Seaweed extract shows promise in protecting neurons in Parkinson’s disease

By Dr. Priyom Bose, Ph.D.Reviewed by Benedette Cuffari, M.Sc.Aug 7 2024

A recent Nutrients study evaluates the neuroprotective properties of Ecklonia cava polyphenols (ECPs) in alleviating neuronal damage caused by rotenone in Parkinson’s disease (PD).

Study: Ecklonia cava Polyphenols Have a Preventive Effect on Parkinson’s Disease through the Activation of the Nrf2-ARE Pathway. Image Credit: C Levers / Shutterstock.com

PD and rotenone

PD is a common neurodegenerative disorder that manifests as motor symptoms, including rigidity, tremor, and motor laxity, as well as non-motor symptoms, such as depression and cognitive impairment. Previous studies have shown that the risk of PD onset increases three-fold every decade after the age of 60.

Due to the rapid aging of the global population, PD cases are estimated to reach 14.2 million by 2040. To date, scientists have failed to develop any treatment to attenuate the progression of PD.

The underlying mechanisms associated with PD pathogenesis include dopaminergic neuronal death, mitochondrial dysfunction, oxidative stress, intracellular reactive oxygen species (ROS) generation, neuroinflammation, and the abnormal accumulation of α-synuclein protein.

PD can be further classified as autosomal dominant/recessive or sporadic. Approximately 10-15% of PD cases are genetically linked, whereas the remaining cases are considered sporadic and may arise due to various risk factors. For example, environmental factors, such as exposure to neurotoxic substances like pesticides, increase the risk of developing sporadic PD.

Rotenone, derived from the roots of tropical legumes like couve, is commonly used as an insecticide and pesticide. Previous studies have shown that oral rotenone administration causes motor and gastrointestinal dysfunction. Mechanistically, rotenone triggers mitochondrial dysfunction by inhibiting respiratory chain electron transport complex I, which subsequently increases ROS generation and apoptosis.

The nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response element (ARE) pathway activates a cascade of cytoprotective genes, including numerous transcription factors linked to the generation of antioxidant enzymes, proteasomes, mitochondrial biogenesis, and anti-inflammatory mediators. Several studies have highlighted that the Nrf2-ARE pathway has a pivotal role in triggering adaptive responses to oxidative stress.

Under normal intracellular conditions, Nrf2 binds to the cysteine-rich protein Kelch-like ECH-associated protein 1 (Keap1) in the cytoplasm to promote Keap1 ubiquitination. In the presence of oxidative stress, Nrf2 attaches to ARE and enhances the production of antioxidant proteins.

Therefore, the Nrf2-ARE pathway could be targeted to protect neurons from oxidative stress using antioxidants. This concept could be exploited in PD prevention and treatment.

About the study

The current study investigates the neuroprotective effects of ECP against rotenone-induced neuronal damage. E. cava is an edible brown alga enriched in polyphenols and phlorotannin, which are associated with antioxidant, anti-inflammatory, and antibacterial effects. The current study utilized commercially available ECPs with a total polyphenol content of 99.4%.

In vitro experiments were performed using the human neuroblastoma cell line SH-SY5Y. To this end, SH-SY5Y cells were treated with varying concentrations of ECP and rotenone, following which cell viability and intracellular ROS levels were assessed. Nicotinamide adenine dinucleotide phosphate (NADPH) dehydrogenase 1 (NQO1) and Nrf2 expression levels were also measured.

After acclimatizing mice to laboratory conditions, they were randomly assigned to the control, rotenone, ECP(L), and ECP(H) groups, each comprising six mice. In the ECP(L) group, mice were treated with 20 mg/kg ECP, whereas mice in the ECP(H) group were treated with 240 mg/kg ECP. All mice were orally administered rotenone daily for 30 days except for the control group.

All mice were subjected to several motor function tests, including the pole and wire-hang tests and non-motor function assessments. At the end of the study period, colon and brain tissues were extracted and subjected to histopathological analysis.

Study findings

The in vitro experiments demonstrated that rotenone toxicity was dose-dependent, with 200 nanomolar (nM) selected as the treatment dose for subsequent ECP efficacy experiments. Following exposure to 200 nM rotenone, 12.5 µg/mL ECP sufficiently restored cell viability and ROS expression to control levels. ECP treatment also led to greater nuclear translocation of Nrf2 as compared to rotenone-alone treated cells, thus indicating activation of an oxidative stress response.

Nrf2 mediates induction of the p62 gene, which supports Nrf2 activation through a positive feedback loop. Following ECP treatment of rotenone-exposed cells, a significant increase in p62 messenger ribonucleic acid (mRNA) levels was observed.

In the motor function tests, ECP-treated mice executed shorter T-run times and exhibited improved muscle strength compared to rotenone-treated mice.

Gastrointestinal dysfunction is a common autonomic symptom reported in PD patients. A histopathological analysis of colon tissues was performed to determine whether ECP treatment also affected nonmotor symptoms. To this end, ECP treatment successfully restored intestinal motor function compared to the effects observed in the colons of retonone-alone-treated mice.  

Tyrosine hydroxylase (TH) is a rate-limiting enzyme involved in the synthesis of dopamine; therefore, TH expression is often used to analyze the function of dopaminergic neurons in the substantia nigra of the midbrain. In the current study, immunohistochemical analysis of mouse brains exposed to rotenone indicated reduced expression of TH as compared to control mice. However, ECP treatment led to a significant recovery of TH-positive expression in a dose-dependent manner.

Conclusions

ECP treatment leads to increased nuclear translocation of Nrf2, NQO1 activity, and NQO1 mRNA expression following exposure to rotenone. Moreover, the study findings demonstrate that ECP restores neuronal damage by ROS suppression and 5’ adenosine monophosphate (AMP)- activated protein kinase (AMPK) activation, indicating this compound's therapeutic potential in treating PD. Nevertheless, future studies are needed to determine the precise mechanisms involved in ECP activity to accelerate its clinical use.