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Background: Assisted living (AL) is an increasingly common residential setting for persons with dementia; yet concerns exist about sub-optimal care of this population in AL given its lower levels of staffing and services. Our objectives were to (i) examine associations between AL setting (dementia care vs. other), COVID-19 pandemic waves, and prevalent antipsychotic, antidepressant, anti-dementia, benzodiazepine, and anticonvulsant drug use among residents with dementia/cognitive impairment, and (ii) explore associations between resident and home characteristics and prevalent medication use., Methods: We conducted a population-based, repeated cross-sectional study using linked clinical and health administrative databases for all publicly funded AL homes in Alberta, Canada, examined between January 2018 - December 2021. The quarterly proportion of residents dispensed a study medication was examined for each setting and period (pandemic vs. comparable historical [2018/2019 combined]) focusing on four pandemic waves (March-May 2020, September 2020-February 2021, March-May 2021, September-December 2021). Log-binomial GEE models estimated prevalence ratios (PR) for period (pandemic vs. historical periods), setting (dementia care vs. other) and period-setting interactions, adjusting for resident (age, sex) and home (COVID-19 cases, health region, ownership) characteristics., Results: On March 1, 2020, there were 2,779 dementia care and 3,013 other AL residents (mean age 83, 69% female) with dementia/cognitive impairment. Antipsychotic use increased during waves 2-4 in both settings, but this was more pronounced in dementia care than other AL during waves 3 and 4 (e.g., adjusted [adj]PR 1.20, 95% CI 1.14-1.27 vs. adjPR 1.09, 95% CI 1.02-1.17, interaction p = 0.023, wave 3). Both settings showed a statistically significant but modest increase in antidepressant use and decrease in benzodiazepine use. For dementia care AL residents only, there was a statistically significant increase in gabapentinoid use during several waves (e.g., adjPR 1.32, 95% CI 1.10-1.59, wave 3). Other than a modest decrease in prevalent anti-dementia drug use for both settings in wave 2, no other significant pandemic effects were observed., Conclusions: The persistence of the pandemic-associated increase in antipsychotic and antidepressant use in AL residents coupled with a greater increase in antipsychotic and gabapentinoid use for dementia care settings raises concerns about the attendant risks for residents with cognitive impairment., (© 2024. The Author(s).)

Background: People with multiple sclerosis (pwMS) are at risk of concurrently using multiple central nervous system (CNS)-active drugs, yet the prevalence of CNS-active polypharmacy remains unmeasured in pwMS., Objective: The objective is to measure the prevalence of CNS-active polypharmacy in pwMS., Methods: This serial, cross-sectional study measured CNS-active polypharmacy in people with MS in the United States from 2008 to 2021 using insurance claims data. CNS-active polypharmacy was defined as the concurrent prescription of ⩾3 CNS-active drugs for >30 continuous days. CNS-active drugs included antidepressants, antiepileptics, antipsychotics, benzodiazepines, nonbenzodiazepine benzodiazepine receptor agonist hypnotics, opioids, and skeletal muscle relaxants., Results: The number of subjects included at each time point ranged from 23,917 subjects in 2008 to 55,797 subjects in 2021. In 2021, subjects with CNS-active polypharmacy were more likely to be 46-65 years of age and have CNS-related comorbidities compared to those without CNS-active polypharmacy. From 2008 to 2021, the age-adjusted prevalence of CNS-active polypharmacy among female subjects increased from 19.8% (95% confidence interval (CI) = 19.1-20.4) to 26.4% (95% CI = 25.9-26.8) versus 15.9% (95% CI = 14.8-17.0) to 18.6% (95% CI = 17.9-19.2) in male subjects., Conclusion: The prevalence of CNS-active polypharmacy has increased among people with MS with a growing disparity by sex., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: H.N., J.W., T.M.K., and E.H. have nothing to disclose. L.F. has received fees for consultancy and/or advisory board participation from Hoffmann-La Roche, Genentech, Novartis, EMD Serono, Sanofi, and Horizon Therapeutics; has received honorarium for participation in educational programs from Medscape, Inc and the MS Association of America; has received speaking fees from Sanofi, EMD Serono, and the MS Association of America; and has received program sponsorship from EMD Serono and grant support from NIH/NINDS, PCORI, Genentech, and EMD Serono through her institution.

