Cholinergic – Hyperhidrosis Research . org

July 17, 2026

A neurocutaneous Na(V)1.8 channelopathy underlies a genetic subtype of primary idiopathic hyperhidrosis

Sci Adv. 2026 Jul 17;12(29):eaed3221. doi: 10.1126/sciadv.aed3221. Epub 2026 Jul 17.

ABSTRACT

Primary idiopathic hyperhidrosis (PIH) is a poorly understood disorder characterized by excessive sweating. We identify a genetically defined subset of PIH associated with rare coding changes in voltage-gated Na⁺ (Na_V) channels. Whole-exome sequencing of hereditary PIH families revealed gene-level enrichment within the Na_V channel family, with SCN10A (Na_V1.8) most strongly implicated. A knock-in mouse carrying the clinically observed Na_V1.8^p.R14L substitution recapitulated excessive sweating. Na_V1.8 was detected in a subset of postganglionic neurons in thoracic sympathetic ganglia in humans and mice, where p.R14L produced a gain-of-function profile that enhanced cholinergic responsiveness. Excessive sweating in mutant mice was reversible with Na_V channel inhibition, including clinically used agents and a Na_V1.8-preferential compound. Together, these findings define a targetable neurocutaneous channelopathy underlying a subset of PIH and support a model in which excessive sweating arises from either gland-intrinsic dysfunction or altered sympathetic drive, motivating stratified therapeutic approaches.

PMID:42467787 | DOI:10.1126/sciadv.aed3221

August 6, 2023

PAI1 inhibits the pathogenesis of primary focal hyperhidrosis by targeting CHRNA1

Orphanet J Rare Dis. 2023 Jul 21;18(1):205. doi: 10.1186/s13023-023-02808-0.

ABSTRACT

BACKGROUND: Primary focal hyperhidrosis (PFH) may be attributed to the up-regulation of the cholinergic receptor nicotinic alpha 1 subunit (CHRNA1) in eccrine glands. Plasminogen activator inhibitor-1 (PAI1, encoded by SERPINE1) is reported to inhibit the expression of CHRNA1, while the role of PAI1 in hyperhidrosis is unknown.

METHODS: Serpine1 KO mice, Serpine1-Tg mice, and wild type BALB/c mice were intraperitoneally injected with pilocarpine hydrochloride to induce PFH. Cisatracurium (CIS, antagonist of CHRNA1) or PAI-039 (small-molecule inhibitor of PAI1) was pre-administrated before the induction of hyperhidrosis. On the other hand, Chrna1-expressing AAV was constructed and administered to Serpine1-Tg mice with hydrochloride stimulation. Hydrochloride-related biomarkers, such as acetylcholine (ACH) in the serum, calcium voltage-gated channel subunit alpha1 C (CACNA1C), and aquaporin 5 (AQP5) in sweat glands of mice were assayed with ELISA, RT-PCR, and Western blot.

RESULTS: The administration of PAI-039 or Pai1 knock-out increased Chrna1 expression, sweat secretion, and hydrochloride-related biomarkers (ACH, CACNA1C, and AQP5) expression. On the other hand, CIS administration diminished the strengthened hyperhidrosis phenotype induced by Pai1 knock-out with decreased sweat gland secretion.

CONCLUSION: PAI1 inhibits CHRNA1-mediated hydrochloride-induced hyperhidrosis, with decreased sweat gland secretion and diminished ACH, AQP5, and CACNA1C expression. These results indicate the potential to utilize PAI1 to alleviate PFH.

PMID:37542348 | DOI:10.1186/s13023-023-02808-0

April 20, 2022

Transfersomal eosin topical delivery assisted by fractional CO2 laser for photodynamic treatment of palmar hyperhidrosis: case study

Drug Deliv Transl Res. 2022 Apr 20. doi: 10.1007/s13346-022-01164-z. Online ahead of print.

