22 research outputs found
Electroceutical Treatment for Charcot-Marie-Tooth (CMT) Disease
No full textElectroceuticals; Bioelectronic medicine; Charcot-Marie-Tooth disease; Peripheral demyelinating neuropathy; Myelination수초화는 신경계의 정상적인 정보 전달을 기능적으로 수행하는데 있어 필수적이다. 말초신경계(PNS)에서 수초의 손실은 샤르코-마리-투스 (CMT) 질환과 같은 탈수초성 신경질환을 발생시킨다. CMT 질환은 전 세계 약 3백만 명에 영향을 미치는 가장 흔한 유전성 말초신경병증이다. CMT 질환은 축삭 변성과 탈수초화라는 두 가지 주요 병리생리학적 원인으로 발생되며 CMT 질환의 대다수가 탈수초화로 인해 발생된다. CMT 질환은 밝혀진 지 한 세기가 더 지났음에도 불구하고, 아직까지 승인된 치료법이 없는 상황이다. 이로 인해 수백만명의 환자들이 여전히 이 질환으로 고통받고 있으며, 이는 삶의 질을 크게 저하시킨다. 아스코르비산, 뉴로트로핀, 고지방 식단 등의 생화학적 접근과 세포 치료 및 유전자 치료 등의 여러 방법에 대한 연구가 진행되었음에도 불구하고 이 질환에 대한 치료제는 안타깝게도 여전히 개발되지 못했다. 또한, 선행 접근법들은 임상 시험에서 효과적인 결과를 보이지 못하였으며, 온 몸에 걸쳐 작용하기 때문에 심각한 부작용이 지적되었다. 따라서, CMT 치료를 위해서는 새로운 패러다임이 필요하며, 기존의 화학약물적 접근이 아닌 생물물리학적 방법을 고안하였다.
전자약은 신경계의 언어를 밀접하게 모사할 수 있어, 유망한 신경 조절 방법이다. 또한, 전자약은 비교적 국소적인 방식으로, 부작용의 가능성을 최소화한다는 장점이 있다. 전기자극(ES)은 파킨슨병, 간질 및 척수 손상과 같은 다양한 중추신경계(CNS) 신경병증의 치료에 이용되어져 왔다. 말초신경계(PNS)에서 ES는 신경 손상과 같은 후천성 말초신경병증에 대해 가능성을 보여주었으나, CMT질환과 같은 유전성 말초신경병증에 대한 치료 효능은 아직 연구된 바 없었다. 본 논문에서는 세 단계의 전자약 연구를 통해 탈수초성 CMT질환에 대한 치료 가능성을 고찰한다.
첫 번째 연구는 야생형 배근신경절의 체외 배양을 이용한 ex vivo 말초신경계 모델을 사용하여 전기자극이 말초신경계에서 수초화를 향상시키는 능력을 연구하였다. 1 시간 동안 20 Hz의 전기자극을 인가하였을 때, 수초화 과정에 필수적인 지질 생합성이 상승되는 것을 확인하였다. 지질 이미징을 통해 전기자극이 수초막을 이루는 지질의 양을 증가시켰음을 관찰하였다. 이 연구를 통해 전기자극이 야생형 말초신경계에서 수초화를 향상시키는 능력이 있음을 보여주었으며, 탈수초성 CMT 질환에도 응용 가능성을 보여주었다.