Background: Central nervous system (CNS) medications are linked to higher morbidity and mortality in older adults. Hospitalization allows for deprescribing opportunities. This qualitative study investigates clinician and patient perspectives on CNS medication deprescribing during hospitalization using a behavioral change framework, aiming to inform interventions and identify recommendations to enhance hospital deprescribing processes., Methods: This qualitative study focused on hospitalists, primary care providers, pharmacists, and patients aged ≥60 years hospitalized on a general medicine service and prescribed ≥1 CNS medications. Using semi-structured interviews and focus groups, we aimed to evaluate patient medication knowledge, prior deprescribing experiences, and decision-making preferences, as well as provider processes and tools for medication evaluation and deprescribing. Rapid qualitative analysis applying the Capability, Opportunity, Motivation, and Behavior (COM-B) framework revealed themes influencing deprescribing behavior in patients and providers., Results: A total of 52 participants (20 patients and 32 providers) identified facilitators and barriers across deprescribing steps and generated recommended strategies to address them. Clinicians and patients highlighted the opportunity for CNS medication deprescribing during hospitalizations, facilitated by multidisciplinary teams enhancing clinicians' capability to make medication changes. Both groups also stressed the importance of intensive patient engagement, education, and monitoring during hospitalizations, acknowledging challenges in timing and extent of deprescribing, with some patients preferring decisions deferred to outpatient clinicians. Hospitalist and pharmacist recommendations centered on early pharmacist involvement for medication reconciliation, expanding pharmacy consultation and clinician education on deprescribing, whereas patients recommended enhancing shared decision-making through patient education on medication adverse effects, tapering plans, and alternatives. Hospitalists and PCPs also emphasized standardized discharge instructions and transitional care calls to improve medication review and feedback during care transitions., Conclusions: Clinicians and patients highlighted the potential advantages of hospital interventions for CNS medication deprescribing, emphasizing the necessity of addressing communication, education, and coordination challenges between inpatient and outpatient settings., (© 2024 The American Geriatrics Society.)

Importance: High-risk medications that contribute to adverse health outcomes are frequently prescribed to older adults. Deprescribing interventions reduce their use, but studies are often not designed to examine effects on patient-relevant health outcomes., Objective: To test the effect of a health system-embedded deprescribing intervention targeting older adults and their primary care clinicians for reducing the use of central nervous system-active drugs and preventing medically treated falls., Design, Setting, and Participants: In this cluster randomized, parallel-group, clinical trial, 18 primary care practices from an integrated health care delivery system in Washington state were recruited from April 1, 2021, to June 16, 2022, to participate, along with their eligible patients. Randomization occurred at the clinic level. Patients were community-dwelling adults aged 60 years or older, prescribed at least 1 medication from any of 5 targeted medication classes (opioids, sedative-hypnotics, skeletal muscle relaxants, tricyclic antidepressants, and first-generation antihistamines) for at least 3 consecutive months., Intervention: Patient education and clinician decision support. Control arm participants received usual care., Main Outcomes and Measures: The primary outcome was medically treated falls. Secondary outcomes included medication discontinuation, sustained medication discontinuation, and dose reduction of any and each target medication. Serious adverse drug withdrawal events involving opioids or sedative-hypnotics were the main safety outcome. Analyses were conducted using intent-to-treat analysis., Results: Among 2367 patient participants (mean [SD] age, 70.6 [7.6] years; 1488 women [63%]), the adjusted cumulative incidence rate of a first medically treated fall at 18 months was 0.33 (95% CI, 0.29-0.37) in the intervention group and 0.30 (95% CI, 0.27-0.34) in the usual care group (estimated adjusted hazard ratio, 1.11 (95% CI, 0.94-1.31) (P = .11). There were significant differences favoring the intervention group in discontinuation, sustained discontinuation, and dose reduction of tricyclic antidepressants at 6 months (discontinuation adjusted rate: intervention group, 0.23 [95% CI, 0.18-0.28] vs usual care group, 0.13 [95% CI, 0.09-0.17]; adjusted relative risk, 1.79 [95% CI, 1.29-2.50]; P = .001) and secondary time points (9, 12, and 15 months)., Conclusions and Relevance: In this randomized clinical trial of a health system-embedded deprescribing intervention targeting community-dwelling older adults prescribed central nervous system-active medications and their primary care clinicians, the intervention was no more effective than usual care in reducing medically treated falls. For health systems that attend to deprescribing as part of routine clinical practice, additional interventions may confer modest benefits on prescribing without a measurable effect on clinical outcomes., Trial Registration: ClinicalTrials.gov Identifier: NCT05689554.

