ABSTRACT: Parkinson’s disease (PD) is a progressive and debilitating neurodegenerative disease affecting almost 1 million Americans and 10 million people worldwide. It is commonly characterized by resting tremors, muscle rigidity, bradykinesia, and unstable balance and coordination. Alpha-1-adrenergic receptor antagonists, such as terazosin, doxazosin, and alfuzosin, which are commonly used in benign prostatic hypertrophy, have shown some promise in recent clinical trials for the treatment of PD; however, additional studies are needed to determine the efficacy and safety of these agents in PD.
Parkinson’s disease (PD) is a progressive, age-related, neurodegenerative disease. It is the second most common neurodegenerative disease after Alzheimer’s disease (AD). PD affects more than 10 million people worldwide. In the United States, approximately 1 million people are living with PD, and this number is expected to increase to 1.2 million people by 2030 as the population ages. Over 60,000 patients are diagnosed with PD annually, at the average age of 60 years. In addition, men are 50% more likely to be diagnosed with PD than are women. Patients diagnosed before the age of 50 years are considered to have early onset disease. This form of PD affects about 5% to 10% of patients and is oftentimes inherited or attributed to a specific gene mutation.1-3
PD has been determined to primarily result from dopaminergic neuron loss and collection of Lewy bodies in the substantia nigra section of the brain. This loss of dopamine has been linked to the movement disorders associated with the disease. Patients often exhibit classic motor symptoms of resting tremors, limb rigidity, bradykinesia, and difficulty with balance and coordination. Nonmotor symptoms are also prevalent and can sometimes precede motor symptoms. The following are attributed to the development of autonomic dysfunction symptoms: orthostatic hypotension, constipation, lower urinary tract symptoms, and sexual dysfunction. In more advanced stages of PD, patients may present with additional nonmotor symptoms, such as increased pain, sleep disturbances, diminished mood and affect, cognitive decline, and psychosis.3,4
Currently, the mainstay treatments for PD aim to improve associated motor symptoms; however, disease progression has not been delayed. There is no one-size-fits-all approach to therapy, as it must be individualized and may frequently require modifications based on the progression of symptoms. Pharmacotherapy consisting of carbidopa/levodopa is the most effective for symptomatic treatment. This therapy can also be combined with other classes of medications, including dopamine agonists (e.g., pramipexole, ropinirole), catechol-O-methyltransferase inhibitors (e.g., entacapone, tolcapone), monoamine oxidase (MAO) inhibitors (e.g., selegiline, phenelzine), and anticholinergic agents (e.g., trihexyphenidyl, benztropine). Other critical components to effective treatment plans should include dietary modifications, lifestyle changes, and physical, occupational, and speech therapy. For patients who qualify, deep brain stimulation is also a viable surgical option for increased “off” periods and dyskinesias associated with increased levodopa doses.5
Proposed Adrenergic Mechanisms
Locus Coeruleus Cell Loss
Cells in the locus coeruleus (LC) are believed to result in a deficiency in the noradrenergic system of the brain, which may play a key role in the progression of various neurodegenerative diseases, such as AD and PD.6,7 Between the fourth and ninth decades of life, the number of LC cells and the concentration of noradrenaline in normal-aged human brains are reduced by 25% and 50%, respectively.6-8 In patients with PD at autopsy, LC cell numbers have been found to be decreased by 78.5% to 83.2% (mainly in the substantia nigra) compared with normal age-matched controls.6,9,10
Furthermore, reductions of more than 80% of noradrenaline in the substantia nigra and ventral tegmental area of PD brains postmortem have been reported.11 Along with this depletion of noradrenaline, a decrease of 50% to 60% in dopaminergic cell bodies in the substantia nigra usually leads to the manifestation of classic signs of PD, such as rigidity, bradykinesia, resting tremor, and gait or balance issues.6,12 In addition, animal studies focusing on PD have found potential neuroprotective and/or compensatory effects due to changes in neurochemical, behavioral, and electrophysiological indices of neurotransmission in the nigrostriatal dopaminergic system and influences on associated experimental lesions.6,13