다음 연구는 전자약이 탈수초성 CMT 질환에 대한 치료 가능성을 탐구하기 위한 첫 번째 단계를 수행했다. 체외 질환 모델을 구성하고자 CMT 질환의 가장 흔한 유형인 CMT1A의 주요 생체 분자적 특성인 PMP22 유전자의 과발현 및 PMP22의 세포내 응집을 모방하는 유전자 조작 슈반 세포를 제작하였다. 고효율 스크리닝(High throughput screening, HTS) 플랫폼을 이용한 전기자극 주파수 스크리닝 결과, 1시간동안 20 Hz의 전기자극을 인가하는 것이 PMP22 응집을 감소시키고 세포막 내 분포를 개선하는 등 최적의 치료 효과를 나타냄을 확인하였다. 또한 이 최적의 전기자극 조건은 (1) 수초화 관련 주요 단백질을 인코딩하는 유전자의 상승, (2) 양성 조절 인자를 인코딩하는 유전자의 상승 및 음성 조절 인자를 인코딩하는 유전자의 감소, 그리고 (3) 양성 조절 경로의 활성화 및 음성 조절 경로의 억제와 같이 치료 가능성에 대한 근거를 보여주었다. 본 연구를 통해 전자약 접근 방식이 탈수초성 CMT 질환에 대한 치료 가능성을 제시하였다.
이후의 연구에서 대표적인 CMT 질환 동물 모델인 Tr-J 쥐를 사용하여 탈수초성 CMT 질환에 대한 전자약의 치료 효능을 깊이 연구하였다. In vitro 공배양모델을 통해 말초신경계의 수초화를 개선하는 최적 전기자극 조건(주파수)을 확인하였으며, 이후 ex vivo 모델을 통해 이를 검증하였다. 이후 좌골신경에 전극을 삽입하여 일주일에 한 번씩 총 3 주간 말초신경에 전기자극을 인가하였으며, 이로 인해 수초화가 유의미하게 개선됨을 확인하였다. 또한 최적의 전기자극 조건을 인가하였을 때 Tr-J 쥐에서 수초 막의 구조가 복구되었음을 나타내는 수초막의 PMP22 및 콜레스테롤 분포의 개선 등 질병과 관련된 생물분자학적 이상이 개선되었음을 확인하였다. 또한, 3주간의 전기자극 기간 동안 쥐의 행동양상이 점진적으로 개선되었다. 말초신경계의 수초화, 생물분자학적 특성 및 행동양상에 대한 분석을 통해 전기자극이 Tr-J 쥐의 질환과 관련된 형질을 건강한 상태로 개선시키는 것을 확인하였다. 따라서, 이번 연구에서는 대표적인 동물 모델을 통해 탈수초성 CMT 질환에 대한 전자약의 치료 효능을 입증하였다.
본 논문에서 진행된 순차적인 연구들은 전자약을 통해 탈수초성 CMT 질환을 치료할 수 있는 가능성을 일관성 있게 보여주는 중요한 연구 결과들을 제공하였다. 본 연구는 기존의 생화학적 방식의 치료에서 벗어나, 신경계의 신호 전달을 잘 모방할 수 있는 전자약과 같은 생물물리학적 접근(치료) 방식을 제시함으로써 새로운 치료 패러다임을 제시하고 있다. 본 논문의 결과는 CMT 질환으로 고통받는 수백만 환자들에게 희망을 제공하며, 앞으로 탈수초성 CMT 질환을 치료하기 위한 전자약 기반 치료법의 초석을 제공한 연구라 사료된다.
|The myelin sheath is crucial for neuronal signal propagation. Therefore, the loss of myelin from the peripheral nervous system (PNS) can lead to peripheral demyelinating neuropathies. One such example is Charcot-Marie-Tooth (CMT) disease, which is the most commonly inherited peripheral neuropathy, affecting nearly three million people worldwide, and currently lacking any approved treatment. Although several biochemical approaches have been attempted, none have successfully passed clinical trials, either due to insufficient efficacy or potential systemic side effects. Therefore, it is imperative to explore an alternative biophysical approach, such as electroceuticals.
The communication language of the nervous system closely resembles electric signals, suggesting the possibility that electroceuticals can be biomimetic interventions for neuropathies. Accordingly, electroceuticals have been routinely utilized for various central nervous system neuropathies such as Parkinson’s disease and epilepsy. In contrast, the application of electroceuticals in the PNS has been limited. Although electroceuticals have shown promising efficacy towards acquired peripheral neuropathies, their potential to treat inherited peripheral neuropathies, such as CMT disease, has yet to be investigated. This dissertation introduces a novel electroceutical intervention for demyelinating CMT disease. This dissertation was carried out in three different studies, each resulting in a key milestone.
