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dcyphr | Bioactive Flavonoids and Catechols as Hif1 and Nrf2 Protein Stabilizers - Implications for Parkinson’s Disease

Abstract:


A certain chemical family known as flavonoids activate pathways that combat oxidative stress. Oxidative stress is the phenomenon in which an imbalance in oxidants and antioxidants leads to programmed cell death. The pathways that are activated are the hypoxia inducible factor (HIF) and Nrf2. It is important to note that not all flavonoids are activators of these two pathways. NDGA, a chemical similar to flavonoids, was chosen in this study due to its strong ability to activate the Nrf2 and HIF pathway as well as its bioavailability and stability. NDGA had neuroprotective effects in the animal model of Parkinson’s Disease.


Main:


Flavonoid-rich diets are praised because of their incredible health benefits. These diets are correlated with lowered risk of cancer, heart attack, stroke, and age-related neurodegeneration. Scientists have attributed these benefits to flavonoids activating anti-oxidant and anti-hypoxic programs in the cell. The two most potent programs that are activated are those triggered by hypoxia inducible factor (HIF) and Nrf2. 


HIF:


HIF is a transcription factor responsible for activating many genes involved in glucose uptake, metabolism, extracellular pH control, and programmed cell death. Under normal conditions, HIF is targeted for proteasomal degradation by prolyl hydroxylases (PHDs). However, there are certain molecules - such as flavonoids - that inhibit the PHDs thereby freeing/activating the HIF.


Nrf2:


Nrf2 works in a similar fashion to HIF. Nrf2 is a transcription factor that is responsible for the expression of pro-survival and cytoprotective enzymes. Under normal conditions, Nrf2 is bound to the Keap1 complex which targets Nrf2 for proteasomal degradation. When the Keap1-Nrf2 complex is in the presence of electrophiles, the Keap1 undergoes a conformational change allowing for the Nrf2 to enter the nucleus of the cell. The Nrf2 then binds to the antioxidant response element (ARE) binding site. 


Methods and Materials:


The first step in the study was to demonstrate that flavonoids activate the HIF and Nrf2 pathways. To do this, a luciferase assay and a real-time RT-PCR were performed. 


To model Parkinson’s in neuronal cultures, the researchers made a glutathione depletion model. Both the mouse model of Parkinson’s and the in vitro Parkinson’s model were both treated with NDGA and selected flavonoids. 


To measure cellular viability, an MTT assay was performed. 


Results:


In the glutathione depletion model, certain flavonoids were selected based on their luciferase activity. Most of the chosen flavonoids gave significant recovery to the neuronal culture. NDGA treatment at 2.5 micromolar concentration gave nearly full recovery. 


Within the mouse models of Parkinson’s, slides of the mice’s brains showed a significant decrease in the cell density. However, with NDGA treatment, there was significant recovery in cell density. 


Discussion:


This study showed that different flavonoids may have different effects on the two programs mentioned (HIF and Nrf2). One flavonoid may be a strong HIF activator while not being as strong an Nrf2 activator and vice versa. This is likely due to the different structural requirements for activating HIF versus Nrf2. 


Flavonoids, though their health benefits cannot be ignored, have lacking bioavailability in the brain. NDGA is a promising alternative as it is structurally similar to flavonoids. NDGA also has a higher bioavailability. Lastly, NDGA was proven in this study to have neuroprotective effects in Parkinson’s Disease models.


Conclusion:


In addition to this study showing the promising effects of NDGA and flavonoids in Parkinson’s Disease, it also highlighted the structural requirements for activation of HIF and Nrf2.