Specifically, noradrenergic mechanisms have been found to be involved in cellular signaling and modulation of neurotrophic mechanism. Thus, one theoretical approach to protect or promote recovery from neural damage in PD is the potential use of alpha-adrenergic antagonists to improve PD symptoms and minimize progression of the neurodegenerative disease.6,7,14 Based on preliminary evidence for facilitatory effects of LC cells and the noradrenergic system on nigrostriatal dopamine release, motor function, memory, neuroprotection, and recovery of function after brain injury, rationale exists for the potential benefits of noradrenergic-based approaches, specifically alpha-adrenergic antagonists, in the treatment of central neurodegenerative diseases.6,7,9-14
Potentiation of Phosphoglycerate Kinase 1
Evidence from retrospective epidemiologic studies and animal models has proposed an additional mechanism for disease modification in PD, which involves phosphoglycerate kinase 1 (PGK1). Potentiation of this enzyme may improve cellular function in diseases with mitochondrial deficit (e.g., PD) by increasing adenosine triphosphate generation during times of reduced cellular energy production.15,16 In a study conducted by Chen et al, the alpha-1-adrenergic receptor antagonist terazosin was found to bind to PGK1 and potentiate its effects in animal models.17 Other alpha-1-adrenergic receptor antagonists with similar structural components (e.g., doxazosin and alfuzosin) are also believed to demonstrate these pharmacologic actions, unlike tamsulosin, which has not been determined to interact with or affect PGK1 but has been suggested to perhaps potentiate neurodegeneration.16-18
Recent Clinical Studies
In 2021, the findings of two large, long-term studies aimed at determining the potential benefits of alpha-1-adrenergic receptor antagonists in PD were published.
Sasane et al conducted an epidemiological study on PD that involved 113,450 individuals from the United States with >5 years of follow-up.15 Patients were classified based on tamsulosin use (n = 45,380), terazosin/alfuzosin/doxazosin use (n = 22,690), or as matched controls for age, sex, and Charlson comorbidity index score (n = 45,380). Investigators determined that the incidence of PD in the tamsulosin group was 1.53% compared with 1.10% in the terazosin/alfuzosin/doxazosin group (P <.0001) and 1.01% compared with the matched group (P <.0001). No significant difference was reported between the terazosin/alfuzosin/doxazosin and matched groups with regard to risk for PD (P = .29). Therefore, the results (1) suggest that tamsulosin may potentiate the progression of PD and (2) do not support the use of terazosin/alfuzosin/doxazosin as neuroprotective agents for PD.
Simmering et al conducted a cohort study using active comparator control and propensity score–matched data from national Danish health registries from January 2016 through December 2017, as well as data from the Truven Health Analytics MarketScan database (insurance claims across the U.S.) from January 2001 to December 2017.18 Data collected included that of men who were recently initiated on terazosin/alfuzosin/doxazosin or tamsulosin therapy and had no diagnosis of PD. A total of 52,365 propensity score–matched pairs of terazosin/alfuzosin/doxazosin and tamsulosin recipients were identified in the Danish registries and 94,883 propensity score–matched pairs were identified in the Truven Health Analytics MarketScan database. Men in the Danish cohort who used terazosin/alfuzosin/doxazosin were found to have a hazard ratio (HR) for developing PD of 0.88 (95% CI, 0.81-0.98), while the cohort of men from the Truven Health Analytics MarketScan cohort had an HR of 0.63 (95% CI, 0.58-0.69). Investigators concluded that their findings indicate a lower hazard for developing PD among individuals who use terazosin/alfuzosin/doxazosin compared with those who use tamsulosin.
Neuroprotection for PD has become one of the key target areas for minimizing the risk and/or progression of PD. As a result, alpha-1-adrenergic receptor antagonists are believed to have a potential role in PD treatment due to their mechanisms and effects on LC cells and PGK1. Despite some promising preliminary data, additional studies are needed to determine what (if any) potential benefits and risks these medications have in preventing or slowing the progression of PD.REFERENCES
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