Precision medicine focus on the central nervous system: Non-invasive therapeutic agent delivery with focused ultrasound and microbubbles.

Focused ultrasound (FUS) combined with microbubble (MB) treatment is a promising strategy capable of accurately delivering molecular medicines and gene therapy to treat various disease states. The rapid progression and use of FUS technology, from its inception to applications in contemporary medicine, exemplifies the significance and expanding potential of this technology. FUS for drug delivery in the brain can overcome challenging obstacles posed by the blood-brain barrier (BBB) in treating central nervous system (CNS) disorders. Both FUS and magnetic resonance imaging-guided FUS are non-invasive techniques for effectively opening the BBB and enhancing the transportation of molecular medicines and imaging agents into the brain. By integrating MBs into this process, it is possible to disrupt the BBB, facilitating delivery of therapeutic compounds including neuropeptides, proteins, antibodies, chemotherapeutic drugs and recently viruses accurately into the CNS. The safety and versatility of ultrasound makes it an attractive approach for administering molecular medicines, with potential applications extending beyond neurological disorders to include cancer treatment and other medical fields. Preclinical and clinical studies confirm that FUS is safe and efficient in enhancing drug administration, particularly where delivery to a precise location in the CNS is required. Combination therapies that utilize FUS and MBs also provide synergistic responses in cancer therapy. Further refining FUS and MB approaches both from a mechanical and reagent perspective will be forthcoming in the future and prove valuable in precisely defining targets and broadening therapeutic applications. Continued development and applications of FUS and MB technologies will improve therapeutic outcomes and advance patient care in multiple diseases states. This will elevate FUS and MBs from infrequently used medical options to mainstream medical applications.

Gastrodin, a Promising Natural Small Molecule for the Treatment of Central Nervous System Disorders, and Its Recent Progress in Synthesis, Pharmacology and Pharmacokinetics.

Gastrodia elata Blume is a traditional medicinal and food homology substance that has been used for thousands of years, is mainly distributed in China and other Asian countries, and has always been distinguished as a superior class of herbs. Gastrodin is the main active ingredient of G. elata Blume and has attracted increasing attention because of its extensive pharmacological activities. In addition to extraction and isolation from the original plant, gastrodin can also be obtained via chemical synthesis and biosynthesis. Gastrodin has significant pharmacological effects on the central nervous system, such as sedation and improvement of sleep. It can also improve epilepsy, neurodegenerative diseases, emotional disorders and cognitive impairment to a certain extent. Gastrodin is rapidly absorbed and widely distributed in the body and can also penetrate the blood-brain barrier. In brief, gastrodin is a promising natural small molecule with significant potential in the treatment of brain diseases. In this review, we summarised studies on the synthesis, pharmacological effects and pharmacokinetic characteristics of gastrodin, with emphasis on its effects on central nervous system disorders and the possible mechanisms, in order to find potential therapeutic applications and provide favourable information for the research and development of gastodin.

Lactylation: A Novel Post-Translational Modification with Clinical Implications in CNS Diseases.

Lactate, an important metabolic product, provides energy to neural cells during energy depletion or high demand and acts as a signaling molecule in the central nervous system. Recent studies revealed that lactate-mediated protein lactylation regulates gene transcription and influences cell fate, metabolic processes, inflammation, and immune responses. This review comprehensively examines the regulatory roles and mechanisms of lactylation in neurodevelopment, neuropsychiatric disorders, brain tumors, and cerebrovascular diseases. This analysis indicates that lactylation has multifaceted effects on central nervous system function and pathology, particularly in hypoxia-induced brain damage. Highlighting its potential as a novel therapeutic target, lactylation may play a significant role in treating neurological diseases. By summarizing current findings, this review aims to provide insights and guide future research and clinical strategies for central nervous system disorders.

Emerging Role of Extracellular Vesicles as Biomarkers in Neurodegenerative Diseases and Their Clinical and Therapeutic Potential in Central Nervous System Pathologies.

