Abstract
Parkinson’s disease (PD) is characterized by a gradual degeneration of the dopaminergic neurons in the substantia nigra pars compacta (SNpC). Levodopa, the standard PD treatment, provides the missing dopamine in SNpC, but ultimately after a honeymoon with levodopa treatment the neurodegenerative process and the progression of the disease continue. Aimed at prolonging the life of dopaminergic cells, we prepared the levodopa precursors SuperDopa (SD) and SueprDopamide (SDA), in which levodopa is merged with the antioxidant N-acetylcysteine (NAC) into a single molecule. Rotenone is a mitochondrial complex inhibitor often used as experimental model of PD. In vivo, SD and SDA treatment show a significant relief of motor disabilities in rotenone-injected rats. SD and SDA also lower rotenone-induced-α-synuclein (α-syn) expression in human SH-SY5Y cells, and α-syn oligomerization in α-syn-overexpressing-HEK293 cells. In the neuronal SH-SY5Y cells, SD and SDA reverse oxidative stress-induced phosphorylation of cJun-N-terminal kinase (JNK) and p38-mitogen-activated kinase (p38MAPK). Attenuation of the MAPK-inflammatory/apoptotic pathway in SH-SY5Y cells concurrent with protection of rotenone-triggered motor impairment in rats, is a manifestation of the combined antioxidant/anti-inflammatory activity of SD and SDA together with levodopa release. The concept of joined therapies into a single molecule, where levodopa precursors confer antioxidant activity by enabling NAC delivery across the BBB, provides a potential disease-modifying treatment for slowing PD progression.
Highlights
Neurodegenerative diseases share neuroinflammation as a common mechanism resulting from activated microglia that release pro-inflammatory cytokines
Mitochondrial membrane potential Initially, we explored the effects of Auf on the mitochondria, recording mitochondrial membrane potential (MMP)
SD and SDA but not Levodopa ethyl ester (LDEE), exhibited a concentrationdependent decrease in Auf-induced phosphorylation of JNK and p38MAPK (Fig. 6A, B). These findings show the antioxidant activity of SD and SDA, which could be attributed to the thiol group of the Cys residue, most likely through preventing the dissociation of Trx/apoptosis signal-regulating kinase1 (ASK1) [23]
Summary
Neurodegenerative diseases share neuroinflammation as a common mechanism resulting from activated microglia that release pro-inflammatory cytokines. The loss of 9-type dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) has been shown to be responsible for the first motor symptoms of Parkinson’s disease (PD). PD progresses with time, and patients experience diminished duration of benefit from each dose. The diminished effectiveness over time is accompanied by the development of medicationrelated complications such as motor fluctuations, and levodopainduced dyskinesia [1]. The decrease in efficacy of levodopa is attributed mainly to the continuous loss of DA cells, presenting an unmet medical need with no approved drug therapy. It requires a disease-modifying approaches that would delay or slow the clinical progression of the disease (reviews [1–3])
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
