The Role of β-Adrenergic Blockers in Parkinson’s Disease

Abstract

Genetic studies have identified numerous factors linking β-adrenergic blockade to Parkinson’s disease (PD), including human leukocyte antigen genes, the renin–angiotensin system, poly(adenosine diphosphate-ribose) polymerase 1, nerve growth factor, vascular endothelial growth factor, and the reduced form of nicotinamide adenine dinucleotide phosphate. β-Adrenergic blockade has also been implicated in PD via its effects on matrix metalloproteinases, mitogen-activated protein kinase pathways, prostaglandins, cyclooxygenase 2, and nitric oxide synthase. β-Adrenergic blockade may have a significant role in PD; therefore, the characterization of β-adrenergic blockade in patients with PD is needed.

Introduction

Parkinson’s disease (PD) is the second most common form of neurodegeneration among elderly individuals. The PD is clinically characterized by tremors, rigidity, slowness of movement, and postural imbalance. Dopaminergic therapies in the form of l-dopa, dopamine (DA) agonists, or monoamine oxidase B inhibitors significantly improve the characteristic motor symptoms of bradykinesia and rigidity, with a beneficial effect upon tremor in a proportion of patients. ¹ However, the relationship between β-adrenergic antagonism and PD has been well established. In the brain, β-adrenergic receptors are widely distributed in different regions, including the frontal, parietal, piriform, and retrosplenial cortices, medial septal nuclei, olfactory tubercle, midbrain, striatum, hippocampus, and thalamic nuclei. ^2,3 The adrenergic receptors (or adrenoceptors) are a class of G-prote-in-coupled receptors that are targets of the catecholamines, especially norepinephrine (NE; noradrenaline) and epinephrine (adrenaline). Many cells possess these receptors, and the binding of a catecholamine to the receptor will generally stimulate the sympathetic nervous system. There are 2 main groups of adrenergic receptors, α and β. β receptors have the subtypes β₁, β₂ and β₃. All 3 are linked to G_s proteins (although β₂ also couples to G_i), which in turn are linked to adenylate cyclase. Agonist binding thus causes a rise in the intracellular concentration of the second messenger cyclic adenosine monophosphate (cAMP). Downstream effectors of cAMP include cAMP-dependent protein kinase A (PKA), which mediates some of the intracellular events following hormone binding. β-adrenergic receptors can participate in the modulation of neuronal activity of cerebral structures involved in motor control. Microiontophoretic administration of nonselective β-adrenergic receptors agonist isoproterenol significantly decreased firing rate and responses to superior cerebellar peduncle stimulation in 82% of studied neurons in a dose-dependent manner. Similar changes were induced by ejection of selective β₁-adrenergic receptors agonist dobutamine, while fenoterol (selective β₂-adrenergic receptors) increased or reduced firing rate in 32% and 19% of rat primary motor cortex (M1), respectively. Nonselective β-adrenergic receptors antagonist propranolol enhanced both the background and evoked activity in 84% of tested neurons. ⁴ The subthalamic nucleus (STN) is one of the key structures in idiopathic PD. ⁵ During the course of the disease, the nucleus develops a bursting 25 to 45 Hz firing pattern that is associated with the development of clinical motor symptoms, including akinesia and rigidity. The spiking activity of the STN was temporarily suppressed, after the application of the β-adrenergic blocker metoprolol. A transient reduction in PD symptoms (rigidity) was detected during the suppression of STN spiking activity in patients with PD. ⁶ Akathisia improved in 4 patients with idiopathic PD after low-dose propranolol treatment. ⁷ The NE has been suggested to modulate the expression of l-3,4-dihydroxyphenylalanine (l-dopa)-induced dyskinesia (LID). Targeting the NE system may provide relief from both PD and LID. Barnum et al ^{4 , 8} demonstrated that moderate NE loss reduced the development and expression of abnormal involuntary movements and rotations in hemiparkinsonian rats. These authors also showed that the β-adrenergic receptor blocker maintained its antidyskinetic effects in DA-treated NE-lesioned rats. The nonselective β-adrenergic receptor blocker, propranolol, significantly attenuated established LID in patients with PD. ⁹ The aberrant striatal signaling associated with LID was normalized after propranolol cotreatment, and intrastriatal propranolol acutely reduced LID in a 6-hydroxydopamine (6-OHDA)-lesioned rat model. ¹⁰ Improvement in tremor was observed within 2 to 4 weeks after the initiation of β-adrenergic receptor nipradilol therapy; the efficacy rate tended to be higher in the essential tremor group than in the PD group. ¹¹ Arotinolol, a peripheral β-adrenergic receptor blocker, significantly suppressed postural tremor in a dose-dependent manner in monkeys with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism. ¹² Nadolol, another peripheral β-adrenergic receptor blocker, yielded a 34% reduction in tremor distance but no change in tremor frequency in idiopathic PD. ¹³ However, a Cochran Collaboration review revealed that it is impossible to determine whether β-adrenergic receptor blocker therapy is effective and safe for the treatment of tremor in PD. ¹⁴ These findings suggest that β-adrenergic receptor blockade may play a role in PD; herein, we discuss the potential role of β-adrenergic receptor blockers in PD.