The first study explored the possibility of enhancing myelination in the PNS via electrical stimulation (ES). This was done by investigating how different ES frequencies affect myelination in the wild-type (WT) mouse, using the dorsal root ganglion (DRG) explant, an ex vivo PNS model. ES at 20 Hz for 1 hr significantly enhanced the myelination in the DRG explant, driven by upregulation in the lipid biosynthesis pathway, which is essential for the myelination process. Furthermore, the ES condition also led to higher abundance of myelin membrane lipids. These findings are consequential, since the myelin membrane is highly enriched in lipids, which play several structural and regulatory roles during myelination. This study suggested that ES has the ability to enhance myelination in the PNS.
In the second study, in order to identify the therapeutic possibility towards CMT disease, the effects of electroceuticals were investigated using a cellular in vitro disease model composed of engineered Schwann cells (SCs), which are the myelin-forming cells of the PNS. One of the key biomolecular abnormalities of demyelinating CMT disease is the intracellular aggregation of peripheral myelin protein 22 (PMP22). ES led to significant amelioration of this phenomenon, by reducing PMP22 aggregation in the perinuclear region, as well as increasing its distribution in the cell membrane. Furthermore, ES induced upregulation in the expression of genes encoding important myelin proteins, as well as myelination regulating pathways, inducing pro-myelinating effects in the disease model SCs. This study showed the therapeutic possibility of electroceuticals towards demyelinating CMT disease and encouraged further comprehensive investigation.
Subsequently, the third and final study involved a comprehensive investigation of electroceuticals using a representative animal model of demyelinating CMT disease, the Trembler-J (Tr-J) mouse. The therapeutic effects of electroceuticals were assessed on the changes in myelination at the in vitro, ex vivo and in vivo stages, as well as key biomolecular abnormalities and behavioral phenotypes of the Tr-J mice. ES at 20 Hz for 1 hr significantly improved the myelination in the Tr-J mouse, at the in vitro, ex vivo and in vivo stages. ES also ameliorated key biomolecular abnormalities associated with demyelinating CMT disease and restored the myelin membrane integrity by improving the distribution of myelin membrane lipids. Furthermore, in vivo ES made gradual improvements in the behavioral phenotype of the Tr-J mice across a three-week period. The results from this comprehensive study suggested that electroceuticals can ameliorate demyelinating CMT disease phenotypes in a representative animal model.
Overall, this dissertation introduces the therapeutic potential of electroceuticals towards CMT disease via step-by-step investigations, utilizing a WT ex vivo PNS model, a cell-engineered in vitro disease model, and a representative animal model. Furthermore, the therapeutic effects of electroceuticals were assessed based on comprehensive investigations of the changes in myelination, biomolecular pathways, as well as behavioral phenotypes (for the in vivo study). The three studies of this dissertation suggested the novel possibility of an electroceutical treatment for CMT disease. It is expected that further elucidation of the mechanistic pathways, as well as the development of non-invasive neuromodulation interfaces will facilitate the clinical translation of electroceuticals to treat human CMT patients. This dissertation lays the groundwork for a future bioelectronic medicine for this intractable neuropathy from which millions of people are suffering worldwide.I. Introduction 1
1.1 Importance of the myelin sheath and SCs 2
1.2 Charcot-Marie-Tooth disease 5
1.3 Conventional treatment approaches 5
1.4 Electroceuticals in the treatment of neuropathies 7
1.5 Research objectives and chapter outlines 8
II. Electrical stimulation enhances myelination in the wild-type mouse peripheral nervous system 12
2.1 Introduction 13
