Neurogenic dysphagia: current pharmacogenomic perspectives

Neurogenic dysphagia (ND) is characterized by a swallowing disorder where nervous system, muscle, and neuromuscular diseases are involved. DRD1 , COMT , BDNF , and APOE are genes that may have a predictive role in the occurrence and evolution of ND. Many drugs that improve swallowing or can induce or exacerbate swallowing difficulties are related to dopamine metabolism and substance P. These pharmacological treatments for ND include dopamine precursors (levodopa), dopamine agonists (amantadine, apomorphine, cabergoline, and rotigotine), and TRP channel activators (capsaicin, piperine, and menthol). Since treatment outcomes are highly dependent on the genomic profiles of ND patients, personalized treatments should rely on pharmacogenetic procedures to optimize therapeutic interventions. Knowledge of the pharmacogenetic profiles of these drugs would minimize the occurrence of adverse drug reactions (especially to antidopaminergic medications) that may induce dysphagia and optimize pharmacological treatment that can ameliorate it. This knowledge should also be applied to the use of medications that control symptoms associated with dysphagia, such as sialorrhea, xerostomia, reflux, or hiccups. is a selective Mechanism: It displays potent antagonism of serotonin 5-HT2A and 5-HT2C, dopamine D1-4, histamine H1 and α 1-adrenergic receptors, moderate antagonism of 5-HT3 and muscarinic M1-5 receptors, and binding to GABA-A, BZD, and β -adrenergic receptors. Mechanism: Blocks postsynaptic mesolimbic dopaminergic receptors in the brain. Has actions at all levels of CNS, particularly at subcortical levels; also acts on multiple organ systems. It also exhibits weak ganglionic blocking, has a strong α -drenergic blocking effect, and depresses the release of hypothalamic and hypophyseal hormones. Depresses the reticular activating system anticholinergic sedative Mechanism: An alkaloid isolated from the plant Piper nigrum that has a role as an NF-kappaB inhibitor, a plant metabolite, a food component, and a human blood serum metabolite. It is a member of benzodioxoles, an N-acylpiperidine, a piperidine alkaloid, and a tertiary carboxamide. Effect: Skin and mucous membrane agents, local anesthetics, topical Mechanism: A local anesthetic with counterirritant qualities, widely used to relieve minor irritation. also acts a weak κ -opioid receptor agonist. Mechanism: Competitively inhibits acetylcholine and other cholinergic stimuli at autonomic effectors innervated by postganglionic cholinergic nerves and, to a lesser extent, on smooth muscles that lack cholinergic innervation. Doses used to decrease gastric secretions likely to cause dryness of mouth (xerostomia). Antagonizes histamine and serotonin Effect: Anticholinergic agents, antimuscarinics/antispasmodics sites output, Mechanism: Inhibits the transmission of mono/polysynaptic reflexes at the spinal cord level, possibly by hyperpolarization