Genetic Factors Associated With β-adrenergic Inhibition and Parkinson’s Disease

Genetic studies provide an excellent opportunity to link molecular variations with epidemiological data. Variations in DNA sequences such as polymorphisms exert modest and subtle biological effects. Receptors play a crucial role in the regulation of cellular function, and small changes in their structure can influence intracellular signal transduction pathways.

Studies have suggested that human leukocyte antigen (HLA) genes are located in the major histocompatibility complex (MHC) class II loci and that several genes in the MHC region promote susceptibility to PD. Significantly increased MHC class II expression was detected in the cerebrospinal fluid (CSF) monocytes of patients with PD. ¹⁵ The HLA genes have also been implicated in PD, and large numbers of HLA-DR-positive reactive microglia have been detected in the substantia nigra (SN) and nigrostriatal tract of patients with PD. ^16,17 The HLA-DR-positive microglia has also been detected in these regions in Parkinson’s-associated dementia patients in Guam. ¹⁷ The HLA-DRB1*03 was more common in patients with PD compared with controls. ¹⁸ A higher frequency of HLA-DRB1*0301 was demonstrated in the Chinese Han population, but a lower frequency of HLA-DRB1*0406 was observed in European populations compared with that in Asian populations. ¹⁹ The variant rs3129882 was identified in genome-wide association study of the HLA gene region, and this variant has been associated with an increased risk of PD in Chinese patients. ²⁰ The highly polymorphic HLA-DRB1 locus contains the variant rs660895, which was also reported in patients with PD. ²¹ The HLA rs3129882 variant was detected in Chinese Han patients with late-onset sporadic PD. ²² Moreover, a correlation between HLA-DR and HLA-DQ gene polymorphisms and the anti-β-receptor antibodies in familial cardiomyopathy has been suggested. ²³ Cardiac β-adrenergic receptors and adenylate cyclase activity in dilated cardiomyopathy have been shown to be modulated by circulating autoantibodies against the cardiac β₁-adrenoceptor, the presence of which is regulated by the HLA-DR. ²⁴ Propranolol abrogated interferon-γ-induced increases in HLA class II expression and interleukin 1β secretion. ²⁵ Expression of HLA-DR was significantly reduced in the lymphocytes of carvedilol-treated patients with chronic heart failure (CHF). ²⁶ These findings suggest that β-adrenergic blockers might affect PD via the suppression of MHC class II antigen expression.