Objective: Evaluation of neonatal morbidity after maternal central neurotropic drug exposure., Methods: Retrospective single-center level-III neonatology cohort analysis of neonates after CND from 2018 to 2021. Control group of neonates born to mothers without CND cared for at the maternity ward., Results: Significantly more frequent therapy need of neonates with CND [OR 23 (95% CI: 7.8-62); RR 14 (95% CI: 5.4-37); p  < 0.01]. Neonates after CND had lower Apgar-scores LM 1 [CND 8.1; CG 8.6; p  < 0.05]; LM 5 [CND 9; CG 9.7; p  < 0.01]; LM 10 [CND 9.6; CG 9.9; p  < 0.05]. The first symptom occurred in 95.35% within 24 h (mean: 3.3 h). CND group showed significantly more often preterm delivery [OR 3.5; RR 3.2; p  < 0.05], and especially cumulative multiple symptoms [OR 9.4; RR 6.6; p  < 0.01] but no correlation to multiple maternal medication use ( p  = 0.3)., Conclusions: Neonates exposed to CND are at increased risk for postnatal therapy, often due to multiple symptoms. Neonates should be continuously monitored for at least 24 h.

This article gives valuable insight into the effect of selected groups of medications on dental treatment outcome and prognosis. The review emphasizes the importance of thorough medical history, which may have an impact on the prognosis of dental treatment. We discuss drugs acting on the central nervous system, gastrointestinal tract, respiratory tract, endocrine system, and bone metabolism among others. Other pertinent drugs are discussed elsewhere in this special issue., Competing Interests: Disclosure D.C. Thomas, S.K. Shah, J. Chawla, L. Sangalli declare no conflict of interest. Funding statement: None. Statement of institutional review board approval or waiver: Institutional review and approval were not necessary for this article., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Central nervous system (CNS) medication use is common among older adults, yet the impact of hospitalizations on use remains unclear. This study details CNS medication use, discontinuations, and user profiles during hospitalization periods., Methods: Retrospective cohort study using electronic health records on patients ≥65 years, from three hospitals (2018-2020), and prescribed a CNS medication around hospitalization (90 days prior to 90 days after). Latent class transitions analysis (LCTA) examined profiles of CNS medication class users across four time points (90 days prior, admission, discharge, 90 days after hospitalization)., Results: Among 4666 patients (mean age 74.3 ± 9.3 years; 63% female; 70% White; mean length of stay 4.6 ± 5.6 days (median 3.0 [2.0, 6.0]), the most commonly prescribed CNS medications were antidepressants (56%) and opioids (49%). Overall, 74% (n = 3446) of patients were persistent users of a CNS medication across all four time points; 7% (n = 388) had discontinuations during hospitalization, but of these, 64% (216/388) had new starts or restarts within 90 days after hospitalization. LCTA identified three profile groups: (1) low CNS medication users, 54%-60% of patients; (2) mental health medication users, 30%-36%; and (3) acute/chronic pain medication users, 9%-10%. Probability of staying in same group across the four time points was high (0.88-1.00). Transitioning to the low CNS medication use group was highest from admission to discharge (probability of 9% for pain medication users, 5% for mental health medication users). Female gender increased (OR 2.4, 95% CI 1.3-4.3), while chronic kidney disease lowered (OR 0.5, 0.2-0.9) the odds of transitioning to the low CNS medication use profile between admission and discharge., Conclusions: CNS medication use stays consistent around hospitalization, with discontinuation more likely between admission and discharge, especially among pain medication users. Further research on patient outcomes is needed to understand the benefits and harms of hospital deprescribing, particularly for medications requiring gradual tapering., (© 2024 The American Geriatrics Society.)