The emerging role of extracellular vesicles (EVs) in central nervous system (CNS) diseases is gaining significant interest, particularly their applications as diagnostic biomarkers and therapeutic agents. EVs are involved in intercellular communication and are secreted by all cell types. They contain specific markers and a diverse cargo such as proteins, lipids, and nucleic acids, reflecting the physiological and pathological state of their originating cells. Their reduced immunogenicity and ability to cross the blood-brain barrier make them promising candidates for both biomarkers and therapeutic agents. In the context of CNS diseases, EVs have shown promise as biomarkers isolable from different body fluids, providing a non-invasive method for diagnosing CNS diseases and monitoring disease progression. This makes them useful for the early detection and monitoring of diseases such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis, where specific alterations in EVs content can be detected. Additionally, EVs derived from stem cells show potential in promoting tissue regeneration and repairing damaged tissues. An evaluation has been conducted on the current clinical trials studying EVs for CNS diseases, focusing on their application, treatment protocols, and obtained results. This review aims to explore the potential of EVs as diagnostic markers and therapeutic carriers for CNS diseases, highlighting their significant advantages and ongoing clinical trials evaluating their efficacy.

Mimickers of nervous system involvement among patients with Behçet's syndrome.

OBJECTIVES: We aimed to identify conditions mimicking nervous system involvement among patients with Behçet's syndrome (BS) and to determine clinical, laboratory and imaging findings that may help in the differential diagnosis. METHODS: We screened the charts of 500 consecutive BS patients to identify those who were referred to neurology at any time during their follow-up. The final diagnoses, presenting signs and symptoms, laboratory and imaging results were retrieved from patient charts. Patients who did not have a follow-up visit during the last 3 months were invited to the clinic. RESULTS: Among the 500 BS patients, 116 (23%) had been referred to neurology. Among these, 29 (5.8%) were diagnosed with typical central nervous system involvement of BS (NeuroBS). The type of NeuroBS was parenchymal involvement in 21 patients, cerebral venous sinus thrombosis in 7 patients, and both in 1 patient. 30 patients (6%) had other conditions related to the nervous system, 46 (9.2%) did not have a nervous system disorder, and their symptoms recovered spontaneously, and 11 (2.2%) were lost to follow-up without a definite diagnosis. Of the 30 BS patients who were diagnosed with another nervous system condition, 14 (46%) had primary headache syndromes, 6 (20%) had psychiatric disorders, 2 had entrapment neuropathy, and 1 each had epilepsy, glial tumor, multiple sclerosis, Meniere's disease, optic neuritis, neuroretinitis, steroid myopathy and polyneuropathy. CONCLUSION: Nervous system conditions other than NeuroBS are frequent among BS patients referred to neurology. Caution is required to avoid misdiagnosis of these patients as NeuroBS.

Emerging roles of cannabinoid receptor CB2 receptor in the central nervous system: therapeutic target for CNS disorders.

RATIONALE: The endocannabinoid system (ECS) belongs to the G protein-coupled receptor family of cell membranes and is associated with neuropsychiatric conditions, and neurodegenerative diseases. Cannabinoid 2 receptors (CB2) are expressed in the central nervous system (CNS) on microglia and subgroups of neurons and are involved in various behavioural processes via immunological and neural regulation. OBJECTIVE: The objective of this paper is to summarize and explore the impact of CB2 receptors on neuronal modulation, their involvement in various neurological disorders, and their influence on mood, behavior, and cognitive function. RESULTS: The activation of CB2 appears to protect the brain and its functions from damage under neuroinflammatory actions, making it an attractive target in a variety of neurological conditions such as Parkinson's disease (PD), multiple sclerosis (MS), Alzheimer's disease (AD), and Huntington's disease (HD). During inflammation, there is an overexpression of CB2 receptors, and CB2 agonists show a strong anti-inflammatory effect. These results have sparked interest in the CB2 receptors as a potential target for neurodegenerative and neuroinflammatory disease treatment. CONCLUSION: In conclusion, CB2 receptors signalling shows promise for developing targeted interventions that could positively affect both immune and neuronal functions, ultimately influencing behavioral outcomes in both health and disease.

Therapeutic indications for HDAC6 inhibitors in the peripheral and central nervous disorders.