Trace amines, including tyramine, tryptamine, octopamine, and β-phenylethylamine (β-PEA), exist in low concentrations in the brain. Metabolically, these trace amines are closely associated with DA, NE, and serotonin neurotransmitter systems in the brain. ^27,28 Trace amines produce amphetamine-like responses, such as increases in alertness and euphoria and decreases in appetite, insomnia, and tremor. ²⁹ Trace amines function independently of classical amine transmitters and mediate some of their effects via specific receptors, such as trace amine-associated receptors (TAARs). The receptors for trace amines belong to a family of G-protein-coupled receptors. ³⁰ In humans, TAAR1 responds to tyramine, β-PEA, octopamine, and DA, and TAAR4 is activated by tyramine and β-PEA. ³⁰ A relatively high level of tyramine and β-PEA is present in the nigrostriatal and mesolimbic regions of the brain. ^31,32 Dopaminergic neurons synthesize β-PEA, and specific high-affinity binding sites for β-PEA and tyramine have been described in the striatum and other DA-rich areas. ^{33 –35} Both β-PEA and tyramine suppress inhibitory synaptic potentials in neurons of the central nervous system (CNS), supporting an emerging role for these trace amines as neuromodulators. ³⁶ There is evidence suggesting that trace amines coexist with DA in dopaminergic cells ³⁷ and activate motor activity through interactions with the dopaminergic system. ³⁸ The β-PEA stimulates the release of DA from the cytoplasmic pool and behaves as a DA receptor agonist with a rapid and brief action. ³⁹ Trace amines indirectly activate DA autoreceptors through an increased efflux of newly synthesized DA. ⁴⁰ Numerous studies have indicated that trace amine dysregulation may play a role in PD. In vivo, β-PEA may exert behavioral effects on the caudate nucleus through the increased release of both DA and 5-hydroxydopamine (5-OHDA). ⁴¹ Both 5- and 6-OHDA, identified as naturally occurring amines in human urine, have been detected in patients with Parkinson’s treated with l-dopa in significantly higher concentrations than those detected in untreated patients and normal controls. ⁴² The expression of octopamine was below control levels in all groups of patients with PD, including patients in the early stages of the disease. ⁴³ The major extracellular metabolite of DA, 3-methoxytyramine (3-MT), induces behavioral effects in a DA-independent manner, and these effects are partially mediated through TAAR1. In normal mice, the central administration of 3-MT induced a temporary mild hyperactivity with the concomitant onset of abnormal movements. ⁴⁴ Trace amines such as tyramine and β-PEA reduce DA-induced responses in midbrain dopaminergic neurons via G-protein-independent signaling mechanisms and render dopaminergic neurons less sensitive to autoreceptor feedback inhibition, thereby enhancing their sensitivity to stimulation. ⁴⁵ The TAAR1 knockout (KO) mice exhibited enhanced sensitivity to the psychomotor-stimulating effects of amphetamine, which were temporally correlated with significantly larger increases in the release of both DA and NE in the dorsal striatum and were associated with a 262% increase in the proportion of striatal high-affinity DA D₂ receptors. ⁴⁶ The TAAR1 is significantly involved in motor control and exerts an inhibitory effect on locomotion. ⁴⁷ Moreover, numerous adrenergic ligands and 3-methylated metabolites of catecholamine neurotransmitters act as TAAR1 (rTAAR1) agonists in rats. These results suggest that trace amines and catecholamine metabolites may serve as endogenous ligands for a novel intercellular signaling system widely distributed throughout the vertebrate brain and periphery. ⁴⁸ Tyramine and β-PEA are allosteric antagonists of β_1-2-adrenergic receptors, whereas octopamine acts as an orthosteric β₂-adrenergic receptor antagonist and is a β₁-adrenergic receptor agonist. ⁴⁹ However, β-adrenergic receptor blockers have endocrine-disrupting potential in aquatic organisms with tyramine and octopamine receptors. ⁵⁰

The primary function of the renin–angiotensin system (RAS) is to maintain fluid homeostasis and regulate blood pressure. Several components and receptors of the RAS have been identified in the CNS, ^{51 –54} suggesting that the RAS might be involved in brain activity. Garrido-Gil et al ⁵⁵ demonstrated the presence of major RAS components in dopaminergic neurons, astrocytes and microglia in both the monkey and human substantia nigra compacta (SNc). Angiotensin types 1 and 2 (Ang 1 and 2) and renin–prorenin receptors are located at the surface of dopaminergic neurons and glial cells and have also been observed in the cytoplasm and nucleus, which suggests the presence of an intracrine or intracellular RAS in the monkey and human SNc. Levels of angiotensin-converting enzyme (ACE) activity are reduced in the CSF of patients with PD and increase with dopaminergic treatments. ^56,57 Grammatopoulos et al ⁵⁸ observed a maximal reduction in α-synuclein-induced toxicity of 85% and a 19% reduction in inclusion formation when cultures were treated with Ang 2 in the presence of the AT₁ receptor antagonist losartan and AT₂ receptor antagonist PD123319. These data suggest that agents acting on the RAS may be useful for preventing and/or treating of PD. In the striatum and nigra, the depletion of DA by reserpine induced a significant increase in the expression of AT₁ and AT₂, which diminished with the increasing restoration of DA function. Similarly, 6-OHDA-induced chronic dopaminergic denervation resulted in a significant increase in AT₁ and AT₂ expression, which diminished with l-dopa administration. A significant reduction in AT₁ messenger RNA (mRNA) expression was also observed after the administration of DA to cultures of microglial cells. ⁵⁹ These findings suggest an important interaction between the dopaminergic and the local RAS in the basal ganglia, which may be a major factor in the progression of PD. The AT₁ receptor antagonist candesartan protected dopaminergic neurons in the nigrostriatal tract against neurotoxin-induced cell death. ⁶⁰ Moreover, catecholamines alter the release of AT II. Ming et al ⁶¹ demonstrated that isoproterenol enhances the stimulatory effect of dexamethasone on AT gene expression via β₂-adrenergic receptors in mouse hepatoma cells. Isoproterenol promoted an increase in the release of AT II from isolated perfused mesenteric arteries, and this release was blocked by propranolol treatment. ⁶² In other studies, isoproterenol increased the secretion of AT II in neuronal cultures, cultured bovine aortic endothelial cells, and the brachial arteries of patients with hypertension. ^{63 –65} Propranolol treatment reduced plasma renin activity (PRA) and AT I, AT II, and AT-(1-7) expression in the portal vein and periphery of cirrhotic patients compared with nontreated patients. ⁶⁶ Carvedilol inhibited basal and stimulated ACE production in human endothelial cells ⁶⁷ and exhibited beneficial effects on ACE activity and PRA levels in patients with CHF. ⁶⁸ In addition, proliferating infantile hemangiomas express 2 essential components of the RAS, namely ACE and the AT II receptor, which are responsible for the propranolol-induced accelerated involution of large proliferating infantile hemangioma. ^{69 –71} Taken together, these findings suggest that the RAS is activated in patients with PD and that β-adrenergic blockers may play a role in PD by modulating the RAS.