Background: Niemann-Pick disease type C is a rare lysosomal storage disorder. We evaluated the safety and efficacy of N -acetyl-l-leucine (NALL), an agent that potentially ameliorates lysosomal and metabolic dysfunction, for the treatment of Niemann-Pick disease type C., Methods: In this double-blind, placebo-controlled, crossover trial, we randomly assigned patients 4 years of age or older with genetically confirmed Niemann-Pick disease type C in a 1:1 ratio to receive NALL for 12 weeks, followed by placebo for 12 weeks, or to receive placebo for 12 weeks, followed by NALL for 12 weeks. NALL or matching placebo was administered orally two to three times per day, with patients 4 to 12 years of age receiving weight-based doses (2 to 4 g per day) and those 13 years of age or older receiving a dose of 4 g per day. The primary end point was the total score on the Scale for the Assessment and Rating of Ataxia (SARA; range, 0 to 40, with lower scores indicating better neurologic status). Secondary end points included scores on the Clinical Global Impression of Improvement, the Spinocerebellar Ataxia Functional Index, and the Modified Disability Rating Scale. Crossover data from the two 12-week periods in each group were included in the comparisons of NALL with placebo., Results: A total of 60 patients 5 to 67 years of age were enrolled. The mean baseline SARA total scores used in the primary analysis were 15.88 before receipt of the first dose of NALL (60 patients) and 15.68 before receipt of the first dose of placebo (59 patients; 1 patient never received placebo). The mean (±SD) change from baseline in the SARA total score was -1.97±2.43 points after 12 weeks of receiving NALL and -0.60±2.39 points after 12 weeks of receiving placebo (least-squares mean difference, -1.28 points; 95% confidence interval, -1.91 to -0.65; P<0.001). The results for the secondary end points were generally supportive of the findings in the primary analysis, but these were not adjusted for multiple comparisons. The incidence of adverse events was similar with NALL and placebo, and no treatment-related serious adverse events occurred., Conclusions: Among patients with Niemann-Pick disease type C, treatment with NALL for 12 weeks led to better neurologic status than placebo. A longer period is needed to determine the long-term effects of this agent in patients with Niemann-Pick disease type C. (Funded by IntraBio; ClinicalTrials.gov number, NCT05163288; EudraCT number, 2021-005356-10.)., (Copyright © 2024 Massachusetts Medical Society.)

Background: Behavioral and psychological symptoms of dementia (BPSD) and prescribed central nervous system (CNS) active drugs to treat them are prevalent among persons living with Alzheimer's disease and related dementias (PLWD) and lead to negative outcomes for PLWD and their caregivers. Yet, little is known about racial/ethnic disparities in diagnosis and use of drugs to treat BPSD., Objective: Quantify racial/ethnic disparities in BPSD diagnoses and CNS-active drug use among community-dwelling PLWD., Methods: We used a retrospective cohort of community-dwelling Medicare Fee-for-Service beneficiaries with dementia, continuously enrolled in Parts A, B and D, 2017-2019. Multivariate logistic models estimated rates of BPSD diagnosis and, conditional on diagnosis, CNS-active drug use., Results: Among PLWD, 67.1% had diagnoses of an affective, psychosis or hyperactivity symptom. White (68.3%) and Hispanic (63.9%) PLWD were most likely, Blacks (56.6%) and Asians (52.7%) least likely, to have diagnoses. Among PLWD with BPSD diagnoses, 78.6% took a CNS-active drug. Use was highest among whites (79.3%) and Hispanics (76.2%) and lowest among Blacks (70.8%) and Asians (69.3%). Racial/ethnic differences in affective disorders were pronounced, 56.8% of white PLWD diagnosed; Asians had the lowest rates (37.8%). Similar differences were found in use of antidepressants., Conclusions: BPSD diagnoses and CNS-active drug use were common in our study. Lower rates of BPSD diagnoses in non-white compared to white populations may indicate underdiagnosis in clinical settings of treatable conditions. Clinicians' review of prescriptions in this population to reduce poor outcomes is important as is informing care partners on the risks/benefits of using CNS-active drugs.

Background: In the past few decades, considerable progress has been made in CNS drug discovery, and various new CNS agents have been developed. Pyrimidine is an important scaffold in the area of medicinal chemistry. Recently, pyrimidine-containing compounds have been successfully designed as potent CNS agents. Substantial research has been carried out on pyrimidine-bearing compounds to treat different disorders of CNS in various animal models., Methods: Utilizing various databases, including Google Scholar, PubMed, Science Direct, and Web of Science, the literature review was conducted. The specifics of significant articles were discussed with an emphasis on the potency of pyrimidines derivatives possessing CNS activity., Results: Recent papers indicating pyrimidine derivatives with CNS activity were incorporated into the manuscript. (46) to (50) papers included different pyrimidine derivatives as 5-HT agonist/antagonists, (62) to (67) as adenosine agonist/antagonist, (70) to (75) as anticonvulsant agents, (80) to (83) as cannabinoid receptor agonists, (102) to (103) as nicotinic and (110) as muscarinic receptor agonists. The remaining papers (113) to (114) represented pyrimidine-based molecular imaging agents., Conclusion: Pyrimidine and its derivatives have been studied in detail to evaluate their efficacy in overcoming multiple central nervous system disorders. The article covers the current updates on pyrimidine-based compounds as potent CNS and molecular imaging agents and will definitely provide a better platform for the development of potent pyrimidine-based CNS drugs in the near future., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Our objective was to determine potential drug interactions (DI) between pangenotypic direct-acting antivirals (pDAA) and concomitant central nervous system (CNS) medication in patients with chronic hepatitis C virus (HCV). Transversal design. Patients aged ≥ 18 years on treatment with pDAA during 2017 were included. The variables collected were comorbidity, concomitant CNS medication and potential DI. The pDAA analyzed were a) Sofosbuvir/Velpatasvir (SOF/VEL), b) Glecaprevir/Pibrentasvir (GLE/PIB) and c) Sofosbuvir/Velpatasvir/Voxilaprevir (SOF/VEL/VOX). Descriptive statistical analysis. We recruited 1,170 patients (mean age 60.1 years, 56.4% male). Mean concomitant drug use was 3.2 per patient/year. The percentages of potential / possible DI between the DAAs and the concomitant drugs on the CNS were: 2.7% contraindications, 11.3% significant and 4.2% weak. By pDAA, the percentages were: SOF/VEL (2.7%; 0.0%; 4.4%), GLE/GDP (2.7%; 26.5%; 1.6%) SOF/VEL/VOX (2.7%; 6.8%; 4.4%), respectively. Concomitant CNS medication was used in one third of HCV patients. It is important to select a pDAA with a low rate of potential DI to simplify treatment. SOF/VEL is a good alternative compared with the other pDAA studied, mainly due to the concomitant use of antipsychotics and analgesics.

