aging effects, which can help reduce oxidation and inflammatory reactions in the brain, thereby protecting the health of the nervous system. In addition, Cistanche can also promote the growth and repair of nerve cells, thereby enhancing the connectivity and function of neural networks. These effects can help improve memory, learning ability, and thinking speed, and can also prevent the occurrence of cognitive dysfunction and neurodegenerative diseases.

Click Know to improve short-term memory

Although helpful in relieving symptoms, none of these approaches interfere with the neurodegenerative process, and some concerns regarding the accelerated neurodegeneration caused by levodopa metabolism and subsequent increase in oxidative stress have been raised [416]. 

Recent developments in the treatment of PD focus on [417] immunotherapies to restrict the propagation of α-synuclein, neurotrophic factors, such as GDNF (glial cell-derived neurotrophic factor), regenerative therapies using cell-based and genetic approaches to replace the function of the lost dopaminergic neurons, re-establishing the balance between neurotransmitters by targeting non-dopaminergic neurotransmission, interfering with the neuroinflammatory response, or improving the stereotactical surgical treatments. 

As for supporting/improving mitochondrial function and targeting oxidative stress, the clinical trials performed so far and their conclusions are described below. Creatine acts as an antioxidant and improves mitochondrial function [418]. 

Although a pilot study reported in 2006 could not detect any improvement in the UPDRS scores of PD patients after 2–4 g creatine/day for 2 years [419], a subsequent phase 2 multi-center, double-blind, pilot study of minocycline and creatine was conducted in 195 patients with early untreated PD to test efficacy in slowing disease progression (National Institute for Neurological Disorders and Stroke Parkinson's Disease Neuroprotection Trial, NCT00063193) and showed promising results [420], followed by a larger phase 3 double-blind, parallel-group, placebo-controlled study (NET-PD LS-1, NCT00449865), which enrolled 1741 participants who were administered 10 creatine/day for 5 years, which failed to show improvements in clinical outcome [421]. 

Vitamin E has also been evaluated in several studies, with mixed results. After a population-based study showed a negative association between vitamin E intake and incident PD [422], similar subsequent studies failed to confirm the decreased PD risk associated with dietary antioxidants [423]. 

A pilot open-label study evaluated the efficacy of tocopherol in slowing down the disease progression and claimed that vitamin E can postpone the need for levodopa therapy by 2.5 years [424], a claim contradicted by the findings of a subsequent multicenter, randomized, placebo-controlled study (DATATOP) carried out on 800 patients to evaluate the effect of selegiline and/or tocopherol versus placebo on the onset of disability prompting the need for levodopa therapy [425] and which found beneficial effects for selegiline but not for tocopherol. 

At present, a phase 2 pilot, randomized, double-blind, placebo-controlled trial (NCT04491383) is recruiting 100 participants in Singapore to assess the efficacy of tocotrienols in delaying motor disability in PD [394]. 

Since complex I activity was found reduced in PD, coenzyme Q10, an antioxidant and electron acceptor for complexes I and II seemed a reasonable approach. A randomized, double-blind, placebo-controlled trial that enrolled 80 early-stage PD patients showed that 300–1200 mg coenzyme Q10/day could significantly reduce disability in a dose-dependent manner [426]. 

However, a large phase 3 multi-center, randomized, double-blind, placebo-controlled clinical trial which included 600 participants (QE3, NCT00740714) failed to show clinical benefits for 1200 or 2400 mg of coenzyme Q10 daily [427]. To overcome the reduced BBB permeability of coenzyme Q10, it was delivered in a nano-dispersed solution in doses of 300 mg (equivalent to 1200 mg coenzyme Q10)/day to 132 participants in phase 3 clinical trial (NCT00180037), which also showed null results [428]. 

A mitochondria-targeted synthetic coenzyme Q10 analog, MitoQ, has positive charges and lipophilic properties, enabling it to easily cross the BBB and accumulate within mitochondria. 

However, it also failed to alter the disease course in a phase 2 clinical trial which enrolled 128 participants (NCT00329056) [429]. Glutathione is an endogenous antioxidant molecule that has been tested in several clinical trials. 

While the intravenous administration of 1200 mg/day of reduced glutathione was shown to significantly improve disability [430], a subsequent trial with 700 mg glutathione/day given also IV failed to confirm these results [431]. 

After a phase 1 safety trial (NCT01398748), intranasally administered glutathione was tested in a phase 2b study on 45 participants over 12 weeks for efficacy on disease progression ((in) GSH, NCT02424708) but showed null results [432]. 

Studies with other dietary antioxidants are in preclinical phases, but, considering the poor BBB penetration of these compounds [433], it is unlikely that they will successfully translate in clinical settings. 

Melatonin, being amphiphilic, can cross the BBB and exhibit antioxidant activity in the central nervous system. After promising results in animal models, the effect of 3 mg melatonin/day for 4 weeks on motor performances and quality of sleep was assessed in a small study involving 18 PD patients. 

Sleep disturbances are common complaints in PD and may herald a more aggressive course and a more rapid progression toward cognitive decline [434]. The trial showed that melatonin improved the subjective quality of sleep but had no effect on motor performance [435]. 