Poly(adenosine diphosphate-ribose) polymerase 1 (PARP-1) is a nuclear protein that promotes either neuronal death or survival under certain stress conditions. The overexpression of PARP-1 has been reported in the dopaminergic neurons of the SN in PD. ⁷² Poly(adenosine diphosphate-ribose) polymerase 1 is also implicated in MPTP-induced neurotoxicity in vivo. ⁷³ The MPTP is a neurotoxin that induces parkinsonian symptoms in human and animals, but mice lacking the PARP gene are spared from MPTP neurotoxicity. ⁷⁴ In vitro studies have shown that PARP-1 participates in the regulation of α-synuclein expression through binding to the Rep1 polymorphic site upstream of the SNCA gene. ⁷⁵ The PARP inhibitors attenuate neuronal death after MPPT-induced neurotoxicity in mice. ^76,77 The pharmacological inhibition of PARP-1 reduces α-synuclein- and MPTP-induced cytotoxicity in in vitro models of PD. ⁷⁸ The PARP-1 variants are protective against PD. ⁷⁹ Moreover, rabbits treated with ketamine exhibited reduced left ventricular ejection fractions and ventricular conduction velocity and increased susceptibility to ventricular arrhythmia. Metoprolol treatment prevented these pathophysiological alterations. The expression of PARP-1 and apoptosis-inducing factor were increased after ketamine treatment and sharply reduced after metoprolol administration. ⁸⁰ Propranolol treatment markedly suppressed PARP activation in skeletal muscle biopsies from pediatric patients with burn. ⁸¹ Propranolol also protected against staurosporine-induced DNA fragmentation and PARP cleavage in SH-SY5Y neuroblastoma cells. ⁸² The nonselective β-blocker carvedilol significantly inhibited apoptosis and suppressed activated PARP-1 cleavage in human cardiac tissue. ⁸³ Carvedilol significantly reduced ischemia–reperfusion-induced poly- and mono-adenosine diphosphate-ribosylation in heart perfusion and rheological models. ⁸⁴ Carvedilol also reduced PARP activity in the hippocampus and protected neurons against death after transient forebrain ischemia. ⁸⁵ Metipranolol reduced the sodium nitroprusside-induced breakdown of PARP-1 in the eyes and retinas of rats. ⁸⁶ These findings suggest that PARP-1 is activated in patients with PD and that β-adrenergic antagonists may affect PD through the suppression of PARP-1.

Nerve growth factor (NGF) is a small secreted protein that is important for the growth, maintenance, and survival of certain target neurons. The NGF has been implicated in maintaining and regulating the septohippocampal pathway, which is involved in learning and memory. ^{87 –89} The NGF is also present in the human SN ⁹⁰ and the adrenal gland. ⁹¹ The NGF concentrations are reduced in the SN of patients with PD and in rat models of PD. ^92,93 The NGF levels showed greater reductions during the early stages of PD, ⁸⁹ implying that reduced NGF may be involved in the pathogenesis of the disease. The NGF protects the DA neurotoxicity induced by MPTP, rotenone, and 6-OHDA via different pathways. ^{94 –96} The chronic infusion of NGF into the rat striatum resulted in cholinergic hyperinnervation and the reduced spontaneous activity of striatal neurons. ⁹⁷ Moreover, NGF increased the survival of dopaminergic grafts, rescued nigral dopaminergic neurons and restored motor dysfunction in a rat model of PD. ^98,99 l-dopa induces the synthesis of NGF and growth hormone in patients with PD. ¹⁰⁰ Clenbuterol, a long-acting β₂-adrenergic agonist, significantly increased both NGF mRNA and protein expression in Swiss mouse 3T3 cells. ¹⁰¹ The exposure of nerve cells to isoproterenol, a β-adrenergic agonist, increased NGF mRNA expression, and this effect was blocked by propranolol. ^102,103 Interestingly, NGF acts with the β₂-adrenoceptor to induce spontaneous nociceptive behavior during temporomandibular joint inflammatory hyperalgesia. However, the coadministration of carrageenan with the β₂-adrenoceptor antagonist ICI 118.55 significantly reduced NGF-induced nociception. ¹⁰⁴ The neuroprotective effects of β-adrenergic receptor antagonists during cerebral ischemia may be associated with nociceptive pain. ^{105 –107} Brain injury is reduced and neurological outcomes are improved after middle cerebral artery occlusion in mice lacking the β₂-adrenergic receptor agonist and in wild-type mice pretreated with a β₂-adrenergic receptor antagonist. ¹⁰⁸ Taken together, β-adrenergic receptor antagonists may play a role in PD through the regulation of NGF secretion.