Asparagine endopeptidase (AEP), also called legumain, is a pH-dependent endolysosomal cysteine protease that cleaves its substrates after asparagine residues. Recent studies showed that it possesses δ-secretase activity and that it is implicated in numerous neurological diseases such as Alzheimer's disease (AD). Following evidence of aryl-morpholines as useful asparagine endopeptidase inhibitors, a series of morpholinoanilines with diverse substituents at ortho position were synthesized in view of improving the potency and scope of this molecular scaffold, allowing to identify ethyl 2-isonipecotate-4-morpholinoaniline possessing inhibition potency in the nanomolar range. CNS MPO (CNS MultiParameter Optimization) calculations revealed that most of the compounds developed in this work show physicochemical parameters in the desirable range for CNS drug candidates., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The world faces an exceptional new public health concern caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), subsequently termed the coronavirus disease 2019 (COVID-19) by the World Health Organization (WHO). Although the clinical symptoms mostly have been characterized, the scientific community still doesn´t know how SARS-CoV-2 successfully reaches and spreads throughout the central nervous system (CNS) inducing brain damage. The recent detection of SARS-CoV-2 in the cerebrospinal fluid (CSF) and in frontal lobe sections from postmortem examination has confirmed the presence of the virus in neural tissue. This finding reveals a new direction in the search for a neurotherapeutic strategy in the COVID-19 patients with underlying diseases. Here, we discuss the COVID-19 outbreak in a neuroinvasiveness context and suggest the therapeutic use of high doses of melatonin, which may favorably modulate the immune response and neuroinflammation caused by SARS-CoV-2. However, clinical trials elucidating the efficacy of melatonin in the prevention and clinical management in the COVID-19 patients should be actively encouraged., (© 2020. Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: To perform a systematic review of the diagnosis and treatment of patients with pulsatile tinnitus secondary to middle ear myoclonus., Databases Reviewed: PubMed, EMBASE, and Scopus., Methods: A systematic review was performed using standardized methodology. Computerized and manual searches were performed to identify studies of all ages (patients) who had middle ear myoclonus (intervention). All study designs were assessed. Extracted data included demographics, clinical features, duration of followup as well as the diagnosis and reversibility of symptoms with medical or surgical intervention. Studies were included if they included subjects with middle ear myoclonus. Exclusion criteria included letters/commentaries and reviews., Results: Twenty articles representing 115 subjects with middle ear myoclonus were included. The mean age was 29.7 (range 6-67). The follow-up period ranged from 5 weeks to 36 months. Primary treatment consists of medical therapy utilising anxiolytics, antiepileptics, botulinum toxin and surgical treatment involving division of middle ear muscular tendon(s). In total, 60 patients underwent middle ear muscular tenotomies, with division of both stapedius and tensor tympani tendons being the most prevalent (88%). Limitations in the data arose from study design, related comorbidities such as palatal myoclonus, and concomitant drug administration. No study provided any objective criteria to diagnose this condition or evaluate post-treatment outcome., Conclusion: Middle ear myoclonus is an entity that is poorly assessed in the literature. There is a lack of consensus regarding the criteria and strategies for both diagnosing and treating this condition. Although level of evidence of current studies remains modest, it is felt that a stepwise approach is deemed best, with therapeutic decisions being made on an individual basis, evaluating each patient's specific circumstances and priorities., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Drug supply disruptions have increased during the COVID-19 pandemic, especially for medicines used in the ICU. Despite reported shortages in wealthy countries, global analyses of ICU drug purchasing during COVID-19 are limited., Research Question: Has COVID-19 impacted global drug purchases of first-, second-, and third-choice agents used in intensive care?, Study Design and Methods: We conducted a cross-sectional time series study in a global pharmacy sales dataset comprising approximately 60% of the world's population. We analyzed pandemic-related changes in units purchased per 1,000 population for 69 ICU agents. Interventional autoregressive integrated moving average models tested for significant changes when the pandemic was declared (March 2020) and during its first stage from April through August 2020, globally and by development status., Results: Relative to 2019, ICU drug purchases increased by 23.6% (95% CI, 7.9%-37.9%) in March 2020 (P < .001) and then decreased by 10.3% (95% CI, -16.9% to -3.5%) from April through August (P = .006). Purchases for second-choice medicines changed the most, especially in developing countries (eg, 29.3% increase in March 2020). Despite similar relative changes (P = .88), absolute purchasing rates in developing nations remained low. The observed decrease from April through August 2020 was significant only in developed countries (-13.1%; 95% CI, -17.4% to -4.4%; P < .001). Country-level variation seemed unrelated to expected demand and health care infrastructure., Interpretation: Purchases for intensive care medicines increased globally in the month of the COVID-19 pandemic declaration, but before peak infection rates. These changes were most pronounced for second-choice agents, suggesting that inexpensive, generic medicines may be purchased more easily in anticipation of pandemic-related ICU surges. Nevertheless, disparities in access persisted. Trends seemed unrelated to expected demand, and decreased purchasing from April through August 2020 may suggest overbuying. National and international policies are needed to ensure equitable drug purchasing during future pandemics., (Copyright © 2021 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