INTRODUCTION
Neurogenic dysphagia (ND) refers to any swallowing disorder associated with central and peripheral nervous system conditions, as well as muscle and neuromuscular diseases. ND is linked to multiple degenerative and nondegenerative congenital, traumatic, vascular, neoplastic, and iatrogenic disorders as diverse as cerebral palsy, traumatic brain injury (TBI), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Parkinson's syndromes, myasthenia gravis (MG), and myositis [1] . Based on clinical observations, ND can be classified into the following seven distinct phenotypes, which are particularly useful when etiological diagnosis is in doubt: (i) premature bolus spillage; (ii) delayed swallowing reflex, both characteristic of stroke; (iii) predominance of residue valleculae, common in patients with Parkinson's disease; (iv) predominance of residue in the piriform sinus, characteristic of myositis, motor neuron disease, or brainstem stroke; (v) pharyngolaryngeal movement disorder, observed in patients with parkinsonism and stroke; (vi) fatigable swallowing weakness in individuals with myasthenia gravis; and (vii) complex disorder, as occurs in ALS [2] .
The importance of dysphagia stems mostly from the increased risk of death caused by aspiration pneumonia, and conditions related to dehydration or malnutrition [3,4] . In addition to these factors, aging reduces the frequency of spontaneous swallowing [5] . To ensure proper diagnosis and management of ND, it is mandatory to: (i) obtain a complete medical history; (ii) perform screenings that assess the risk of aspiration (e.g., a swallowing test with water and other consistencies); (iii) conduct counseling tests and clinically evaluate dysphagia by videofluoroscopy (VFSS), swallowing endoscopy (FEES), or manometry, and other additional tests such as ultrasonography or electromyography); (iv) perform treatments based on dietary therapeutic interventions, behavioral interventions, oral hygiene measures, neurostimulation, pharmacotherapy, and surgical treatments [6] . In this third step, the management of special groups such as tracheostomized patients and patients with nasogastric tubes is of particular interest [6] .
The treatment of ND is mainly based on rehabilitation therapies performed by speech therapists and other non-pharmacological approaches. However, some medications may be effective in improving impairment during the different phases of swallowing [6,7] . The majority of medications used to treat oropharyngeal dysphagia have a general effect on swallowing function that is independent of the underlying neurological disease; this allows for standardized use [8] . Pharmacotherapy, however, produces limited results and should therefore not be used as a stand-alone treatment, but rather as an adjunct to other therapies [8] . Furthermore, medications such as antidopaminergic agents, anticholinergic drugs, or benzodiazepines induce or exacerbate dysphagia [9][10][11][12] .
In view of these considerations, research into specific ND-related genes may be useful in the prognosis of this condition. Because pharmacogenetics also plays a key role in both the diagnosis and the correct pharmacological management of patients with dysphagia, to increase the benefit of compounds that can improve swallowing difficulty and minimize the risk with the use of dysphagia-inducing drugs, in this review, we highlight these ND mechanisms from a pharmacogenomic perspective.

DOPAMINE AS A NEUROTRANSMITTER
Dopamine is a neurotransmitter of high relevance in the swallowing process. Its precursor, L-DOPA, is synthesized from the essential amino acid tyrosine or indirectly through phenylalanine, a non-essential amino acid. Dopamine β-hydroxylase (DBH) catalyzes the conversion of dopamine to norepinephrine (NE), and NE is then converted into epinephrine by phenylethanolamine N-methyltransferase with S-adenosyl-L-methionine as the cofactor. Dopamine is degraded by monoamine oxidase (MAO-A and MAO-B), catechol-O-methyl transferase (COMT), and aldehyde dehydrogenase (ALDH), which act sequentially [13] .
Dopamine is synthesized and acts primarily in the central nervous system (CNS). Dopaminergic neurons project to different brain regions along the mesolimbic, mesocortical, nigrostriatal, and tuberoinfundibular pathways. Dopamine exerts its effects by binding to five G-protein-coupled receptors (D1-D5); of these, D1 receptors are the most abundant in the CNS. These receptors are divided into D1-like (D1 and D5) and D2-like (D2, D3, and D4) receptors. D1-like receptors exert a stimulatory effect through sodium channels or an inhibitory effect through potassium channels. At the peripheral level, dopamine does not cross the blood-brain barrier and is synthesized independently. Dopamine is present in plasma as dopamine sulfate, and only a small unconjugated amount can be synthesized by peripheral tissues [14,15] .

DOPAMINE AND SWALLOWING
The swallowing process requires, at least in part, dopamine activity and its binding to its receptors [16] . Although most dopamine receptors would theoretically be relevant to ND, the role of the dopamine D1 receptor (DRD1) is particularly important in this condition. For example, DRD1 antagonists alter the swallowing reflex and reduce substance P (SP) levels in peripheral organs [17] . Specifically, in the striatum in an animal model of Huntington's chorea, Drd1a, SP, and dynorphin expression is downregulated, whereas the expression of the dopamine D2 receptor (Drd2) and enkephalin is upregulated after ablation of D1 receptor-expressing cells [18] . In this animal model, the resulting phenotype includes swallowing disturbances and poor oromotor coordination with tongue protrusion [18] . This role of DRD1 has also been observed in certain single nucleotide polymorphisms (SNPs) in humans. The DRD1 rs4532 polymorphism confers a worse prognosis of swallowing function in individuals over the age of 65 following a stroke. Other SNPs, such as DRD2 rs1800497 and DRD3 rs6280, do not appear to be involved in ND [19] . Moreover, interactions between the COMT rs165599 and BDNF rs10835211 polymorphisms are linked to dysphagia with increasing age; the effect of the SNP rs10835211 heterozygosity is dependent on the status of SNP rs165599 [20] .