Angiogenesis is a complex process that involves coordinated endothelial cell activation, proliferation, migration, tube formation, and capillary sprouting. In addition, angiogenesis requires the participation of numerous intracellular signaling pathways. Vascular endothelial growth factor (VEGF) is a key mediator of angiogenesis and has been shown to have neuroprotective effects on DA neurons in models of 6-OHDA-induced toxicity, reducing amphetamine-induced rotational behavior and preserving tyrosine hydroxylase-positive neurons and fibers. ¹⁰⁹ In rat midbrain cultures, increased levels of VEGF-B transcription have been reported following the addition of the neurotoxin rotenone. ¹¹⁰ An increase in the number of VEGF-positive neurons and blood vessels has also been demonstrated in the SN of mice with MPTP-induced neurotoxicity. ¹¹¹ Wada et al ¹¹² further demonstrated the upregulated expression of VEGF in the SN of patients with PD. In PD animal models, the neuroprotective effects of VEGF are dose dependent. Indeed, low doses of VEGF have been shown to have a neuroprotective effect on DA neurons and result in behavioral improvement, whereas high doses of VEGF induced angiogenesis and glial proliferation. ¹¹³ Chronic treatment with l-dopa dose dependently induced the expression of VEGF in the basal ganglia nuclei. However, when coadministered with l-dopa, a small molecule inhibitor of VEGF signaling significantly attenuated the development of dyskinesia and completely blocked the angiogenic response and associated increase in blood–brain barrier permeability induced by the treatment. ¹¹⁴ These findings suggest that VEGF plays a role in the pathophysiology of l-dopa-induced dyskinesia. Moreover, the β-adrenergic receptor agonist isoproterenol significantly increased protein levels of VEGF in human choroidal endothelial cells. ¹¹⁵ The NE treatment increased VEGF levels in cultured nasopharyngeal carcinoma (NPC) tumor cells, and this increase was inhibited by propranolol treatment. The NE also induced invasiveness in all NPC cell lines in a dose-dependent manner, and this induction was blocked by propranolol treatment. ¹¹⁶ Propranolol significantly reduced VEGF activity in a phorbol myristate acetate (PMA)-activated human leukemic cell line. ¹¹⁷ This drug also repressed gastric cancer cell growth through its downstream effects on VEGF. ^118,119 Alternatively, NE increased the expression of VEGF, and these effects were inhibited by propranolol treatment in pancreatic cancer cells. ^120,121 In addition, epinephrine enhanced the expression of VEGF in colon adenocarcinoma cells. The stimulatory action of epinephrine on colon cancer growth was blocked by treatment with atenolol and ICI 118.551, which are β₁- and β₂-selective antagonists, respectively. ¹²² β₂-Adrenergic receptor blockade regulated VEGF production in a mouse model of oxygen-induced retinopathy. ¹²³ Hypoxia-inducible factor 1α (HIF-1α) and VEGF mRNA and protein expression were upregulated in a rat model of volume-overload heart failure; these abnormalities were reversed with carvedilol treatment. ¹²⁴ These findings suggest that β-adrenergic antagonists modulate VEGF expression in PD.