The concept of "Neurovascular Unit" (NVU) was put forward, so that the research goal of Central Nervous System (CNS) diseases gradually transitioned from a single neuron to the structural and functional integrity of the NVU. Zebrafish has the advantages of high homology with human genes, strong reproductive capacity and visualization of neural circuits, so it has become an emerging model organism for NVU research and has been applied to a variety of CNS diseases. Based on CNKI (https://www.cnki.net/) and PubMed (https://pubmed.ncbi.nlm.nih.gov/about/) databases, the author of this article sorted out the relevant literature, analyzed the construction of a zebrafish model of various CNS diseases，and the use of diagrams showed the application of zebrafish in the NVU, revealed its relationship, which would provide new methods and references for the treatment and research of CNS diseases., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Competing Interests: Intérêts concurrents: Aucun déclaré.

Central nervous system (CNS) disease is one of the most notorious arch-criminals of human health across the world. Although considerable efforts have been devoted to promote the development of CNS drugs, ideal therapeutical effects are yet far from enough. The blood-brain barrier remains a major player that impedes the full potential of CNS therapeutical agents as it blocks the entry of CNS drugs into the brain. The past few decades have witnessed the upspring of prodrug strategies as a promising method to accelerate CNS drug development. The prodrug strategy with the ability to overcome the formidable blood-brain barrier enhances the delivery to the brain and hence improves the effects of the CNS therapeutics. In this Feature Article, we summarize the reported barriers and strategies for CNS therapeutics and spotlight prodrug design strategies to improve the efficiency of crossing the blood-brain barrier.

Results: Exposure of 0.2 mM H 2 O 2 in lenses resulted in obvious cloudiness and typical pathological changes of cataract such as rupture of the lens capsule, degenerative lens epithelial cells (LECs), etc. Rg1 effectively prevented lens opacity caused by H 2 O 2 . After Rg1 treatment, lens WSP content, the level of SOD, total GSH, and reduced GSH were increased, while the level of MDA and oxidized GSH were decreased. In addition, MDA concentration of lens by Rg1 treatment only was found to be lower than the controls. Rg1 attenuated H 2 O 2 -induced cell injury at the concentration of 0.4 mM that it elevated cell activity, and peaked at 0.6 mM., Conclusions: This study demonstrated that Rg1 might have the capability to protect lens against oxidative stress-induced cataract, at least by local administration. Abbreviations: LECs: lens epithelial cells; Rg1: Ginsenoside Rg1; SD: Sprague-Dawley; ROS: reactive oxygen species; SOD: Superoxide Dismutase; GSH: glutathione; MDA: Malonediadehyde; H 2 O 2: Hydrogen peroxide.

