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Page 309 Guerra et al. J Transl Genet Genom 2022;6:304-21 https://dx.doi.org/10.20517/jtgg.2022.08

neurons or by increasing dopamine release from presynaptic fibers Inhibitor: MAOB
Effect: Antiparkinsonian agents, adamantanes, dopamine agonists Transporter genes: SLC22A1 (Substrate/inhibitor), SLC22A2 (Substrate/inhibitor)

(melastatin), TRPS (soromelastatin), TRPN (no mechanoreceptor potential C), and TRPA (ankyrin); (ii) Group 2 consists of TRPP (polycystic) and TRPML
[49]
(mucolipin) . 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 . These receptors are expressed on trigeminal, vagal, and glossopharyngeal nerve terminals; these nerves are critical in the
[50]
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
[55]
receptors [53,54] . A recent meta-analysis revealed the effectiveness of TRP channel agonists in treating ND . Capsaicin produces the highest therapeutic
outcomes by lowering the risk of laryngeal penetration and pharyngeal residue and increasing bolus velocity . Capsaicin also induces the release of SP, a
[54]
neurotransmitter involved in amplifying the inflammatory response and nociceptive sensitization. Since DBH inhibits capsaicin, a pharmacogenetic study in
[37]
patients with variants of interest is mandatory . As mechanistic genes, TRPV1 Val585Ile and UCP2 -866 G/A variants correlate with the capsinoid therapeutic
[56]
response . All three, but mainly capsaicin, inhibit CYP group enzymes (CYP3A4, CYP2C9, and weak in CYP2D6). Furthermore, capsaicin and piperine
inhibit CYP1A2 . In silico, piperine weakly inhibits CYP2D6 WT and CYP2D6*53 . Capsaicin and the other compounds, in addition to exhibiting large
[57]
[58]
[37]
heterogeneity in their metabolic genes, exert anti-inflammatory effects by modulating pleiotropic genes such as TNF andILs [Table 3].

OTHER DRUGS USED IN NEUROGENIC DYSPHAGIA
Angiotensin-converting enzyme inhibitors (ACE inhibitors) inhibit substance P degradation . These drugs reduce the cough threshold and subsequently can
[59]
be used in aspiration prophylaxis; however, results from studies on perindopril, lisinopril, or imidapril are inconclusive [59-61] . Imidapril is effective in controlling
dysphagia after stroke . In one study, levetiracetam was beneficial to the recovery of dysphagia in post-stroke patients . Several reports describe the
[30]
[62]
usefulness of cough provocation tests with irritants (citric acid, tartaric acid, and mannitol) as a diagnostic tool [63-65] , 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 . It should furthermore be noted
[37]
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

[67]
symptomatic dysphagia has been previously discussed ; rs6265 polymorphisms exert disparate effects on pharyngeal stimulation in healthy subjects and
[20]
appear to influence a better prognosis in swallowing after stroke or poor tolerance to esophageal electrostimulation in carriers of the Met allele [68-70] .
[71]
Furthermore, a study with a large sample of elderly individuals showed that e4 homozygous APOE carriers have low swallowing evaluation scores . Finally,