ABSTRACT

Hyperhidrosis is a condition in which the cholinergic receptors on the eccrine glands are overstimulated, resulting in excessive sweating. It is considered a serious cosmetic and psychological problem that affects the patient’s quality of life. Searching for novel treatment modalities is required to minimize the side effects and to attain better patient satisfaction.Photodynamic therapy (PDT), using eosin as a photosensitizer, is developed as a promising modality of the treatment of palmar and axillary hyperhidrosis. In this study, we treated six cases suffering palmar hyperhidrosis by applying the fractional CO₂ laser prior to PDT session. For PDT, a hydrogel of eosin loaded in a transfersomes as a nano-delivery carrier was applied for 5 min, followed by irradiation by intense pulsed light (IPL). The prepared transfersomes loaded by eosin were spherical in shape with encapsulation efficiency of 33 ± 3.5%, particle size 305.5 ± 5.7 nm, average zeta potential of – 54 ± 7.6 mV with 80 ± 4% of the loaded eosin was released after 3 h. Two cases achieved 90% improvement after four sessions, three patients needed six sessions to show 75% improvement, while one patient showed only 25% improvement after six sessions. This resulted in shortening the time of PS application and decreasing the number of sessions required to achieve acceptable improvement. More clinical studies on large number of patients are required to optimize the results.

PMID:35441986 | DOI:10.1007/s13346-022-01164-z

January 23, 2021

CHRNA1 promotes the pathogenesis of primary focal hyperhidrosis.

CHRNA1 promotes the pathogenesis of primary focal hyperhidrosis.

Mol Cell Neurosci. 2021 Jan 18;:103598

Authors: Lin JB, Kang MQ, Huang LP, Zhuo Y, Li X, Lai FC

Abstract
The aim of the study was to elucidate the involvement of cholinergic receptor nicotinic alpha 1 subunit (CHRNA1) in the pathogenesis of primary focal hyperhidrosis (PFH). The hyperhidrosis mouse model was constructed using pilocarpine injection. The expression levels of CHRNA1 in sweat gland tissues of PFH patients and hyperhidrosis mice were compared using Western blots and quantitative real-time PCR (qRT-PCR) analyses. Sweat secretion in hyperhidrosis mice treated with small-interfering RNA (siRNA) targeting CHRNA1 (si-CHRNA1) or non-specific siRNA were compared. Sweat secretory granules in the sweat gland cells of hyperhidrosis mice were examined using transmission electron microscopy. The serum level of acetylcholine was measured using enzyme-linked immunosorbent assay, while markers associated with PFH, including Aquaporin 5 (AQP5) and Calcium Voltage-Gated Channel Subunit Alpha1 C (CACNA1C), were assessed using immunohistochemical assay and Western blots. Brain-derived neurotrophic factor (BDNF) and Neuregulin 1 (NRG-1) in sympathetic ganglia axons of hyperhidrosis mice were quantified using Western blots. CHRNA1 up-regulation is a characteristic of the sweat glands of PFH patients and Hyperhidrosis mice. Silencing CHRNA1 decreased sweat secretion and the number of sweat secretory granules of hyperhidrosis mice. Serum acetylcholine, as well as AQP5 and CACNA1C expression in the sweat glands, was reduced by siCHRNA1. BDNF1 and NRG-1 levels in the sympathetic ganglia axons were also attenuated by siCHRNA1 treatment. CHRNA1 up-regulation is a potential biomarker of PFH and downregulating CHRNA1 could alleviate the symptoms of PFH through inactivating the sympathetic system.

PMID: 33476802 [PubMed – as supplied by publisher]

December 20, 2020

Fractional CO2 Laser for Transcutaneous Drug Delivery of Onabotulinum Toxin in Palmar Hyperhidrosis.

Fractional CO2 Laser for Transcutaneous Drug Delivery of Onabotulinum Toxin in Palmar Hyperhidrosis.