2.2 Experimental section 15
2.2.1 Materials 15
2.2.2 DRG culture 15
2.2.3 ES device 17
2.2.4 ES of DRGs 17
2.2.5 Immunocytochemistry 19
2.2.6 RNA sequencing 19
2.2.7 Real-time PCR (or qPCR) 20
2.2.8 Citrate and carnitine assays 20
2.2.9 ToF-SIMS imaging 22
2.2.10 Statistical analyses 22
2.3 Results and discussion 22
2.3.1 ES enhances DRG myelination 22
2.3.2 ES upregulates lipid biosynthesis in the DRG 29
2.3.3 ES increases lipid abundance in the myelin membrane 36
2.4 Conclusion 40
III. Evaluation of electroceuticals using cell-engineered in vitro CMT disease model 41
3.1 Introduction 42
3.2 Experimental section 44
3.2.1 Materials 44
3.2.2 Generation and culture of PMP22-overexpressed Schwannoma cells 44
3.2.3 ES apparatus 45
3.2.4 Simulation of the electric field 45
3.2.5 Immunocytochemistry 45
3.2.6 Real-time PCR (or qPCR) 47
3.2.7 Cell death assay 47
3.2.8 Western blot 47
3.2.9 Statistical analyses 47
3.3 Results and discussion 49
3.3.1 Validation of PMP22-overexpressed Schwannoma cells 49
3.3.2 The HTS device and in vitro ES 51
3.3.3 ES ameliorates PMP22 localization abnormality 53
3.3.4 ES induces pro-myelinating effects 58
3.4 Conclusion 61
IV. Evaluation of electroceuticals using an animal model of CMT disease 62
4.1 Introduction 63
4.2 Experimental section 66
4.2.1 Materials 66
4.2.2 Animal usage and ethics approval 66
4.2.3 Preparation of Matrigel-coated coverslips 67
4.2.4 Neuron-SC in vitro coculture 67
4.2.5 DRG ex vivo explant culture 70
4.2.6 In vitro and ex vivo ES 72
4.2.7 In vivo ES 72
4.2.8 Behavioral test 74
4.2.9 Immunostaining and imaging 74
4.2.10 ToF-SIMS imaging 74
4.2.11 Real-time PCR (or qPCR) 75
4.2.12 TEM imaging 75
4.2.13 Statistical analyses 77
4.3 Results and discussion 77
4.3.1 Optimal ES condition improves myelination in in vitro coculture 77
4.3.2 Validation of myelination improvement in ex vivo explant culture 81
4.3.3 Amelioration of biomolecular distribution abnormality 85
4.3.4 Upregulation of genes involved in cholesterol biosynthesis 89
4.3.5 Restoration of myelin membrane integrity 91
4.3.6 Gradual rehabilitation in behavioral phenotypes 94
4.3.7 Improvement in PNS myelination in vivo 96
4.4 Conclusion 102
V. Summary and outlook 103
5.1 Summary 104
5.2 Future perspective and challenges 106
Summary in Korean 108
References 110DoctordCollectio
An electroceutical approach enhances myelination via upregulation of lipid biosynthesis in the dorsal root ganglion
No full textAs the myelin sheath is crucial for neuronal saltatory conduction, loss of myelin in the peripheral nervous system (PNS) leads to demyelinating neuropathies causing muscular atrophy, numbness, foot deformities and paralysis. Unfortunately, few interventions are available for such neuropathies, because previous pharmaceuticals have shown severe side effects and failed in clinical trials. Therefore, exploring new strategies to enhance PNS myelination is critical to provide solution for such intractable diseases. This study aimed to investigate the effectiveness of electrical stimulation (ES) to enhance myelination in the mouse dorsal root ganglion (DRG) - an ex vivo model of the PNS. Mouse embryonic DRGs were extracted at E13 and seeded onto Matrigel-coated surfaces. After sufficient growth and differentiation, screening was carried out by applying ES in the 1-100 Hz range at the beginning of the myelination process. DRG myelination was evaluated via immunostaining at the intermediate (19 days in vitro (DIV)) and mature (30 DIV) stages. Further biochemical analyses were carried out by utilizing ribonucleic acid sequencing, quantitative polymerase chain reaction and biochemical assays at both intermediate and mature myelination stages. Imaging of DRG myelin lipids was carried out via time-of-flight secondary ion mass spectrometry (ToF-SIMS). With screening ES conditions, optimal condition was identified at 20 Hz, which enhanced the percentage of myelinated neurons and average myelin length not only at intermediate (129% and 61%) but also at mature (72% and 17%) myelination stages. Further biochemical analyses elucidated that ES promoted lipid biosynthesis in the DRG. ToF-SIMS imaging showed higher abundance of the structural lipids, cholesterol and sphingomyelin, in the myelin membrane. Therefore, promotion of lipid biosynthesis and higher abundance of myelin lipids led to ES-mediated myelination enhancement. Given that myelin lipid deficiency is culpable for most demyelinating PNS neuropathies, the results might pave a new way to treat such diseases via electroceuticals. © 2022 The Author(s). Published by IOP Publishing Ltd.1
