Icaritin Provides Neuroprotection in Parkinson's Disease by Attenuating Neuroinflammation, Oxidative Stress, and Energy Deficiency.

Hao Wu,Xi Liu,Ze-Yu Gao,Yi Sun,Xiao-Ping Pu,Ming Lin,Xin Zhao

doi:10.3390/antiox10040529

Abstract

Neuroinflammation, oxidative stress, and mitochondrial dysfunction are all important pathogenic mechanisms underlying motor dysfunction and dopaminergic neuronal damage observed in patients with Parkinson’s disease (PD). However, despite extensive efforts, targeting inflammation and oxidative stress using various approaches has not led to meaningful clinical outcomes, and mitochondrial enhancers have also failed to convincingly achieve disease-modifying effects. We tested our hypothesis that treatment approaches in PD should simultaneously reduce neuroinflammation, oxidative stress, and improve alterations in neuronal energy metabolism using the flavonoid icaritin in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. Using matrix-assisted laser desorption/ionization–mass spectrometry imaging (MALDI-MSI), coupled with biochemical analyses and behavioral tests, we demonstrate that icaritin improves PD by attenuating the the NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome activity and stabilizing mitochondrial function, based on our extensive analyses showing the inhibition of NLRP3 inflammasome, reduction of NLRP3-mediated IL-1β secretion, and improvements in the levels of antioxidant molecules. Our data also indicated that icaritin stabilized the levels of proteins related to mitochondrial function, such as voltage-dependent anion channel (VDAC) and ATP synthase subunit beta (ATP5B), as well as those of molecules related to energy metabolism, such as ATP and ADP, ultimately improving mitochondrial dysfunction. By employing molecular docking, we also discovered that icaritin can interact with NLRP3, VDAC, ATP5B, and several blood–brain barrier (BBB)-related proteins. These data provide insights into the promising therapeutic potential of icaritin in PD.

Highlights

IntroductionThe exact cause of neurodegenerative diseases, which are defined by common degenerative responses to diverse neurological processes, has not been fully elucidated [1]
We found that the MPTP-treated mice had deficits in the open field (Figure 1C and (Di–ii)), rotarod (Figure 1E), and vertical grid (Figure 1(Fi–ii)) tests, all of which were reversed by treatment with icaritin or selegiline, which inhibits monoamine oxidase (MAO)-B
We aimed to identify small molecules involved in the energy metabolism in substantia nigra to confirm the neuroprotective effect of icaritin

Summary

Introduction

The exact cause of neurodegenerative diseases, which are defined by common degenerative responses to diverse neurological processes, has not been fully elucidated [1]. Parkinson’s disease (PD) is a common neurodegenerative disease characterized by the preferential loss of dopaminergic neurons in substantia nigra and intracellular inclusions, and clinical symptoms include tremor, stiffness, and bradykinesia [2]. Substantia nigra is a part of midbrain, the top most structure present in the brain stem. It divides the cerebellar peduncles into anterior crus cerebri and posterior tegmentum of mid brain

Results

Discussion

Conclusion