The use of dopaminergic agonists in the treatment of neurogenic dysphagia
Levodopa, rotigotine, cabergoline, apomorphine, and amantadine are dopamine agonists that have been used generically to treat a variety of neurological conditions associated with oropharyngeal dysphagia [8] . The drug that provides the best outcome is controversial because of conflicting outcomes across different studies. However, among these, levodopa is the most widely used, and it is also used to evaluate the swallowing response during the Fiberoptic Endoscopic Evaluation of Swallowing (FEES) test [21,22] . Most studies have focused on the effect of dopaminergic agonists in Parkinson's disease, and several publications show that these drugs improve dysphagia, especially in the oral phase and, to a lesser extent, in the pharyngeal phase [23][24][25] . This clinical improvement is related to swallowing alterations due to nigrostriatal dopamine deficits and to other structures such as the pedunculopontine nucleus or the medulla [23] . In a small group of patients, an improvement in bolus fragmentation, vallecular stasis, and laryngeal penetration was observed, together with a shortening of the swallowing phase; these findings are associated with an improvement in bucco-linguo-facial motility [26] . Paradoxically, and despite most articles reporting a beneficial effect, one clinical trial showed that levodopa could worsen dysphagia by inhibiting brainstem reflexes [27] . Overall, however, the results appear to support its use in PD patients despite the lack of highquality evidence [28] . Although dopaminergic agonists have a modest effect on the motor symptoms of progressive supranuclear palsy, they help some patients improve their swallowing [21] . However, these drugs can also be employed in acquired neurological conditions. Following a lacunar stroke involving the basal ganglia, for example, levodopa decreases the risk of aspiration by shortening the latency of the swallowing reflex, as shown after examining the submental electromyographic activity and the visual observation of the laryngeal movement [29] . This reduction, according to monocentric randomized trials in which imaging and physical signs were evaluated, is also observed with other dopamine agonists such as cabergoline and amantadine; the elderly population, in particular, may benefit from treatment with dopamine agonists [30,31] .
The search for new compounds to treat ND also includes natural supplements that contain dopamine, for use mainly in groups where dosage or side effects may be contraindicated, such as children or the elderly. Natural sources of dopamine include Mucuna pruriens, Vicia faba, or Musa cavendishii [32][33][34] . In fact, several studies in patients with Parkinson's disease reveal the effectiveness of these treatments with extracts derived from these products; these compounds reduce the risk of adverse effects such as dyskinesias as well as induce epigenetic and pharmacoepigenetic modifications [35,36] .

Pharmacogenetics of dopaminergic agonists in the treatment of neurogenic dysphagia
Anti-ND drugs exhibit different specific pharmacogenetic profiles [ Table 1] [37] . All of the medications used to treat ND show, among others, DRD1 as a mechanistic gene and the binding of drugs to this receptor. All of the anti-ND drugs have COMT as substrates, where COMT shortens the activity of these dopaminergic drugs [38] . Moreover, the COMT rs4680 polymorphism may induce motor complications such as dyskinesia during treatment with levodopa [38][39][40] . Levodopa also has DBH as substrate [37] . ADORA2A SNPs and HOMER1 variants are associated with L-DOPA-induced adverse motor (e.g., dyskinesia) and psychotic symptoms [41,42] . A haplotype integrating -141CIns/Del, rs2283265, rs1076560, C957T, TaqIA, and rs2734849 polymorphisms at the DRD2/ANKK1 gene region is linked to L-DOPA-induced motor dysfunction [43] . SLC6A3 is a genetic modifier of the treatment response to L-DOPA [44] . The multi-drug resistance gene (MDR1) C1236T polymorphism may also influence pharmacotherapy [45] and SNPs in genes that encode the dopamine transporter (DAT; SLC6A3) and the vesicular monoamine transporter 2 (VMAT2; SLC18A2) [46] . Despite the fact that dopamine agonist therapy has applicability in other ND diseases, these studies focus on Parkinson's disease, which limits inferences in other acquired or degenerative neurological illnesses.