Seroprevalence of HBsAg among adolescents and adults in the Muhayil Aseer region of KSA: 25 years after the introduction of national vaccination
No full textAbstractObjectiveThe objective of this work was to investigate the seroprevalence and associated risk factors of HBsAg among adolescents and adults in the Muhayil Aseer region of KSA.MethodsA cross-sectional study was conducted on a selected sample of adolescents and adults in the Muhayil Aseer region of KSA. A comprehensive questionnaire-based interview was performed for all participants, blood samples were taken, and sera were tested for HBsAg.ResultsThe study included 133 adolescents and 938 adults. A seroprevalence of 1.5% and 6.1% were recorded among adolescents and adults, respectively. The study showed that persons without the hepatitis B vaccination carried a significantly higher risk for developing sero-positivity for HBsAg.ConclusionThe present study further endorsed the effectiveness of vaccination in preventing hepatitis B virus (HBV) infection. Strict preventive measures against HBV infection need to be fostered in the study area
The prospect of electroceutical intervention and its implementation toward intractable neuromuscular diseases
No full textThe treatment of intractable neuromuscular diseases (INMDs) via biochemical interventions has remained challenging. Treatments using electrical stimulation (ES), or electroceuticals, can potentially shift the paradigm in the treatment of INMDs, since (1) their localized nature minimizes the risks for systemic side effects and (2) they conform with the innate neuromuscular communication. In addition, the recent developments in electrical interfaces for the neuromuscular system can advance the possibility of the clinical adoption of electroceuticals. In this review, we first introduce the studies that have explored the potential of ES in the treatment or management of INMDs. We then highlight the recent advancements in interfaces to deliver ES to the neuromuscular system, focusing on their miniaturization, flexibility, and non-invasive implantation. This review sheds light on the therapeutic benefits and implementation of electroceuticals toward INMDs and will hopefully encourage further in-depth research that can transform their treatment landscape. © 2024 Elsevier Inc.FALSEsciescopu
A GIS-based analysis of the incidence and prevalence of type 2 diabetes in Saudi Arabia
No full textThis research investigates type 2 diabet type 2 diabeteses (T2D) and its risk factors, analyzes its prevalence and progression and identifies which risk factors affect different regions of Saudi Arabia by utilizing the 2013 Saudi Health Interview Survey.
Our findings showed a high prevalence of T2D in Saudi Arabia (11.5%), with the highest in Hail and Aseer at 16.9% and 15.3%, respectively. On the other hand, Eastern had the lowest at 7.9%.
Overall, we found that age and BMI were the most effective predictors. Age was the most effective, impacting all thirteen regions. The group aged 65 years and older had the highest risk; the 45- to 64-year-old age group, however, had the highest number of diagnoses. Al-Madinah had the highest prevalence of T2D in this age group at 56.9%. The 15- to 44-year-old group had the highest risk in Aseer at 4.8%. In Northern Borders, the odds ratio was the highest for the 65 plus age group, at 59.15. BMI was an effective predictor of T2D in nine regions. In Eastern, the odds ratio for the obese group was 4.3 compared to people of normal weight. In Al-Jouf, obese women had the highest percentage of T2D at 44.44% of cases.
