Levodopa: A novel therapeutic prospect for liver disease

Abstract

In this article, we discuss the recently published study by Wang et al, which investigated the therapeutic potential of levodopa, a well-known drug used to treat Parkinson’s disease, for the treatment of liver diseases. The study revealed that levodopa, a dopamine precursor, exerts therapeutic effects by modulating dopamine receptor D1 signaling and activating Hippo/Yes-associated protein 1 pathway, which plays an important role in liver fibrosis. Furthermore, given that dysregulation of the brain-liver axis, including the dopaminergic reward circuit, has been implicated in the progression of liver diseases, particularly those exacerbated by stress, the purpose of this article is to make a further investigation on the potential of levodopa in regulating metabolic dysfunction and addressing maladaptive eating behaviors. Considering the important role of dopamine in regulating lipid metabolism, inflammation, and fibrosis in the liver, levodopa may present as a promising therapeutic candidate for chronic liver diseases characterized by altered dopamine sensitivity.

Key Words: Levodopa; Liver diseases; Liver fibrosis; Dopamine receptor D1; Hippo/YAP pathway; Metabolic dysfunction-associated liver disease; Eating behaviors

Core Tip: This article discusses the potential of levodopa as a novel therapeutic prospect for liver diseases, particularly liver fibrosis and metabolic liver disease. Levodopa, which is traditionally used in the treatment of Parkinson’s disease, may influence liver fibrosis through the modulation of dopamine receptor D1 signaling and the activation of Hippo/Yes-associated protein 1 pathway. In addition, its potential impact on eating behavior and metabolic regulation may propose it a broader application for patients with stress-exacerbated liver disease.

TO THE EDITOR

We read with great interest the recent study by Wang et al[1], which explored that levodopa, a drug traditionally used in the treatment of Parkinson’s disease (PD), demonstrated a capacity to alleviate liver fibrosis in a CCl₄-induced rat model. This discovery represents a significant advancement in the application field of levodopa, proposing an innovative repurposing method and opening a new therapeutic avenue for liver diseases.

CURRENT USE OF LEVODOPA AND ITS MECHANISMS

Levodopa, a precursor to dopamine, plays an essential role in regulating a wide array of physiological functions within the central nervous system (CNS), including motor control, reward processing, mood regulation, and cognitive processes[2]. Since its introduction in the 1960s as the principal treatment for PD, levodopa has been regarded as the gold standard for alleviating motor symptoms such as tremors, rigidity, bradykinesia, and postural instability[3]. After levodopa crosses the blood-brain barrier, the enzyme dopa decarboxylase converts it into dopamine. This process compensates for the loss of dopamine-producing neurons in the substantia nigra. As a result, levodopa helps restore motor function[4]. Although levodopa is primarily known for its effects on the CNS, emerging research has begun to explore its influence on peripheral systems. Notably, its potential role in modulating metabolic disorders and tissue fibrosis is of growing interest[5,6].

INNOVATION AND VALUE OF THE STUDY

The study conducted by Wang et al[1] represents a substantial advancement by demonstrating that levodopa can reduce liver fibrosis through the modulation of the dopamine receptor D1 (DRD1)-Hippo/Yes-associated protein 1 (YAP1) signaling pathway. This finding is particularly innovative, as it repurposes an extensively studied drug that is traditionally used for neurological disorders, for the treatment of liver diseases, an area where therapeutic options are still limited.

A pivotal innovation of this research lies in the identification of dopamine receptors in peripheral tissues. Specifically, DRD1, a member of the G-protein-coupled receptor family, is expressed in various tissues, including liver tissue. Activation of DRD1 triggers downstream signaling events via coupling to the Gαs protein, which activates the cAMP-PKA signaling axis[7]. These pathways have been implicated in regulating cellular processes such as inflammation, fibrosis, and cell proliferation. Furthermore, DRD1 signaling has been shown to activate the Hippo/YAP1 pathway, a critical regulator of cellular responses to stress and injury[8]. Thus, the levodopa’s ability to modulate DRD1 signaling provides a novel approach to managing liver fibrosis and inflammation.

Moreover, the results of this study highlight the capacity of levodopa to modulate peripheral dopamine signaling, suggesting that this drug may have broader therapeutic implications. The exploration of DRD1 receptor activation and its downstream effects on liver fibrosis introduces a novel mechanism for fibrosis management, especially in patients with chronic liver diseases such as cirrhosis and metabolic dysfunction-associated steatotic liver disease (MASLD), for whom fibrosis progression remains a major clinical challenge[9].

LIMITATIONS AND EMERGING RESEARCH OPPORTUNITIES

While the findings presented in this study are compelling, several important limitations must be addressed in future investigations.

