Benserazide

Cardiovascular autonomic dysfunction was frequently observed in patients with Parkinson's disease (PD), and severe blood pressure (BP) fluctuations posing significant clinical challenges. Although current dopaminergic drugs, (e.g. levodopa/benserazide, selegiline, and piribedil) could improve motor symptoms, the underlying mechanisms of catecholamine storm triggered by concomitant use remained to be fully elucidated.

A 62-year-old female with PD was admitted in May 2025 due to abnormal BP fluctuations accompanied by fatigue lasting 20 days. In 2021, she was diagnosed with PD and received long-term treatment with levodopa/benserazide (125 mg tid), selegiline (2.5 mg tid), and piribedil (50 mg tid). Systolic blood pressure (SBP) measured in the hospital varied from 57 to 217 mmHg. A 24-hour peak urinary dopamine level of 36,733 µg/24 h was documented. Multidisciplinary consultation led to discontinuation of selegiline and piribedil while levodopa/benserazide was maintained. Within 72 h, her urinary dopamine levels decreased by 77% (to 8,424 µg/24 h), and standard deviation of BP was reduced from 29.59 to 9.95 mmHg-a 66% decrease. During 3-month follow-up period, the patient's home monitored SBP remained stable between 110 and 135 mmHg although her motor symptoms have advanced manifesting as ipsilateral limb tremors and increased muscle tone.

This case demonstrated that combined dopaminergic therapy could induce catecholamine storm via synergistic effects, leading to life-threatening fluctuations in BP. Timely identification and adjustment of treatment regimens could effectively reverse cardiovascular risk. However, it was crucial to carefully consider the balance between the progression of motor symptoms and changes in medication treatment.

Aggregates of the protein α-synuclein may initially form in the gut before propagating to the brain in Parkinson's disease (PD). Indeed, our prior work supports that enteroendocrine cells, specialized intestinal epithelial cells, could play a key role in the development of this disease. Enteroendocrine cells natively express α-synuclein and form synapses with enteric neurons as well as the vagus nerve. Severing the vagus nerve reduces the load of α-synuclein aggregates in the brain, suggesting that this nerve is a conduit for gut-to-brain spread. Enteroendocrine cells line the gut lumen; as such, they are in constant contact with metabolites of the gut microbiota. We previously found that when enteroendocrine cells are exposed to nitrite─a potent oxidant produced by gut bacterial Enterobacteriaceae─a biochemical pathway is initiated that results in α-synuclein aggregation. Here, we detail the cellular and molecular mechanisms involved. First, we holistically profiled nitrite-exposed enteroendocrine cells through untargeted proteomics. Next, we performed targeted analyses that specifically probed the mechanistic role of dopamine, as our prior findings suggested that dopamine is critical for nitrite-induced α-synuclein aggregation. In dopamine-free HeLa cells treated with nitrite, α-synuclein aggregation was indeed suppressed. Proteomic signatures in dopamine-free cells treated with nitrite were distinct from those in nitrite-treated enteroendocrine cells, highlighting pathways relevant to intestinal development of PD. Intriguingly, we observed that enteroendocrine cells maintain viability upon exposure to nitrite and in the presence of α-synuclein aggregates. This cellular robustness suggests that these cells may be a reservoir of toxic α-synuclein aggregates. As a possible antidote, our findings show that benserazide and α-methyl tyrosine─chemical inhibitors of dopamine biosynthesis─limited aggregation. Curious about mechanisms of disease etiology outside of α-synuclein aggregation, we also profiled the enteroendocrine cell lipidome─an emerging area of interest in PD research─to motivate future targeted studies delineating the roles of dysregulated lipid metabolism in disease onset. Overall, these studies lay a foundation for mechanistically informed therapeutic targets to prevent the intestinal formation of α-synuclein aggregates before they spread to the brain.