INTRODUCTION: Inhibition of the enzymatic function of HDAC6 is currently being explored in clinical trials ranging from peripheral neuropathies to cancers. Advances in selective HDAC6 inhibitor discovery allowed studying highly efficacious brain penetrant and peripheral restrictive compounds for treating PNS and CNS indications. AREAS COVERED: This review explores the multifactorial role of HDAC6 in cells, the common pathological hallmarks of PNS and CNS disorders, and how HDAC6 modulates these mechanisms. Pharmacological inhibition of HDAC6 and genetic knockout/knockdown studies as a therapeutic strategy in PNS and CNS indications were analyzed. Furthermore, we describe the recent developments in HDAC6 PET tracers and their utility in CNS indications. Finally, we explore the advancements and challenges with HDAC6 inhibitor compounds, such as hydroxamic acid, fluoromethyl oxadiazoles, HDAC6 degraders, and thiol-based inhibitors. EXPERT OPINION: Based on extensive preclinical evidence, pharmacological inhibition of HDAC6 is a promising approach for treating both PNS and CNS disorders, given its involvement in neurodegeneration and aging-related cellular processes. Despite the progress in the development of selective HDAC6 inhibitors, safety concerns remain regarding their chronic administration in PNS and CNS indications, and the development of novel compound classes and modalities inhibiting HDAC6 function offer a way to mitigate some of these safety concerns.

Pearls & Oy-sters: Vocal Cord Palsy as the Presenting Manifestation of Neurosarcoidosis.

Neurosarcoidosis poses a significant diagnostic challenge due to the diversity of presenting symptoms. We report a case of a 64-year-old woman with a history of hypertension and diabetes who presented with 3 weeks of progressive dysphonia and dysphagia. Initial differential diagnosis included myasthenia gravis, Guillain-Barré syndrome, infections such as syphilis or HIV, and neurosarcoidosis. Laryngoscopy and EMG demonstrated cranial nerve X and XII palsy. MRI brain was unrevealing, but a CT of the head and neck showed radiologic evidence of left vocal cord paralysis and asymmetric prominence of the left lingual tonsillar tissue. Her clinical findings, elevated CSF-ACE (angiotensin-converting enzyme) and CSF sIL-2R (soluble interleukin-2 receptor), and a previous thoracic tissue biopsy showing granulomas led to a 'probable' diagnosis of neurosarcoidosis after the thorough exclusion of other diagnoses. The patient was treated with pulse steroids and outpatient initiation of infliximab. There was prompt improvement in dysphagia and gradual amelioration of dysarthria and dysphonia. This case illustrates cranial nerve X and XII palsy as the presentation of neurosarcoidosis. In addition, it demonstrates the value of CSF sIL-2R as a biomarker for neurosarcoidosis and highlights the growing popularity of using steroid-sparing agents for treatment to achieve better outcomes with fewer side effects.

Neurosarcoidosis: Clinical, biological, and MRI presentation of central nervous system disease in a national multicenter cohort.

INTRODUCTION: Neurosarcoidosis (NS) is a systemic inflammatory granulomatous disease affecting of patients with sarcoidosis. Its diagnosis is difficult as there is no specific test for it. Because of its rarity, the management of NS has so far only been described in case series and short retrospective cohorts. The objective of this study is description of the clinical, paraclinical presentation and the therapeutic management of central nervous system (CNS) involvement in NS patients in France. METHODS: This multicenter, retrospective, observational study involved patients hospitalized between 2010 and 2019 with a diagnosis of sarcoidosis and CNS involvement. RESULTS: We included 118 patients (38 with isolated NS, 80 with NS associated with systemic sarcoidosis). NS was the initial presentation in 78% of patients, with cranial nerve involvement (36%), medullary symptoms (23%), and seizures (21%). Twenty-one percent of the patients had already been diagnosed with systemic sarcoidosis. The most frequent biological abnormality was lymphopenia (62.5%), while angiotensin-converting enzyme was increased in 21%. Meningitis was present in 45% and hyperproteinorachia in 69.5% of cases. MRI mainly revealed white matter abnormalities and leptomeningeal enhancement (34%). Corticosteroids were the most useful treatment, and immunosuppressive agents were used in steroid-resistant patients and to limit side effects. Methotrexate, cyclophosphamide, and anti-TNFα were also used, exhibiting good efficacy. CONCLUSIONS: This cohort contributes to a better understanding of the clinical phenotype and associated imaging and biological abnormalities. Sharing of clinical, biological, and imaging data, as well as the therapeutic responses, of patients with NS helps to better understand and manage this disease that affects a small number of patients per center. A database project could be implemented in the future to enable this.

[Research progress in osthole for prevention and treatment of central nervous system diseases].