Antidopaminergics and neurogenic dysphagia
In a significant number of cases, the causes of ND can be induced or exacerbated by certain drugs [9][10][11] . Many patients with different neurological conditions are treated with antidopaminergic medication [10,11] . Adverse reactions are especially frequent in senescence and are relevant since they are reversible, and dysphagia may be the only or the predominant extrapyramidal symptom. Although it is recommended that drug intake be minimized as much as possible, this is not feasible in many cases. It is therefore recommended that the drug dose be adjusted to avoid the aforementioned side effects. Knowing the pharmacogenetic profiles of these drugs is, therefore, very important to therapeutic strategies [37] [ Table 2].
Antipsychotics, as antidopaminergic medications, are primarily metabolized through CYP1A2/2D6/3A4/2C19 [47] . Of these, CYP2D6 is the most relevant because 40% of these neuroleptics are major substrates of this enzyme. CYP2D6, however, is associated with side effects. Other genes such as HTR2A, SLC18A2, GRIK3, and DRD2 are linked to extrapyramidal reactions [48] . Drugs that exert an antidopaminergic effect on DRD1 are of particular interest. In ND, DRD1 is the pathogenic gene that is involved in the pharmacogenomic response to haloperidol, aripiprazole, olanzapine, quetiapine, or risperdone. Other DRDs (not DRD1) pathogenic variants mediate the adverse effects of antipsychotic drugs such as sulpiride, domperidone, and metroclopramide, causing oropharyngeal dysphagia; this suggests that other dopamine-and non-dopamine pathways mediate blocking of the swallowing phase [37] .

TRANSIENT RECEPTOR POTENTIAL CHANNEL (TRP) GENES
Transient receptor potential (TRP) channel genes encode ion channels that are classified into two broad groups: (i) Group 1 includes TRPC (canonical), TRPV (vanilloid), TRPVL (vanilloid-like), TRPM Although the precise mechanism of action of Rotigotine is unknown, it is believed to be due to stimulation of postsynaptic dopamine D2-type autoreceptors within substantia nigra in brain, leading to improved dopaminergic transmission in motor areas in basal ganglia, notably caudate nucleus/putamen regions Effect: Antiparkinsonian agents, non-ergot-derivative dopamine receptor agonists (melastatin), TRPS (soromelastatin), TRPN (no mechanoreceptor potential C), and TRPA (ankyrin); (ii) Group 2 consists of TRPP (polycystic) and TRPML (mucolipin) [49] . Some of these targets represent a therapeutic strategy of interest for dysphagia by stimulating areas that evoke the swallowing reflex. Group 1 genes are the most relevant where TRPV1, TRPA1, and TRPM8, for example, are involved in stimulation of thermal sensitivity and the release of CGRP and inflammatory mediators [50] . These receptors are expressed on trigeminal, vagal, and glossopharyngeal nerve terminals; these nerves are critical in the swallowing process [51,52] . Three compounds of clinical relevance in ND that stimulate these receptors are capsaicin, piperine, and menthol. Capsaicin increases the frequency of spontaneous swallowing by stimulating TRPV1 receptors, piperine stimulates TRPV1/A1 receptors, and menthol stimulates TRPM8 receptors [53,54] . A recent meta-analysis revealed the effectiveness of TRP channel agonists in treating ND [55] . Capsaicin produces the highest therapeutic outcomes by lowering the risk of laryngeal penetration and pharyngeal residue and increasing bolus velocity [54] . Capsaicin also induces the release of SP, a neurotransmitter involved in amplifying the inflammatory response and nociceptive sensitization. Since DBH inhibits capsaicin, a pharmacogenetic study in patients with variants of interest is mandatory [37] . As mechanistic genes, TRPV1 Val585Ile and UCP2 -866 G/A variants correlate with the capsinoid therapeutic response [56] . All three, but mainly capsaicin, inhibit CYP group enzymes (CYP3A4, CYP2C9, and weak in CYP2D6). Furthermore, capsaicin and piperine inhibit CYP1A2 [57] . In silico, piperine weakly inhibits CYP2D6 WT and CYP2D6*53 [58] . Capsaicin and the other compounds, in addition to exhibiting large heterogeneity in their metabolic genes, exert anti-inflammatory effects by modulating pleiotropic genes such as TNF andILs [37] [ Table 3].