Dermatol Surg. 2020 Dec 15;Publish Ahead of Print:

Authors: Agamia NF, Sobhy N, Abd-Elraouf A, Tawfik A

Abstract
BACKGROUND: Palmar hyperhidrosis is a common disorder of excessive sweating due to over-stimulation of cholinergic receptors on eccrine glands.
OBJECTIVE: To compare the efficacy of laser-assisted drug delivery of onabotulinum toxin A (BoNTA) and intradermal BoNTA injections in the management of palmar hyperhidrosis.
PATIENTS AND METHODS: This intrapatient comparative study was conducted on 30 adult patients with idiopathic palmar hyperhidrosis. The palms of the patients were divided into 2 groups. Group 1 was treated with intradermal injections of 50 units of BoNTA, whereas Group 2 was subjected to laser-assisted transcutaneous BoNTA delivery using fractional CO2 laser at different doses (25, 50, and 75 units). Each treatment modality was evaluated using the iodine starch test, hyperhidrosis disease severity scale, and gravimetric scoring.
RESULTS: Delivery of 75 units of BoNTA to the dermis on the right-sided palms assisted by fractional CO2 laser was clinically equivalent to 50 units of injection on the left side. Pain intensity was significantly higher on the injected side than on the other side.
CONCLUSION: Laser-assisted drug delivery of botulinum toxin can be considered an effective and safe alternative for treatment of palmar hyperhidrosis with minimal side effects and complications.

PMID: 33337732 [PubMed – as supplied by publisher]

March 1, 2019

The Treatment of Primary Focal Hyperhidrosis

The Treatment of Primary Focal Hyperhidrosis

Skin Therapy Lett. 2018 Jan;24(1):7

Authors: Wechter T, Feldman SR, Taylor SL

Abstract
Primary focal hyperhidrosis is a relatively common disease that has a significant impact on afflicted patient’s quality of life. The pathogenesis of the disease is thought to stem from increased cholinergic activity on eccrine sweat glands. Topical aluminum chloride based antiperspirants are good first-line agents for all affected body sites. Anticholinergic agents are emerging as effective topical alternatives. Iontophoresis passes an electrical current through the skin and is an excellent treatment option for palmoplantar disease. Botulinum toxin type A injections remain a mainstay second-line treatment. Local procedural advances including microwave thermolysis, laser therapy and focused ultrasound are emerging as safe and effective alternatives for refractory disease. Oral anticholinergics are generally well tolerated and can also be used for intractable disease. Last-line interventions include local surgical options and sympathectomy, though some patients may prefer permanent treatment. Further investigation of novel treatments as well as ways to optimize existing therapeutic options are needed.

PMID: 30817880 [PubMed – as supplied by publisher]

November 11, 2018

Genetic polymorphism analysis of patients with primary hyperhidrosis.

Genetic polymorphism analysis of patients with primary hyperhidrosis.

Clin Cosmet Investig Dermatol. 2018;11:477-483

Authors: Simes BC, Moore JP, Brown TC, Rushforth TJ, Bookout AL, Richardson CL

Abstract
Background: Hyperhidrosis affects 220 million people worldwide. The hallmark of this condition is excessive sweating, which negatively impacts the social, emotional, and occupational lives of these individuals. A familial predisposition has been established; however, the specific genes involved have yet to be identified.
Objective: The aim of this study was to determine possible genetic variations contributing to primary hyperhidrosis, specifically single-nucleotide polymorphisms (SNPs).
Patients and methods: Twenty-one case and 21 control DNA samples were extracted and genotyped for 20 SNPs associated with the Butyrylcholinesterase (BCHE) and Cholinergic Receptor Nicotinic Alpha-7 subunit (CHRNA7) genes.
Results: For rs1126680, the -116A variant allele (P-value=0.15) was found only in hyperhidrosis patients who also had the K-variant allele (P-value=0.65) in rs1803274. Further analysis testing the null hypothesis of independence between the combined genotypes and case/control status yielded a P-value of 0.30.
Conclusion: Our results are consistent with previous research that shows the K-variant requires the -116A variant to be present in order to observe a decrease in BChE activity levels. These results are not statistically significant (P-value >0.05), but the exclusive association between the -116A and K-variants on the BCHE gene in hyperhidrosis patients warrants further investigation using a larger sample size.

PMID: 30349345 [PubMed]