Given the high levels of iron in nigral neurons and the involvement of iron in ROS production, the efficacy of iron chelators was assessed first in a pilot study on 22 participants (DeferipronPD, NCT01539837) and showed non-significant motor improvement [436] followed by a phase 2/3 trial enrolling 37 patients in the active arm and 40 in the placebo arm (FAIR PARK-I, NCT00943748) and which showed reduction of iron in the substantia nigra as well as motor improvement [437]. 

Currently, an extended clinical trial, enrolling 372 participants (FAIR PARK-II, NCT02655315), is active but not recruiting [394]. 

Other agents, such as PPARγ coactivator-1α (PGC-1α) agonists, Nrf2 enhancers, or natural antioxidant compounds are only in preclinical stages [415] except for pioglitazone, a PPARγ coactivator-1α agonist, which, administered in doses of 15–45 mg/day in 210 PD patients (NCT01280123) could not show significant motor benefits [438].

7.3. Targeting Oxidative Stress and Mitochondria in ALS

For years the only approved therapy in ALS was riluzole, a glutamate antagonist that interferes with excitotoxic neuronal death [439]. Based on the results of several studies evaluating the effect of edaravone (3-methyl-1- phenyl-2-pyrazoline-5-one, or MCI-186), the FDA approved the molecule in 2017 for use in ALS [440]. 

Edaravone acts as a free radical scavenger of hydroxyl and peroxyl radicals, hydrogen peroxide, and peroxynitrite [441], and activates the Nrf2/HO-1 signaling pathway, protecting cells against apoptosis [440], thereby offering a modest clinical benefit. Melatonin, an endogenous molecule involved in the regulation of the sleep-wake cycle, exhibits also antioxidant properties [442]. 

In ALS patients it slowed the progression of the motor impairment [443]. However, no clinical trial with melatonin in ALS is currently ongoing [394]. Alpha-lipoic acid is a hydroxyl radical scavenger and induces the ERK/PI3K/Akt pathway, thereby regulating the expression of antioxidant genes. 

Its safety and efficacy in ALS are currently being explored and compared to riluzole in the Explore Neuroprotective Effect of Lipoic Acid in Amyotrophic Lateral Sclerosis (NCT04518540) trial, conducted by the Zhejiang University School of Medicine [394]. 

Dopaminergic drugs, such as pramipexole, reduce oxidative stress [444] and glutamate excitotoxicity [445]. The safety and efficacy of dexpramipexole was evaluated in several phase 1, 2, and 3 clinical studies. 

So far, results published from a phase 3 randomized, double-blind, placebo-controlled, multicenter study that enrolled 942 participants (EMPOWER, NCT 01281189) revealed a good safety profile but non-significant efficacy of the treatment arm compared to placebo [446] despite promising results of phase 2 randomized, double-blind safety and tolerability study (NCT00647296) [447]. 

The results of the extension phase, NCT01622088 are still awaited [394]. Another drug currently used in the treatment of PD, rasagiline, a monoamine oxidase B inhibitor, exhibits also antioxidative and anti-apoptotic activities, making it a potential therapeutic option in ALS. 

Its safety and efficacy were evaluated in two phase 2 trials, an open-label one enrolling 36 participants (NCT01232738), which showed no improved clinical course but suggested reduced apoptosis [448] and a second phase 2, double-blind, placebo-controlled trial (NCT017866030) evaluating efficacy, which showed null results after 12 months of treatment [449]. 

Dietary antioxidants and antioxidant food supplements have also been tested in several trials. A phase 2 trial with high doses of coenzyme Q10 in ALS (NCT00243932) concluded that there is insufficient evidence to justify a phase 3 trial [450], while NCT02588807, a phase 1 trial with food supplements for the treatment of patients with ALS is suspended [394]. 

However, two further studies, planned but not yet recruited, will evaluate the safety and efficacy of coenzyme Q10 with vitamin E, N-acetyl cysteine, and L-cysteine (MICABO-ALS, NCT04244630) and of liposomes polyphenols resveratrol and curcumin (NCT04654689) in patients with ALS.

8. Concluding Remarks

From the repeated failures of drugs targeting mitochondrial dysfunction and oxidative stress in neurodegenerative diseases, it appears that starting these interventions by the time of clinical diagnosis is probably too late. 

Due to the resilience of the brain to insults, the described pathogenetic cascades and loops are already full-blown, and significant neuronal loss has already occurred when clinical symptoms enable diagnosis. Genetic testing in familial neurodegenerative diseases could allow starting these therapies in the preclinical stage. 

Since the present healthcare systems cannot afford extensive and invasive evaluations of the population at large, promoting a healthy lifestyle, with plenty of dietary antioxidant intake and avoidance of exogenous oxidants could postpone the onset of neurodegenerative diseases. 

Hopefully, ongoing research will provide more efficient, multimodal molecules to interfere with the pathogenesis of these diseases, which, due to the aging of the population, are a global threat.

Funding: This research received no external funding.

Acknowledgments: The author wishes to thank José L. Quiles for editing this interesting topical collection, as well as the two anonymous reviewers for appreciating this review.

Conflicts of Interest: The author declares no conflict of interest.

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