February 17th, 2019 Bashayer Althufa

Antioxidants for Parkinson's Disease

      Parkinson's disease (PD) is a chronic neurodegenerative disease that affects 1-2% of the population over 60 years old. In rare cases, PD occurs earlier in life, often progressing unnoticed. Early-onset Parkinson's Disease famously affected the famous boxer, Muhammad Ali at age of 42, and actor Michael Fox at the age of 29. According to the American Parkinson's Disease Association, PD is becoming more and more common, with a new case of PD diagnosed every 9 minutes.


      Symptoms of PD can involve both motor symptoms and non-motor symptoms. With regard to motor symptoms, there are five primary symptoms of PD: tremor, rigidity, bradykinesia, postural instability, and walking/gait problems. On the other hand, non-motor symptoms involve sleep problems, depression and anxiety, change in handwriting, and loss of the sense of smell. Symptoms often vary in intensity and occurrence among patients. Usually, PD is diagnosed when patients are around 60 years old and have reached an advanced stage where symptoms have already obviously manifested.


      Little is known about the underlying causes of PD; however, some studies have implicated genetic, environmental, and traumatic factors. PD is primarily characterized by cell death among dopaminergic neurons in the Substantia Nigra (SN), an area located in the midbrain that controls muscle movement. One study demonstrated that many of PD's symptoms may result from excessive iron accumulation in the SN, which leads to production of harmful radical species, causing neuronal cellular death. Mitochondrial dysfunction also plays a vital role in PD pathology, including an increase in oxidative stress and mutations in the mitochondrial DNA.


      PD is managed by different therapy options depending on the presented symptoms. If the patient suffers from mild symptoms not including uncontrolled movement, they might choose to start with monoamine oxidase-B inhibitor or dopamine agonist. Levodopa, which is a drug prescribed to supply the deficient dopamine, is considered the first line of therapy. However, some clinicians may delay prescribing it due to its long-term movement complications. In addition, improving patient lifestyle via sports and diet is also recommended. Despite the availability of various treatment options, none are able to cure or reverse effects of the disease. Current treatment efficiently controls the symptoms in the short term, but fails to maintain control in the long term. This may result in the adverse progression of the patient's condition, which is also known as an "Off" episode. 


      New therapy options are needed to replace current treatments in order to eventually avoid disease progression and off episodes. The advanced therapeutic strategies used to treat PD are very broad, including the use of small molecules, antibodies, and stem cell therapy.  One of the therapeutic strategies is the use of iron chelators. The iron chelator, Deferiprone, is currently in Phase II clinical trial being evaluated as a neuroprotective in a PD management plan to remove iron from the SN, thus enhancing the survival of dopaminergic neurons. Immunotherapy is also an option to program the body's immune system to target the toxic form of alpha synuclein while leaving the normal monomer form of the protein alone. In PD, a pathogenic alpha synuclein copy forms abnormal aggregation bodies called Lewy bodies, leading to cellular death. BIIB054, a monoclonal antibody targeting the toxic form of alpha synuclein, is currently in clinical trial Phase II. Due to the loss of dopaminergic neurons being a hallmark of PD, scientists are considering the replacement of these neurons via stem cell therapy as a viable form of treatment.  Here, a certain type of cell is planted in the SN to be eventually developed into dopaminergic neurons. Researchers will start the first clinical trial by 2019. However, the cost of the treatment would be a major bottleneck if this therapeutic approach is viable. PD is also associated with metabolic abnormalities and an increased rate of oxidative stress, resulting in the generation of a very harmful hydroxyl radical. Because of this, antioxidants are currently being investigated as an effective therapeutic avenue in most mitochondrial dysfunction diseases, including PD. Studies have shown that antioxidants, such as MitoQ and vitamin E, were effective in reversing neuronal cellular damage in PD-simulating animal and cell line models. However, in human trials, some of the antioxidants have shown decreased potency. Hence, researchers from different disciplines are working on optimizing their efficacy in humans.

 

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