Central nervous system(CNS) disorders can significantly impact patients' daily lives, impairing their ability to work and imposing a substantial financial burden on their families. In recent years, the incidence of CNS diseases has shown a significant increase with the continuous improvement of the quality of life and the aging problem. Therefore, the search for new preventive and curative drugs has been a research hotspot for this group of diseases. Osthole(OST), isolated from Umbelliferae such as Cnidium monnieri, Angelica sinensis, and Heracleum hemsleyanum, possesses a variety of pharmacological effects such as neuroprotective, antioxidant, anti-inflammatory, and antithrombotic effects. There is increasing evidence that OST has demonstrated significant preventive and curative effects in various CNS disease models. This paper systematically reviewed the research progress of OST in preventing and treating CNS diseases by reviewing domestic and international literature to provide more in-depth theoretical support for the future clinical application of OST in the prevention and treatment of CNS diseases.

History of cellular grafting for central nervous system repair-A clinical perspective.

As late as in the 1970s, the evidence supporting that brain function might be restored by replacing dead cells by transplantation of new healthy cells was scarce in experimental animals and lacking in humans. Repairing the human brain was regarded as completely unrealistic by clinicians. Fifty years later, the situation is very different, and cellular grafting has reached patient application in several conditions affecting the CNS. The clinical studies performed so far have shown that cellular grafts can survive, grow, and function also in the diseased adult human brain. However, no proven treatment based on cell transplantation is currently available for any brain disorder. Here, the history of cellular grafting is described from a clinical perspective, including some of the preclinical work that has formed the basis for its translation to patient application. The focus is on cell transplantation for Parkinson disease, which in many ways is paving the way for this field of research. The chapter gives an account of the scientific milestones, the ups and downs, as well as the positive and negative reactions from the scientific and clinical community, and how this research field despite many obstacles has continued to move forward over more than four decades.

Viral vectors for gene delivery to the central nervous system.

Brain diseases with a known or suspected genetic basis represent an important frontier for advanced therapeutics. The central nervous system (CNS) is an intricate network in which diverse cell types with multiple functions communicate via complex signaling pathways, making therapeutic intervention in brain-related diseases challenging. Nevertheless, as more information on the molecular genetics of brain-related diseases becomes available, genetic intervention using gene therapeutic strategies should become more feasible. There remain, however, several significant hurdles to overcome that relate to (i) the development of appropriate gene vectors and (ii) methods to achieve local or broad vector delivery. Clearly, gene delivery tools must be engineered for distribution to the correct cell type in a specific brain region and to accomplish therapeutic transgene expression at an appropriate level and duration. They also must avoid all toxicity, including the induction of inflammatory responses. Over the last 40 years, various types of viral vectors have been developed as tools to introduce therapeutic genes into the brain, primarily targeting neurons. This review describes the most prominent vector systems currently approaching clinical application for CNS disorders and highlights both remaining challenges as well as improvements in vector designs that achieve greater safety, defined tropism, and therapeutic gene expression.

Neurosarcoidosis as a rapidly progressive dementia associated with normal pressure hydrocephalus.

Neurosarcoidosis (NS) is a rare subtype of sarcoidosis with a poor prognosis and diverse clinical presentations that often poses a diagnostic and therapeutic challenge. We describe the case of a 53-year-old male with an initial diagnosis of lingual sarcoidosis, who subsequently developed ataxia and rapidly progressive cognitive impairment. A lumbar puncture revealed hypoglycorrhachia, hyperproteinorrachia, lymphocytic pleocytosis, and elevated IL-6 levels (600 pg/ml). Cerebrospinal fluid flow cytometry showed an elevated CD4 lymphocyte concentration and a CD4+/CD8+ ratio of 3.91, indicative of NS. Brain MRI showed hyperintense periventricular and subcortical lesions on FLAIR/T2 resembling progressive multifocal leukoencephalopathy (PML), although negative PCR for JC virus ruled out the differential diagnosis. Following a favorable evolutionary course with corticosteroid pulses, the patient relapsed with normotensive hydrocephalus, treated with immunosuppressants and ventriculoperitoneal shunting with a good response to date. This case underscores the importance of maintaining a high index of suspicion for NS in individuals with sarcoidosis and neurologic symptoms. In these cases, cerebrospinal fluid biomarkers such as IL-6 and CD4+/CD8+ ratio are essential to guide the diagnosis. Furthermore, it highlights that hydrocephalus is a rare complication and requires a multidisciplinary approach, including medical and neurosurgical treatment.

