Raluca Narita

Background: Parkinson’s Disease (PD) is a global pandemic, with the number of affected individuals projected to increase from 11 million in 2021 to 25 million by 2050.¹ PD is a progressive loss of dopaminergic neurons in the substantia nigra pars compacta resulting in decreased dopamine levels in the brain.^2,3 Autonomic dysfunction, manifesting as blood pressure dysregulation, dysphagia, urinary incontinence, hyperhidrosis, and constipation, is a common but under-addressed aspect of PD that significantly reduces quality of life.^2-5 These symptoms contribute to serious complications such as aspiration pneumonia and malnutrition.^2-5 Current treatments target individual symptoms rather than the underlying causes, leading to polypharmacy issues. Alpha-synuclein misfolding, commonly seen in PD, disrupts central nervous system firing patterns, altering neurotransmitter levels such as acetylcholine and catecholamines, thus contributing to autonomic symptoms.^6-8 Targeting these neurotransmitters may offer a more effective treatment approach.

Objective: This review aims to evaluate how long-term levodopa treatment compares to D1/D2 dopamine agonists in improving autonomic dysfunction in PD and how these findings are reflected in recent clinical trials.

Search Methods: An online search in PubMed was conducted from 2017 to 2023 using the following keywords: “parkinson’s disease”, “autonomic dysfunction”, “levodopa”, “dopamine agonists”, “alpha-synuclein pathology.” ClinicalTrials.gov was also searched from 2017 to 2023 using the following keywords: “Parkinson’s Disease”, “Dopamine”, and “Dopamine Agonists.”

Results: Long-term levodopa with benserazide treatment partially improved baroreflex sensitivity and normalized responses to the Head-Up Tilt Test, suggesting partial improvement in cardiovascular autonomic function.⁹ Rotigotine, a D1/D2-like receptor agonist, showed promising results in a Parkinson’s rat model by increasing bladder capacity and prolonging micturition intervals.¹⁰ These improvements were associated with restored receptor expression and balanced serotonin signaling in micturition-related brain regions, supporting the potential of dopamine agonists for treating non-motor symptoms in PD clinical trials. In human studies, one clinical trial found that L-DOPA affected cardiovascular autonomic responses, with systolic blood pressure and baroreflex activity differing depending on whether participants were in the “On” or “Off” L-DOPA group.¹¹ Interestingly, the Off group often outperformed the On group in autonomic function, a result possibly affected by the study design, which alternated participant exposure to L-DOPA daily rather than maintaining consistent treatment or control conditions.¹¹ Another clinical trial assessed droxidopa, an epinephrine prodrug similar to L-DOPA, and its ability to treat neurogenic orthostatic hypotension, showing that it provided sustained symptom relief and delayed the need for additional interventions, supporting its efficacy in autonomic symptom management. ¹²

Conclusion: Addressing autonomic dysfunction in PD is an urgent, unmet need in medicine and is essential to improving patient prognosis and quality of life. While preclinical studies using L-DOPA and dopamine agonists like Rotigotine show encouraging results, clinical trials have yet to yield consistent outcomes. Future studies should focus on targeting catecholamine and acetylcholine regulation and incorporate long-term, controlled trial designs. Proposed future research includes double-blind trials evaluating L-DOPA/benserazide or D1/D2 agonists versus a placebo over six months, using objective autonomic function metrics to assess efficacy.

Works Cited:

1. Su D, Cui Y, He C, et al. Projections for prevalence of Parkinson’s disease and its driving factors in 195 countries and territories to 2050: modeling study of Global Burden of Disease Study 2021. BMJ. 2025;388:e080952. Published 2025 Mar 5. doi:10.1136/bmj-2024-080952
2. Gu SC, Shi R, Gao C, et al. Autonomic function and motor subtypes in Parkinson’s disease: a multicentre cross-sectional study. Sci Rep. 2023;13(1):14548. Published 2023 Sep 4. doi:10.1038/s41598-023-41662-9
3. Leite Silva ABR, Gonçalves de Oliveira RW, Diógenes GP, et al. Premotor, nonmotor and motor symptoms of Parkinson’s Disease: A new clinical state of the art. Ageing Res Rev. 2023;84:101834. doi:10.1016/j.arr.2022.101834
4. Ben-Shlomo Y, Darweesh S, Llibre-Guerra J, Marras C, San Luciano M, Tanner C. The epidemiology of Parkinson’s disease. Lancet. 2024;403(10423):283-292. doi:10.1016/S0140-6736(23)01419-8
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6. Dagra A, Miller DR, Lin M, et al. α-Synuclein-induced dysregulation of neuronal activity contributes to murine dopamine neuron vulnerability. NPJ Parkinson’s Dis. 2021;7(1):76. Published 2021 Aug 18. doi:10.1038/s41531-021-00210-w
7. Chen J, Liu Y, Su M, et al. The Aggregation of α-Synuclein in the Dorsomedial Striatum Significantly Impairs Cognitive Flexibility in Parkinson’s Disease Mice. Biomedicines. 2024;12(8):1634. Published 2024 Jul 23. doi:10.3390/biomedicines12081634
8. Goldstein DS, Holmes C, Sharabi Y. Cerebrospinal fluid biomarkers of central catecholamine deficiency in Parkinson’s disease and other synucleinopathies. Brain. 2012;135(Pt 6):1900-1913. doi:10.1093/brain/aws055
9. Silva AS, Ariza D, Dias DP, Crestani CC, Martins-Pinge MC. Cardiovascular and autonomic alterations in rats with Parkinsonism induced by 6-OHDA and treated with L-DOPA. Life Sci. 2015;127:82-89. doi:10.1016/j.lfs.2015.01.032
10. Kitta T, Kanno Y, Mizusawa H, et al. Mechanisms of D1/D2-like dopaminergic agonist, rotigotine, on bladder function in a rat model of Parkinson’s disease. Sci Rep. 2022;12(1):4917. doi:10.1038/s41598-022-08612-3
11. University of Utah. Effect of Levodopa on Cardiovascular Autonomic Function in Parkinson’s Disease. ClinicalTrials.gov. https://clinicaltrials.gov/study/NCT05487300. Accessed April 9, 2025.
12. H. Lundbeck A/S. Sustained effect of droxidopa in symptomatic neurogenic orthostatic hypotension (RESTORE). ClinicalTrials.gov. https://clinicaltrials.gov/study/NCT02586623. Accessed April 8, 2025.