The reduced form of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox) enzyme complex mediates critical physiological and pathological processes including cell signaling, inflammation and mitogenesis, through the generation of reactive oxygen species (ROS) from molecular oxygen. The NADPH oxidase is widely expressed in various immune cells, including microglia, macrophages, and neutrophils. Expression of Nox was observed in the nuclei of DA neurons in the SN of patients with PD and animals with 6-OHDA-induced neurotoxicity. ¹²⁵ In the striatum and nigra, the depletion of DA with reserpine induced a significant increase in the expression of the NADPH subunit p47^phox; expression of this subunit decreased with the increasing restoration of DA function. Similarly, 6-OHDA-induced chronic dopaminergic denervation resulted in a significant increase in the expression of p47^phox, which was reduced after l-dopa administration. ⁵⁹ The Nox activation increased zinc-induced DA neurodegeneration and MPPT-, rotenone-, angiotensin-, and paraquat-induced neurotoxicity in animal models of PD ^{126 –130} The inhibition and knockdown of Nox reduced paraquat-induced ROS generation and DA cell death, ¹³⁰ and Nox inhibitors conferred protection against lipopolysaccharide (LPS)-induced toxicity, MPPT-induced oxidative stress, and apoptosis in mesencephalic DA neuronal cells. ^131,132 NADPH oxidase 1 plays a crucial role in modulating the behavior of α-synuclein expression and aggregation in dopaminergic neurons. ¹³³ The knockdown of cytosolic NADP⁺-dependent isocitrate dehydrogenase enhanced MPP⁺-induced oxidative injury in PC12 cells, a model system for neuronal differentiation. ¹³⁴ Moreover, nebivolol, a third-generation selective β₁-adrenoceptor, improved left ventricle dysfunction and survival immediately after myocardial ischemia and inhibited cardiac Nox activation. ¹³⁵ Nebivolol treatment has been associated with improvements in insulin resistance, reduced proteinuria and reduced Nox activity, and the production of ROS in the kidneys and skeletal muscle tissue of transgenic TG(mRen2)27 rats (Ren2). ^136,137 Nebivolol also improved diastolic relaxation, fibrosis, and remodeling in obese Zucker rats and reduced Nox-dependent superoxide production. ¹³⁸ Carvedilol attenuated the increased expression of Nox subunits in the hearts and kidneys of rats after daunorubicin-induced cardiotoxicity and nephrotoxicity. ¹³⁹ Activity of Nox in whole blood and isolated neutrophils was dose dependently inhibited by nebivolol, whereas atenolol, metoprolol, and carvedilol were markedly less effective in Watanabe heritable hyperlipidemic rabbits. ¹⁴⁰ Celiprolol, a specific β₁-antagonist with weak β₂-agonistic activity, suppressed Nox p22^phox, p47^phox, gp91phox, and Nox-1 expression in the left ventricle of deoxycorticosterone acetate-salt hypertensive rats. ¹⁴¹ Taken together, these findings suggest that β-adrenergic antagonists play a role in PD through the suppression of NADPH expression.

The Role of β-Adrenergic Blockers in PD

Matrix metalloproteinases (MMPs) are proteolytic enzymes that are responsible for both extracellular matrix (ECM) remodeling and the regulation of leukocyte migration through the ECM, which is an important step in inflammatory processes. Neuroinflammation significantly contributes to progressive dopaminergic neurodegeneration in PD. The MMPs have been implicated in the degeneration of dopaminergic neurons. Expression of MMP-3 is increased during LPS-induced DA neurotoxicity. ¹⁴² The MMP-9 is also elevated in MPTP-induced parkinsonism in mice. ¹⁴³ The application of dopaminergic neurotoxins to 2 human neuroblastoma cell lines downregulatedthe transcription and translation of tissue inhibitor of metalloproteinase (TIMP)-2, effectively enhancing MMP activity. ¹⁴⁴ Exendin 4, which is an analog of glucagon-like peptide 1, significantly attenuated the loss of SN neurons and the striatal dopaminergic fibers in an MPTP-induced PD model and inhibited the expression of MMP-3. ¹⁴⁵ Moreover, propranolol inhibited human brain endothelial cell tubulogenesis and MMP-9 secretion. ¹⁴⁶ A selective β₃-adrenoceptor agonist prevented human myometrial remodeling and MMP-2 and MMP-9 activation in an in vitro model of chorioamnionitis. ¹⁴⁷ The NE treatment increased MMP-2 and MMP-9 levels in cultured NPC cells, and these increases were inhibited by propranolol treatment. The NE also induced the invasiveness of all NPC cell lines in a dose-dependent manner; this effect could be blocked with an MMP inhibitor and propranolol treatment. ¹¹⁶ Propranolol significantly reduced MMP-2 activity in a PMA-activated human leukemic cell line. ¹¹⁷ Propranolol-induced growth inhibition has been associated with arrest at both G₀/G₁ and G₂/M and repressed gastric cancer cell growth through the downstream inhibition of MMP-2 and MMP-9. ¹¹⁸ The NE increased MMP-2 and MMP-9 expression, and these effects were inhibited by propranolol treatment in pancreatic cancer cells. ^120,121 Epinephrine upregulated MMP-9 activity in human colon adenocarcinoma HT-29 cells, and this effect was blocked by the respective β₁- and β₂-selective antagonists atenolol and ICI 118.551. ¹²² These studies suggest that β-adrenergic antagonists might play an important role in the pathological process of PD through the regulation of TIMP levels and the downregulation of MMPs.