La neurosarcoidosis es un subtipo raro de sarcoidosis con mal pronóstico y diversas presentaciones clínicas que a menudo plantea un reto diagnóstico y terapéutico. Describimos el caso de un varón de 53 años con diagnóstico inicial de sarcoidosis lingual, que posteriormente desarrolló ataxia y deterioro cognitivo de rápida evolución. Una punción lumbar reveló hipoglucorraquia, hiperproteinorraquia, pleocitosis linfocítica y niveles elevados de IL-6 (600 pg/ml). La citometría de flujo del líquido cefalorraquídeo mostró una concentración elevada de linfocitos CD4 y un cociente CD4+/CD8+ de 3.91, indicativo de neurosarcoidosis. La RM cerebral evidenció lesiones hiperintensas periventriculares y subcorticales en FLAIR/T2 que se asemejaban a una leucoencefalopatía multifocal progresiva (LMP), aunque la PCR negativa para el virus JC descartó el diagnóstico diferencial. Tras un curso evolutivo favorable con pulsos de corticoides, el paciente recayó con hidrocefalia normotensiva, tratada con inmunosupresores y derivación ventriculoperitoneal con buena respuesta hasta la fecha. Este caso subraya la importancia de mantener un alto índice de sospecha de neurosarcoidosis en individuos con sarcoidosis y síntomas neurológicos. En estos casos, los biomarcadores del líquido cefalorraquídeo tales como la IL-6 y el cociente CD4+/CD8+ son esenciales para orientar el diagnóstico. Además, destaca que la hidrocefalia es una complicación poco frecuente y requiere un abordaje multidisciplinario, que incluya tratamiento médico y neuroquirúrgico.

Advanced Noninvasive Strategies for the Brain Delivery of Therapeutic Proteins and Peptides.

Recent years have witnessed rapid progress in the discovery of therapeutic proteins and peptides for the treatment of central nervous system (CNS) diseases. However, their clinical applications have been considerably hindered by challenges such as low biomembrane permeability, poor stability, short circulation time, and the formidable blood-brain barrier (BBB). Recently, substantial improvements have been made in understanding the dynamics of the BBB and developing efficient approaches for delivering proteins and peptides to the CNS, especially by using various nanoparticles. Herein, we present an overview of the up-to-date understanding of the BBB under physiological and pathological conditions, emphasizing their effects on brain drug delivery. We summarize advanced strategies and elucidate the underlying mechanisms for delivering proteins and peptides to the brain. We highlight the developments and applications of nanocarriers in treating CNS diseases via BBB crossing. We also provide critical opinions on the limitations and obstacles of the current strategies and put forward prospects for future research.

Tailored Borneol-Modified Lipid Nanoparticles Nasal Spray for Enhanced Nose-to-Brain Delivery to Central Nervous System Diseases.

The nanodrug delivery system-based nasal spray (NDDS-NS) can bypass the blood-brain barrier and deliver drugs directly to the brain, offering unparalleled advantages in the treatment of central nervous system (CNS) diseases. However, the current design of NNDS-NS is excessively focused on mucosal absorption while neglecting the impact of nasal deposition on nose-to-brain drug delivery, resulting in an unsatisfactory nose-to-brain delivery efficiency. In this study, the effect of the dispersion medium viscosity on nasal drug deposition and nose-to-brain delivery in NDDS-NS was elucidated. The optimized formulation F5 (39.36 mPa·s) demonstrated significantly higher olfactory deposition fraction (ODF) of 23.58%, and a strong correlation between ODF and intracerebral drug delivery (R2 = 0.7755) was observed. Building upon this understanding, a borneol-modified lipid nanoparticle nasal spray (BLNP-NS) that combined both nasal deposition and mucosal absorption was designed for efficient nose-to-brain delivery. BLNP-NS exhibited an accelerated onset of action and enhanced brain targeting efficiency, which could be attributed to borneol modification facilitating the opening of tight junction channels. Furthermore, BLNP-NS showed superiority in a chronic migraine rat model. It not only provided rapid relief of migraine symptoms but also reversed neuroinflammation-induced hyperalgesia. The results revealed that borneol modification could induce the polarization of microglia, regulate the neuroinflammatory microenvironment, and repair the neuronal damage caused by neuroinflammation. This study highlights the impact of dispersion medium viscosity on the nose-to-brain delivery process of NDDS-NS and serves as a bridge between the formulation development and clinical transformation of NDDS-NS for the treatment of CNS diseases.