OTHER DRUGS USED IN NEUROGENIC DYSPHAGIA
Angiotensin-converting enzyme inhibitors (ACE inhibitors) inhibit substance P degradation [59] . These drugs reduce the cough threshold and subsequently can be used in aspiration prophylaxis; however, results from studies on perindopril, lisinopril, or imidapril are inconclusive [59][60][61] . Imidapril is effective in controlling dysphagia after stroke [30] . In one study, levetiracetam was beneficial to the recovery of dysphagia in post-stroke patients [62] . Several reports describe the usefulness of cough provocation tests with irritants (citric acid, tartaric acid, and mannitol) as a diagnostic tool [63][64][65] , but it remains to be determined whether such agents are useful for treating dysphagia. Table 3 shows the pharmacogenetic profiles of other drugs used to treat ND [37] . It should furthermore be noted that drugs used to treat ND (including dopaminergic agonists) may influence neuroplasticity and axonal regrowth or sprouting to improve, for example, the level of consciousness that would facilitate swallowing [66] .

OTHER GENES RELATED TO NEUROGENIC DYSPHAGIA
Few reports have linked other genes to dysphagia. However, the BDNF gene has been studied the most in this regard; the influence of the COMT gene on symptomatic dysphagia has been previously discussed [20] ; rs6265 polymorphisms exert disparate effects on pharyngeal stimulation in healthy subjects [67] and appear to influence a better prognosis in swallowing after stroke or poor tolerance to esophageal electrostimulation in carriers of the Met allele [68][69][70] . Furthermore, a study with a large sample of elderly individuals showed that e4 homozygous APOE carriers have low swallowing evaluation scores [71] . Finally,   ADRA1s, ADRA2A, ADRA2B, ADRA2C, BDNF, CHRM1,  CHRM2, CHRM3, CHRM4, CHRM5, DRD1, DRD2, DRD4, HRH1, HTR1A, HTR1B,  HTR1D, HTR1E, HTR2A, HTR2B, HTR2C, HTR6  The T allele of rs17601696 (parent gene FGFR2) is reported to be associated with ND [72] .

PHARMACOGENETICS OF DRUGS EMPLOYED IN OTHER ASSOCIATED OROPHARYNGEAL SYMPTOMS IN NEUROGENIC DYSPHAGIA
Together with strategies aimed at controlling ND, it is also important to manage those factors that may exacerbate symptoms and increase the risk of aspiration. Many patients with CNS conditions exhibit sialorrhea, hiccups, xerostomia, or reflux with swallowing difficulties. Prior to considering systemic drugs, it is recommended that local treatment or physical measures be initiated first [ Table 4] [37] .

Sialorrhea
The most used treatments for the control of hypersalivation in patients with neurological damage are based on their anticholinergic profiles. This includes a heterogeneous group of drugs such as amitriptyline, scopolamine, glycopyrronium chloride, trihexyphenidyl, atropine, or thiopium bromide. These anticholinergic agents present an added benefit in the control of other motor symptoms, as occurs in patients with Parkinson's disease [73] . However, their main drawback is the occurrence of frequent side effects that include sedation, cognitive deficits, constipation, urinary retention, tremor, and blurred vision. Within a population where the prevalence of dementia is high, elderly patients often use drugs with anticholinergic effects, and frequently in combination. Furthermore, in this patient population, polymedication may mask symptoms that are misdiagnosed as pathology unrelated to drug toxicity [74] .
Concerning the pharmacogenetic profile, anticholinergic drug exposure shows associated variants located at chromosome 3p21.1 locus, with the top SNP rs1076425 in the inter-alpha-trypsin inhibitor heavy chain 1 (ITIH1) gene [75] . Subjects with CYP2D6/CYP2C19 PM phenotype increase the risk of adverse reactions due to increased serum drug concentrations [76] . In contrast, polymorphisms of the ARGEF10, ADRB3, ROCK2, and CYP3A4 genes in the cholinergic pathway do not appear to significantly modify parameters related to clinical improvement [77] .