The mitogen-activated protein kinase (MAPK) pathways provide a key link between the membrane-bound receptors that receive cues from signaling molecules and changes in the patterns of gene expression, which include the extracellular signal-regulated kinase (ERK) cascade, the stress-activated protein kinases/c-Jun N-terminal kinase cascade, and the p38 MAPK/RK/HOG cascade. ¹⁴⁸ Increased cytoplasmic ERK1/2 activity has been observed in the brains of human patients with PD, ¹⁴⁹ and degenerating SN neurons typically display phosphorylated-ERK1/2 granules. ¹⁵⁰ The activation of ERK1/2 was induced by the neurotoxin 6-OHDA, and the inhibition of ERK activation enhanced neuronal survival. ^151,152 The mitochondrial localization of ERK2 activity suggests an effect of 6-OHDA on mitophagy and autophagic cell death in PD. ¹⁵³ Dysregulation of the autophagy pathway has been observed in the brains of patients with PD and in animal models of PD. ^154,155 In addition, the activation of p38 MAPK has been demonstrated in the SN of MPTP-treated mouse models of PD. ¹⁵⁶ Moreover, vulnerability to glutamate-induced toxicity in DA neurons is dependent on endogenous DA and MAPK activation. ¹⁵⁶ Interestingly, a genetic deficiency in MAPK kinase 2^{−/ −} prevented MPTP-induced neurotoxicity in mouse models of PD. ¹⁵⁷ Moreover, β-adrenoceptors stimulation has been shown to activate cAMP/PKA and MAPK pathways in pancreatic cancer cells. β₂-Adrenergic antagonists suppressed invasion and proliferation through inhibition of both cAMP/PKA and Ras, which regulate MAPK pathway activation. ¹²¹ The NE stimulated pancreatic cancer cell proliferation, migration and invasion via β-adrenergic receptor-dependent activation of the p38/MAPK pathway. These stimulatory effects were completely abolished by propranolol or the p38/MAPK inhibitor SB203580 ¹⁵⁸ Propranolol was shown to exert its suppressive effects on hemangiomas through the HIF-1α-VEGF-A angiogenesis axis, with effects mediated by the PI3/Akt and p38/MAPK pathways. ¹⁵⁹ β-Adrenergic antagonists may play a role in PD through suppression of the MAPK pathway.

Prostaglandins (PGs) play a role in inflammatory processes. ¹⁶⁰ Cyclooxygenase (COX) participates in the conversion of arachidonic acid into PGs. Prostaglandin E2 (PGE₂) is a key product of COX-2 and is increased in the SN of both patients with PD and animal models of MPTP-induced PD. ^161,162 The lack of COX-2 activity attenuated MPTP-related DNA damage. ¹⁶³ These findings suggest that the loss of genomic integrity can be induced through the concerted actions of COX-2, further supporting a potential contribution of DNA damage to the neurodegeneration in PD. The PGE₂ is also directly and selectively toxic to dopaminergic neurons. ¹⁶⁴ The PGE₂ receptors have been detected on dopaminergic neurons in the rat SN. ¹⁶⁴ Overexpression of COX-2 has been reported in PD and an MPTP-animal model. ¹⁶⁵ , ¹⁶⁶ The COX inhibitors provide neuroprotection in the MPTP-mouse model of PD. ¹⁶⁷ Similarly, the regular use of COX-2 inhibiting nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, has been associated with a reduced incidence of PD. ¹⁶⁸ Moreover, epinephrine increased the release of PGE₂ in human colon adenocarcinoma HT-29 cells, which could be blocked by COX-2 inhibitors or atenolol and ICI 118.551 (β₁- and β₂-selective adrenergic antagonists, respectively). ¹²² β₂-Adrenergic antagonists suppressed COX-2 expression in pancreatic cancer cells. ¹²³ Propranolol inhibited cell proliferation and repressedgastric cancer cell growth through the downstream COX-2 pathway. ^118,119 In addition, the administration of propranolol and a COX-2 inhibitor, which can be applied perioperatively in most patients with cancer, with minimal risk and low cost, counteracted several immunologic and endocrinological perturbations and improved recurrence-free survival rates in mice undergoing primary tumor excision. ^169,170 These findings suggest that β-adrenergic antagonists may play a role in modulating the inflammatory process in PD.