Work status was an important risk factor in Tabuk, Eastern, Al-Jouf, and Aseer. The retired group had the highest prevalence in these regions, except for Aseer where the employed group had the highest risk; retired people in Aseer are still involved in farm work, which may contribute to fewer T2D cases. Smoking status was an effective predictor in Hail, Al-Qassim, Riyadh, and Makkah. Ex-smokers had the highest incidence of T2D. Marital status was an effective predictor for Hail, Al-Qassim, and Riyadh. The divorced group had the highest prevalence of T2D. Education was an effective predictor for Riyadh and Aseer; the illiterate group had the highest risk. Diet was a good predictor only in Aseer. Shisha and hookah use were effective predictors in Riyadh.
Understanding this data can help lower the prevalence of diabetes, provide better diabetes care, and lower healthcare costs for the Ministry of Health.Ph.D.Includes bibliographical referencesby Mamdooh A. Alonaz
Release kinetic profiles and cytotoxicity test of a PDMS-based balloon-type implantable drug delivery device based on PDMS mixing ratios
No full textVarious drug delivery implants have been developed to allow targeted and localized drug delivery by improving the drug bioavailability[1]. However, initial burst, onset time, membrane rupture, conformal contact with tissue, tissue damage and foreign body responses are still the limitations of the existing drug delivery implants. Previously, we proposed and successfully fabricated a soft and flexible polydimethylsiloxane (PDMS)-based balloon-type implantable drug delivery device for a long-term controlled release to minimize the initial burst, onset time, risk of membrane rupture, tissue damage, and better conformal contact with biological tissues [2]. In addition, based on the PDMS membrane thickness the release kinetics profile was successfully demonstrated as the PDMS membrane thickness decreased, the release rate was substantially increased. In this study, we further investigated the release kinetic profile based on the mixing ratio of PDMS and analyzed the in-vitro cytotoxicity of the developed drug delivery device
Comparative study of hearing level pre and post ossiculoplasty in Aseer Central Hospital, Saudi Arabia
No full text<p class="abstract"><strong>Background:</strong> <span lang="EN-IN">Achieving successful hearing outcomes following ossiculoplasty in patients with middle ear diseases depend on several factors. Unfortunately, the literature is confusing concerning the middle ear factors and types of pathologic process that are most important in predicting hearing outcome. The objective of the study was to investigate the improvement or deterioration of hearing after ossiculoplasty and identify the possible prognostic factors.</span></p><p class="abstract"><strong>Methods:</strong> <span lang="EN-IN">Between January, 2012 and December, 2014, 30 ossiculoplasties were performed and followed up by the first author with the help of other authors in Otolaryngology department, Aseer Ceneral hospital, Abha, Kingdom of Saudi Arabia. The patients were followed up at 6 months, 9 months after the operation and then on a yearly basis. Postoperative hearing outcomes were considered successful if the postoperative air-bone gap was within 20 dB while it was considered not successful if it exceeds 20 dB. </span></p><p class="abstract"><strong>Results:</strong> <span lang="EN-IN">The study included 30patients. Their age ranged between 18 and 61 years with a mean of 37.4±10.7 years. Sixty percent of them (n=18) were females and forty percent (n=12) were males. Pre-operative PTA was 37.83±8.97 dB and it decreased to 23.0±12.57 dB postoperatively. This difference was statistically significant (p&lt;0.001) with an average change in ABG of 150 dB across the 30 patients. The successful rate was 50%. the only factor proved to be significantly associated with successful ossiculoplasty was the male gender as 75% of makes compared to 33.3% of females patients reported postoperative air-bone gap within 20 dB, p=0.030. </span></p><p class="abstract"><strong>Conclusions:</strong> <span lang="EN-IN">Successful rate of ossiculoplasty in Asser central hospital is within the globally reported rates. However, further larger prospective study is recommended for better understanding of predictive factors for hearing improvement after ossiculoplasty that may contribute to the surgeon’s judgment and the information given to patients.</span></p></jats:p