First, this research predominantly employs a single animal model of liver fibrosis induced by CCl₄ administration. Although this model is a useful tool for studying liver fibrosis, it may not fully reflect the complexities inherent in patients with other chronic liver diseases such as MASLD and alcoholic liver disease. Therefore, it would be beneficial for future studies to assess the effects of levodopa in models of MASLD, alcoholic liver disease, or even viral hepatitis to determine whether its therapeutic potential extends to these diverse liver pathologies.

Moreover, while the study elucidates the role of levodopa in modulating fibrosis through the DRD1-Hippo/YAP1 pathway, further research is necessary to explore its interactions with other molecular pathways. A more comprehensive understanding of how levodopa interacts with these pathways will be crucial for determining its broader therapeutic applicability in patients with liver diseases.

In addition to its potential for treating liver fibrosis, emerging evidence suggests that levodopa may be beneficial in addressing other chronic liver diseases, such as MASLD[10]. Dopamine signaling has been shown to influence immune cell activation, particularly in macrophages, suggesting a significant anti-inflammatory effect[11]. In the context of MASLD, levodopa may alleviate liver inflammation, improve insulin sensitivity, and potentially prevent the progression from simple steatosis to hepatitis.

Interestingly, the potential therapeutic effects of levodopa on MASLD may arise not only from its ability to improve fibrosis and inflammation, but also from its influence on metabolism and eating behaviors. In particular, the dopamine system plays a key role in regulating reward-driven behaviors, which control food motivation and pleasure derived from eating[12,13]. In the nucleus accumbens and hypothalamus, the reward circuit tightly control both appetite and how the body spends energy. Disruptions in the circuit will contribute to maladaptive eating behaviors, such as overeating, which are often associated with metabolic dysfunction in conditions like MASLD. Meanwhile, emerging evidence has revealed that, in individuals with MASLD, especially comorbid with pressure related disorders, the dopamine signaling is often dysregulated[14]. Stress may induce disruptions in the dopamine system, thereby leading to maladaptive eating behaviors such as emotional eating or overconsumption of high-calorie foods[15]. Under these circumstances, levodopa can restore balance to the reward circuit by enhancing dopamine availability, thereby reducing maladaptive eating behaviors and controlling weight gain and hepatic fat accumulation (Figure 1).

Figure 1 The schematic illustration of the putative mechanisms underlying levodopa-mediated therapeutic effects in liver disease. DRD1: Dopamine receptor D1; YAP1: Yes-associated protein 1.

It is noteworthy that our exploration is based on the findings of a prior animal study. In our experiment, a murine model was constructed by a chronic restraint stress experiment combined with high fat, high fructose, and high cholesterol diets, while the levodopa (10 mg/kg) was intraperitoneally injected daily as intervention from the eighth week. Our research has revealed that levodopa effectively ameliorates alterations in feeding behavior induced by chronic restraint stress combined with high fat, high fructose, high cholesterol diets (Figure 2). This finding points toward dopamine’s role in controlling cravings for high-calorie foods by regulating brain reward circuits. As a result, correcting these behaviors may help reduce excessive calorie intake and prevent liver fat buildup.

Figure 2 The therapeutic effect of levodopa on the body weight and the food consumption in chronic stress-exacerbated metabolic dysfunction-associated steatotic liver disease mice. A: The body weight was recorded weekly; B: The food consumption was recorded weekly. Male C57BL/6 mice aged 6-8 weeks were used in this study (n = 6). A murine model was constructed by a chronic restraint stress experiment combined with high fat, high fructose, and high cholesterol diets, while the levodopa (10 mg/kg) was intraperitoneally injected as intervention from the eighth week. This experiment was conducted under the supervision of the Institutional Animal Ethics Committee of the Shanghai Hospital of Traditional Chinese Medicine. Repeated-measures analysis of variance was employed for the statistical analysis of body weight and food intake. ^aP < 0.05, compared between the control group and the model group; ^bP < 0.05, compared between the model group and the levodopa group.

CONCLUSION

In conclusion, levodopa holds considerable promise as a therapeutic agent for liver diseases. The innovative discovery that levodopa modulates the Hippo/YAP signaling pathway to reduce liver fibrosis opens new possibilities for repurposing this well-established drug for the treatment of liver diseases. Furthermore, its potential to influence eating behaviors could have profound implications for managing stress-exacerbated metabolic disorders. Given the increasing prevalence of liver diseases, particularly MASLD, levodopa’s ability to modulate both hepatic fibrosis and reward-driven eating behaviors offers a dual therapeutic approach for managing these conditions.