Xerostomia
The first line of treatment for xerostomia is to employ local therapies (artificial saliva, sialogogues), avoiding the use of systemic medications (pilocarpine) as the first choices due to their common negative effects. Side effects include blurred vision, bronchoconstriction, hiccup, sweating, hypotension, bradycardia, cutaneous vasodilatation, nausea, diarrhea, or increased urinary frequency [78] . Polymorphisms in CYP2A6 modify the pharmacokinetics of this drug, where the clearance of pilocarpine is significantly lower. In vivo, these slow metabolizers have two inactive CYP2A6 alleles: CYP2A6*4A, CYP2A6*7, CYP2A6*9, or CYP2A6 *10 [79] .

Pharyngolaryngeal reflux
Proton-pump inhibitors (PPI) and H2 receptor antagonists show improvements in gastro-esophageal reflux disease-like symptoms, being PPIs more effective in subjects with negative endoscopic findings [80] . CYP2C19 is the most prominent of the PPI-metabolizing enzymes; CYP2C19-specific single nucleotide polymorphisms reduce clearance proportionally and increase exposure and prolong proton-pump inhibition. Differences in CYP2C19-mediated metabolism lead to marked interpatient variability in acid suppression, drug-drug interaction potential, and clinical efficacy [81][82][83][84] . This phenomenon has also been observed with CYP3A4, but to a lesser degree [82] .

Hiccup
Pharmacologically, multiple drugs with different targets are available to control hiccups. Baclofen is a drug commonly used in intractable hiccups [85] . The ABCC9 SNP (rs11046232, heterozygous AT versus reference TT genotype) is associated with a two-fold increase in oral baclofen clearance [86] . Allelic variants with the ABCC12, SLC28A1, and PPARD SNPs generate variable responses in cerebral palsy [86] . Chlorpromazine, domperidone, and metoclopramide can also be useful. However, since these are antidopaminergic drugs, they should be prescribed with caution because they may worsen dysphagia. Domperidone would be recommended amongst these medications because of its limited transit through the blood-brain barrier and exceptional central effects [87] . Paradoxically, metoclopramide and other antidopaminergic drugs may be beneficial by reducing nausea and vomiting in patients with ND, and therefore the risk of aspiration. In these cases, dose adjustment and patient selection are essential due to the risk of adverse effects [45] .

CONCLUSION
Treatment of ND must be comprehensive and multidisciplinary. Pharmacological treatments are support tools for other therapeutic measures. Dopamine is the main neurotransmitter implicated in these swallowing disorders. Of the genes that encode dopaminergic receptors, DRD1 is the most important in the prediction and treatment of ND. Other genes such as COMT and DBH have also been considered in the management of ND. Polymorphisms in dopaminergic and antidopaminergic agents are associated, respectively, with undesired or insufficient effects and increased risk of swallowing impairment. SP is another main factor in the treatment of ND, which can be altered with antidopaminergic agents. SP degradation is blocked with TRP channel agonists such as capsaicin, piperine, menthol, and ACE inhibitors. Genetic variants influence the therapeutic response of TRP channel agonists. When symptoms coexist that can worsen dysphagia and increase the risk of aspiration (e.g., reflux, xerostomia, sialorrhea, and hiccups), it is recommended to carefully associate other medications with ND treatment due to the risk of adverse effects, which may even include swallowing disorders. Dose adjustment and choice of drug in polypharmacy patients is one of the main objectives of a pharmacogenetic analysis.