The endocannabinoid system (ECS) comprises two cognate endocannabinoid receptors referred to as CB1R and CB2R . ECS dysregulation is apparent in neurodegenerative/neuro-psychiatric disorders including but not limited to schizophrenia, major depressive disorder and potentially bipolar disorder. The aim of this paper is to review mechanisms whereby both receptors may interact with neuro-immune and neuro-oxidative pathways, which play a pathophysiological role in these disorders. CB1R is located in the presynaptic terminals of GABAergic, glutamatergic, cholinergic, noradrenergic and serotonergic neurons where it regulates the retrograde suppression of neurotransmission. CB1R plays a key role in long-term depression, and, to a lesser extent, long-term potentiation, thereby modulating synaptic transmission and mediating learning and memory. Optimal CB1R activity plays an essential neuroprotective role by providing a defense against the development of glutamate-mediated excitotoxicity, which is achieved, at least in part, by impeding AMPA-mediated increase in intracellular calcium overload and oxidative stress. Moreover, CB1R activity enables optimal neuron-glial communication and the function of the neurovascular unit. CB2R receptors are detected in peripheral immune cells and also in central nervous system regions including the striatum, basal ganglia, frontal cortex, hippocampus, amygdala as well as the ventral tegmental area. CB2R upregulation inhibits the presynaptic release of glutamate in several brain regions. CB2R activation also decreases neuroinflammation partly by mediating the transition from a predominantly neurotoxic "M1" microglial phenotype to a more neuroprotective "M2" phenotype. CB1R and CB2R are thus novel drug targets for the treatment of neuro-immune and neuro-oxidative disorders including schizophrenia and affective disorders., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The central nervous system (CNS) is a vital part of the human nervous system, and the incidence of CNS disease is increasing year by year, which has become a major public health problem and a prominent social problem. At present, the drugs most commonly used in the clinic are receptor regulators, and neurotransmitter inhibitors, but they are accompanied by serious side effects. Therefore, the identification of new drugs and treatment strategies for CNS disease has been a research hotspot in the medical field. Celastrol, a highly bio-active pentacyclic triterpenoid isolated from Tripterygium wilfordii Hook. F, has been proved to have a wide range of pharmacological effects, such as anti-inflammation, immunosuppression, anti-obesity and anti-tumor activity. However, due to its poor water solubility, low bioavailability and toxicity, the clinical development and trials of celastrol have been postponed. However, in recent years, the extensive medical value of celastrol in the treatment of CNS diseases such as nervous system tumors, Alzheimer's disease, Parkinson's disease, cerebral ischemia, multiple sclerosis, spinal cord injury, and amyotrophic lateral sclerosis has gradually attracted intensive attention worldwide. In particular, celastrol has non-negligible anti-tumor efficacy, and as there are no 100% effective anti-tumor drugs, the study of its structural modification to obtain better leading compounds with higher efficiency and lower toxicity has aroused strong interest in pharmaceutical chemists. In this review, research progress on celastrol in CNS diseases and the synthesis of celastrol-type triterpenoid analogues and their application evaluation in disease models, such as CNS diseases and autotoxicity-related target organ cancers in the past decade are summarized in detail, in order to provide reference for future better application in the treatment of CNS diseases., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Depression is one of the most frequent psychiatric comorbidities associated with epilepsy having a major impact on the patient's quality of life. Several screening tools are available to identify and follow up psychiatric disorders in epilepsy. Out of various psychiatric disorders, people with epilepsy (PWE) are at greater risk of developing depression. This bidirectional relationship further hinders pharmacotherapy of comorbid depression in PWE as some antiepileptic drugs (AEDs) worsen associated depression and coadministration of existing antidepressants (ADs) to alleviate comorbid depression has been reported to worsen seizures. Selective serotonin reuptake inhibitors (SSRIs) and selective serotonin and norepinephrine reuptake inhibitors (SNRIs) are first choice of ADs and are considered safe in PWE, but there are no high-quality evidences. Similar to observations in people with depression, PWE also showed pharmacoresistant to available SSRI/SNRIs, which further complicates the disease prognosis. Randomized double-blind placebo-controlled clinical trials are necessary to report efficacy and safety of available ADs in PWE. We should also move beyond ADs, and therefore, we reviewed common pathological mechanisms such as neuroinflammation, dysregulated hypothalamus pituitary adrenal (HPA) axis, altered neurogenesis, and altered tryptophan metabolism responsible for coexistent relationship of epilepsy and depression. Based on these common pertinent pathways involved in the genesis of epilepsy and depression, we suggested novel targets and therapeutic approaches for safe management of comorbid depression in epilepsy.

