Adrenoceptor agonists and antagonists and risk of Parkinson's disease

Abstract

We read with great interest the article by Gronich and colleagues 1 on the effects of β2-adrenoceptor agonists and antagonists on the risk of Parkinson's disease (PD). This case-nested study in a large population of adults without PD followed for over 13 years showed that use of propranolol appears to be associated with an increased risk of PD, whereas use of β2-agonists is associated with a decreased risk of PD. These data confirm a recent observation in the Norwegian population, 2 but is in apparent contrast with the results published by Searles Nielsen and colleagues, 3 which demonstrated no change in the risk of PD with beta adrenergic agonist or antagonists after adjusting for medication exposure lagging, demographics, smoking, and overall use of medical care.An intriguing common finding of two of these studies is that the treatment with carvedilol, a compound with alpha and beta adrenergic blocker activity not routinely prescribed for tremor, is consistently associated with a low PD risk, as evidenced by odds ratio (OR) 0.77 (95% confidence interval [CI] = 0.73-0.81) 3 and 0.86 (95% CI = 0.73-1.02), in line with those associated with beta adrenergic agonists. 1 Such an effect on the risk of PD appears to be dose dependent, with carvedilol doses exceeding 25 mg/day conferring a significant protective effect compared to doses of <12.5 mg/day (OR, 0.76; 95%CI = 0.67-0.86; P < 0.001). 3 This interesting observation is worth exploring in more detail, given that it implies that sympathetic nervous system (SNS) overactivity might play an important role in the neurodegenerative process associated with PD. Known triggers of PD, including traumatic brain injuries, microbiota perturbations, air pollution, iron and manganese exposure, male sex, and aging, have been associated with increased sympathetic tone. In addition, there is evidence to suggest that SNS overactivity is separately associated with typical premotor symptoms of PD, including hyposmia, constipation, and REM sleep behavior disorder. 4,5 Finally, SNS overactivity typically drives reduced low-frequency heart rate variability, another clinical sign associated with premotor and early PD. 5 Many of these effects appear to be mediated through alpha-1 adrenergic activation, which could explain why mixed adrenergic blockers like carvedilol show a protective effect on the risk of PD as compared to more selective beta-blockers like metoprolol or propranolol.The exact mechanisms of the hypothetical role of SNS hyperactivity in the pathophysiology of PD, which would run counter the prevailing view of a protective role of beta agonists, remain to be explored in more detail. However, modulation of the adrenergic system may ultimately prove to be useful in the very early stages of the disease (e.g., premotor stage) to delay the onset or slow the progression of neurodegeneration.

The role of the locus coeruleus/norepinephrine system in the pathogenesis of neurodegenerative disorders: An update

“…Clinical and neurochemical evidence also supports locus coeruleus hyperactivity early in neurodegenerative disease, in the presymptomatic phase, suggesting a role in the pathogenesis of the disease [27]. Interestingly, patients exposed to beta-blockers appear to have a lower incidence of dementia [31], while their role in Parkinson's disease is more controversial [32]. It has been recently suggested that the development of amyloid plaques and locus coeruleus degeneration are compensatory processes in response to long-term elevated noradrenergic signalling [33].…”