The ROS play a major role in various cell-signaling pathways. The ROS activates various transcription factors and increases the expression of proteins that control cellular transformation, tumor cell survival, tumor cell proliferation and invasion, angiogenesis, and metastasis. Oxidative stress has been suggested to contribute to the pathogenesis of PD. Lymphocytes from untreated patients with PD exhibit increased oxidative stress. ¹⁷¹ Postmortem analyses of the brains of patients with PD have revealed evidence of increased lipid peroxidation in the SN. ^{172 –174} Superoxide dismutase is also increased in the SN of patients with PD. ¹⁷⁴ Moreover, myocardial tissue sections display increased ROS levels after traumatic brain injuries. Treatment with propranolol reduced cardiac ROS levels. ¹⁷⁵ Carvedilol modulated ROS-induced signaling. Carvedilol significantly reduced ischemia–reperfusion-induced free radical production and NAD⁺ catabolism, lipid peroxidation and red blood cell membrane damage, as determined by free malondialdehyde production in heart perfusion and rheological models. ⁸⁰ Nebivolol improved diastolic dysfunction and myocardial remodeling through reductions in oxidative stress in the transgenic (mRen2) rat. ¹⁷⁶ These findings suggest that β-adrenergic antagonists modulate oxidative stress in PD.

The enzyme nitric oxide synthase (NOS) is involved in the synthesis of nitric oxide (NO), which has also been implicated in PD. Inducible NOS (iNOS), endothelial NOS (eNOS), and neuronal NOS (nNOS) are present in microglia, endothelial cells, and neurons, respectively. ¹⁷⁷ Reciprocal DA-glutamate interactions play a critical role in stimulating striatal nNOS activity. ¹⁷⁸ The electrical and chemical stimulation of the SN and systemic DA D_1/5 receptor agonist administration robustly increases striatal NO efflux ^{179 , 180} NO signaling exerts multiple effects on local striatal circuits and projection neurons involved in regulating basal ganglia output and nigrostriatal DA neuron activity ¹⁸¹ High levels of NOS expression have been detected postmortem in the nigrostriatal region and basal ganglia of the brains of patients with PD. ¹⁸² A significant increase in nitrite content has been observed in the polymorphonuclear leukocytes of patients with PD. ¹⁸³ Both iNO and nNO are increased in both 6-OHDA and MPTP animal models. ^{183 –185} A lack of nNOS but not iNOS activity attenuated MPTP-related DNA damage. ¹⁶³ These results suggest that a loss of genomic integrity can be triggered through the concerted actions of nNOS and further supports the view that DNA damage may contribute to neurodegeneration in PD. Moreover, studies with NOS inhibitors and NOS KO animals have also confirmed the role of NOS in neurodegeneration. ^{185 –187} Reduced and oxidized glutathione have been detected in the SN of patients with PD. ¹⁸⁸ Moreover, metipranolol suppressed nitric oxide-induced lipid peroxidation in the eyes and retinas of rats. ⁸⁶ Nebivolol prevented vascular NOS III uncoupling in experimental hyperlipidemia. ¹⁴⁰ Propranolol suppressed hemangioma growth through the inhibition of eNOS protein expression and the subsequent production of nitric oxide. ¹⁸⁹ Celiprolol activated eNOS through the PI3K-Akt pathway via oxidative stress-induced NF-ĸB activity. ¹⁴¹ These findings suggest that β-adrenergic antagonists may play a role in PD via the inhibition of NOS expression.

Conclusion

β-adrenergic receptor blockade may play a role in PD. Genetic studies have identified proteins that link β-adrenergic receptor antagonism to the pathology of PD, including HLA genes, the RAS, PARP-1, NGF, VEGF, and the NADPH. β-adrenergic receptor inhibition also affects PD via nongenomic mechanisms, including MMPs, MAPK pathways, PGs, COX-2, and NOS. The β-adrenergic receptor blockades are contradicted in asthma and patients with CHF and cautioned to nursing women. Depression has been associated with lipophilic β-adrenergic receptor blockades, such as propranolol. Serious CNS adverse effects, including agitation, confusion, and hallucinations, are rare. However, the most interesting side effect of β-adrenergic receptor blockade is hypotension or symptoms associated with hypotension. Thus, further examination of the relationship between β-adrenergic antagonists and PD is required.