Inflammatory Role of CCR1 in the Central Nervous System.

BACKGROUND: Chemokine ligands and their corresponding receptors are essential for regulating inflammatory responses. Chemokine receptors can stimulate immune activation or inhibit/promote signaling pathways by binding to specific chemokine ligands. Among these receptors, CC chemokine receptor 1 (CCR1) is extensively studied as a G protein-linked receptor target, predominantly expressed in various leukocytes, and is considered a promising target for anti-inflammatory therapy. Furthermore, CCR1 is essential for monocyte extravasation and transportation in inflammatory conditions. Its involvement in inflammatory diseases of the central nervous system (CNS), including multiple sclerosis, Alzheimer's disease, and stroke, has been extensively studied along with its ligands. Animal models have demonstrated the beneficial effects resulting from inhibiting CCR1 or its ligands. SUMMARY: This review demonstrates the significance of CCR1 in CNS inflammatory diseases, the molecules implicated in the inflammatory pathway, and potential drugs or molecules for treating CNS diseases. This evidence may offer new targets or strategies for treating inflammatory CNS diseases.

Aseptic meningitis with recurrent headache episodes, vomiting, and central fever as first manifestation of isolated neurosarcoidosis: a case report.

BACKGROUND: Neurosarcoidosis is a rare entity, usually within the context of systematic sarcoidosis. Isolated neurosarcoidosis and especially a manifestation with pachymeningitis is a notable rarity. CASE REPORT: A 26-year-old patient presented to the emergency department with acute onset, recurrent episodes of occipital headaches spreading over the whole cranium and vomiting without food consumption, for three days. The clinical examination did not reveal any neurological deficits. The laboratory exams showed no pathological findings. A CT examination with angiography did not detect any acute intracranial or vessel pathology. A lumbar puncture was performed to rule out subarachnoid hemorrhage. The results showed a lymphocytic pleocytosis of 400/µL, elevated protein levels of 1077 mg/dL and reduced glucose levels (CSF: 55 mg/dL, Serum: 118 mg/dL). Extensive infectiological examinations did not reveal any signs of infection, including Borrelia spp. and M. tuberculosis. No positive auto-antibodies or vasculitis-related auto-antibodies were detected. The CSF analysis showed negative oligoclonal bands but an isolated increase in ß2-microglobulin, neopterin, and IL-2R levels. The MRI examination revealed a dural gadolinium-enhancement, pronounced in the basal cerebral structures and the upper segment of the cervical spine, consistent with neurosarcoidosis. Corticosteroid treatment rapidly led to a significant improvement of the symptoms. No systemic manifestations of sarcoidosis were found. CONCLUSIONS: This case report aims to highlight aseptic meningitis with atypical, acute onset headache attacks as a possible manifestation of isolated neurosarcoidosis. Neurosarcoidosis is a clinical entity that requires prompt treatment to avoid permanent neurological deficits.

Drug Repurposing for COVID-19 by Constructing a Comorbidity Network with Central Nervous System Disorders.

In the post-COVID-19 era, treatment options for potential SARS-CoV-2 outbreaks remain limited. An increased incidence of central nervous system (CNS) disorders has been observed in long-term COVID-19 patients. Understanding the shared molecular mechanisms between these conditions may provide new insights for developing effective therapies. This study developed an integrative drug-repurposing framework for COVID-19, leveraging comorbidity data with CNS disorders, network-based modular analysis, and dynamic perturbation analysis to identify potential drug targets and candidates against SARS-CoV-2. We constructed a comorbidity network based on the literature and data collection, including COVID-19-related proteins and genes associated with Alzheimer's disease, Parkinson's disease, multiple sclerosis, and autism spectrum disorder. Functional module detection and annotation identified a module primarily involved in protein synthesis as a key target module, utilizing connectivity map drug perturbation data. Through the construction of a weighted drug-target network and dynamic network-based drug-repurposing analysis, ubiquitin-carboxy-terminal hydrolase L1 emerged as a potential drug target. Molecular dynamics simulations suggested pregnenolone and BRD-K87426499 as two drug candidates for COVID-19. This study introduces a dynamic-perturbation-network-based drug-repurposing approach to identify COVID-19 drug targets and candidates by incorporating the comorbidity conditions of CNS disorders.