An Ultrasoft and Flexible PDMS-Based Balloon-Type Implantable Device for Controlled Drug Delivery
No full textNon-biodegradable implants have undergone extensive investigation as drug delivery devices to enable advanced healthcare toward personalized medicine. However, fibroblast encapsulation is one of the major challenges in all non-biodegradable implants, besides other challenges such as high initial burst, risk of membrane rupture, high onset time, non-conformal contact with tissues, and tissue damage. To tackle such challenges, we propose a novel ultrasoft and flexible balloon-type drug delivery device for unidirectional and long-term controlled release. The ultrasoft balloon-type device (USBD) was fabricated by using selective bonding between 2 polydimethylsiloxane (PDMS) membranes and injecting a fluid into the non-bonded area between them. The balloon acted as a reservoir containing a liquid drug, and at the same time, the membrane of the balloon itself acted as the pathway for release based on diffusion. The release was modulated by tuning the thickness and composition of the PDMS membrane. Regardless of the thickness and composition, all devices exhibited zero-order release behavior. The longest zero-order release and nearly zero-order release were achieved for 30 days and 58 days at a release rate of 1.16 mu g/ day and 1.68 mu g/day, respectively. In vivo evaluation was performed for 35 days in living rats, where the USBD maintained zero-order and nearly zero-order release for 28 days and 35 days, respectively. Thanks to the employment of ultrasoft and flexible membranes and device design, the USBD could achieve minimal tissue damage and foreign body responses. It is expected that the proposed device may provide a novel approach for long-term drug delivery with new therapeutic modalities.© 2024 Tausif Muhammad et al.TRUEsciescopuskc
Electroceutical approach ameliorates intracellular PMP22 aggregation and promotes pro-myelinating pathways in a CMT1A in vitro model
No full textCharcot-Marie-Tooth disease subtype 1A (CMT1A) is one of the most prevalent demyelinating peripheral neuropathies worldwide, caused by duplication of the peripheral myelin protein 22 (PMP22) gene, which is expressed primarily in Schwann cells (SCs). PMP22 overexpression in SCs leads to intracellular aggregation of the protein, which eventually results in demyelination. Unfortunately, previous biochemical approaches have not resulted in an approved treatment for CMT1A disease, compelling the pursuit for a biophysical approach such as electrical stimulation (ES). However, the effects of ES on CMT1A SCs have remained unexplored. In this study, we established PMP22-overexpressed Schwannoma cells as a CMT1A in vitro model, and investigated the biomolecular changes upon applying ES via a custom-made high-throughput ES platform, screening for the condition that delivers optimal therapeutic effects. While PMP22-overexpressed Schwannoma exhibited intracellular PMP22 aggregation, ES at 20 Hz for 1 h improved this phenomenon, bringing PMP22 distribution closer to healthy condition. ES at this condition also enhanced the expression of the genes encoding myelin basic protein (MBP) and myelin-associated glycoprotein (MAG), which are essential for assembling myelin sheath. Furthermore, ES altered the gene expression for myelination-regulating transcription factors Krox-20, Oct-6, c-Jun and Sox10, inducing pro-myelinating effects in PMP22-overexpressed Schwannoma. While electroceuticals has previously been applied in the peripheral nervous system towards acquired peripheral neuropathies such as pain and nerve injury, this study demonstrates its effectiveness towards ameliorating biomolecular abnormalities in an in vitro model of CMT1A, an inherited peripheral neuropathy. These findings will facilitate the clinical translation of an electroceutical treatment for CMT1A. © 2023 Elsevier B.V.FALS
