Carvedilol Confers Neuroprotective Activity Through Modulating Ferroptosis Key Players and PINK1/PARKIN Mediated Mitophagy in an Experimental Parkinson's Rat Model

Nov 17, 2025Journal of biochemical and molecular toxicology

Carvedilol may protect brain cells by controlling iron-related cell death and mitochondrial cleanup in a Parkinson's rat model

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Abstract

Carvedilol significantly preserved key proteins involved in neuroprotection in a rotenone-induced Parkinson's disease rat model.

Rotenone exposure resulted in decreased levels of Nrf2, Glutathione peroxidase (GPX4), and PINK1/PARKIN, indicating disruption in neuroprotective mechanisms.
Increased markers of ferroptosis, such as ACSL4 and MDA, were observed following rotenone treatment.
Carvedilol administration preserved Nrf2 and GPX4 levels while increasing catalase, suggesting a protective role in mitochondrial function.
The drug also downregulated ACSL4 and reduced NF-κB and MDA levels, which may help maintain normal mitophagy and inhibit ferroptosis.
Carvedilol improved motor functions and alleviated α-synuclein levels in the striata and substantia nigra of treated rats.

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Parkinson's disease (PD) is the fastest growing neurodegenerative disorder worldwide. Available treatments are only symptomatic, urging the demand for new therapies. Ferroptosis is increasingly reported as a critical player in neurodegeneration. Meanwhile, ferroptosis is activated by impaired mitophagy under rigorous milieu of oxidative stress that disrupts mitochondrial homeostasis. However, the interplay between ferroptosis and mitophagy is not fully elucidated in PD. Carvedilol is a cardiovascular antioxidant, antiferroptotic drug with lipophilic nature that allows its passage via blood brain barrier. Moreover, its effect on modulating mitochondrial balance is emerging in multiple disorders. Therefore, This study aimed to explore the possible neuroprotective mechanistic effects of carvedilol on rotenone-induced PD rat model in context of ferroptosis-mitophagy interaction. Rotenone-induced toxicities were detected by Immunohistochemistry, ELISA, qPCR and western blot analysis techniques. Rotenone disrupted key players of ferroptosis-mitophagy axes. Nrf2, Glutathione peroxidase (GPX4), Catalase, PINK 1/PARKIN levels were drastically decreased. Acyl coA synthetase long chain (ACSL4), MDA and NF-κB levels were significantly increased. Contrarily, carvedilol preserved adequate Nrf2, GPX4, PINK1 and PARKIN levels and increased catalase. Furthermore, it downregulated ACSL4, reduced NF-κB and MDA levels to maintain normal mitophagy and inhibit ferroptosis. Carvedilol's protective effects extended to alleviate α-synuclein and upregulate tyrosine hydroxylase in the striata and substantia nigra leading to distinguished improvements of motor functions. To the best of our knowledge, this is the first study to highlight carvedilol's neuroprotective capacity against PD pathologies in terms of ferroptosis - mitophagy interaction as a novel therapeutic approach to tackle PD at earlier stages.

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Carvedilol Confers Neuroprotective Activity Through Modulating Ferroptosis Key Players and PINK1/PARKIN Mediated Mitophagy in an Experimental Parkinson's Rat Model

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