A novel series of multitargeted molecules were designed and synthesized by combining the pharmacological role of cholinesterase inhibitor and antioxidant of steroid as potential ligands for the treatment of Vascular Dementia (VD). The oxygen-glucose deprivation (OGD) model was used to evaluate these molecules, among which the most potent compound ML5 showed the highest activity. Firstly, ML5 showed appropriate inhibition of cholinesterases (ChEs) at orally 15 mg/kg in vivo. The further test revealed that ML5 promoted the nuclear translocation of Nrf2. Furthermore, ML5 has significant neuroprotective effect in vivo model of bilateral common carotid artery occlusion (BCCAO), significantly increasing the expression of Nrf2 protein in the cerebral cortex. In the molecular docking research, we predicted the ML5 combined with hAChE and Keap1. Finally, compound ML5 displayed normal oral absorption and it was nontoxic at 500 mg/kg, po, dose. We can draw the conclusion that ML5 could be considered as a new potential compound for VD treatment., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Achieving sufficient delivery across the blood-brain barrier is a key challenge in the development of drugs to treat central nervous system (CNS) disorders. This is particularly the case for biopharmaceuticals such as monoclonal antibodies and enzyme replacement therapies, which are largely excluded from the brain following systemic administration. In recent years, increasing research efforts by pharmaceutical and biotechnology companies, academic institutions and public-private consortia have resulted in the evaluation of various technologies developed to deliver therapeutics to the CNS, some of which have entered clinical testing. Here we review recent developments and challenges related to selected blood-brain barrier-crossing strategies - with a focus on non-invasive approaches such as receptor-mediated transcytosis and the use of neurotropic viruses, nanoparticles and exosomes - and analyse their potential in the treatment of CNS disorders.

Lithium (Li) is the most widely used mood stabilizer in treating patients with bipolar disorder. However, more than half of the patients do not or partially respond to Li therapy, despite serum Li concentrations in the serum therapeutic range. The exact mechanisms underlying the pharmacokinetic-pharmacodynamic (PK-PD) relationships of lithium are still poorly understood and alteration in the brain pharmacokinetics of lithium may be one of the mechanisms explaining the variability in the clinical response to Li. Brain barriers such as the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB) play a crucial role in controlling blood-to-brain and brain-to-blood exchanges of various molecules including central nervous system (CNS) drugs. Recent in vivo studies by nuclear resonance spectroscopy revealed heterogenous brain distribution of Li in human that were not always correlated with serum concentrations, suggesting regional and variable transport mechanisms of Li through the brain barriers. Moreover, alteration in the functionality and integrity of brain barriers is reported in various CNS diseases, as a cause or a consequence and in this regard, Li by itself is known to modulate BBB properties such as the expression and activity of various transporters, metabolizing enzymes, and the specialized tight junction proteins on BBB. In this review, we will focus on recent knowledge into the role of the brain barriers as key-element in the Li neuropharmacokinetics which might improve the understanding of PK-PD of Li and its interindividual variability in drug response., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Abstract: Older adults are the leading users of medications, where this can be associated with a high number of potentially inappropriate medications (PIMs) and of potentially inappropriate prescribing (PIP) and consequent harm to health. No Brazilian study evaluating potentially inappropriate prescribing in older patients with Alzheimer's disease (AD) was found. This study determined and analyzed the prevalence of PIP and PIM prescribed for older people with AD.A cross-sectional study was carried out at the Specialty Drugs Pharmacy in the city of Sorocaba, São Paulo State, Brazil. The MEDEX system provided the register in older people with AD and data were collected during interviews with patients and/or caregivers between June and September 2017. The PIMs were identified according to the 2019 Beers Criteria. The association between PIMs and independent variables was analyzed by Poisson regression.This study included 234 older patients with AD. The prevalence of PIP prescribed was 66.7% (n = 156). Of the 1073 medications prescribed, 30.5% (n = 327) were inappropriate with most affecting the central nervous system or cardiovascular, particularly quetiapine (12.8%) and acetylsalicylic acid (11.6%), respectively. Around 45.2% of the PIMs should be avoided in older people, especially sertraline (14.2%) and clonazepam (7.4%). After adjusted analysis, the PIMs were associated with the diagnosis of depression (P = 0.010) and the number of comorbidities (P = 0.005).There was a high number of PIMs among older people, a substantial number of which should have been avoided in this population. Health care professionals can apply these findings to improve safety in the use of medications for treating patients with AD., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Importance: Community-dwelling older adults with dementia have a high prevalence of psychotropic and opioid use. In these patients, central nervous system (CNS)-active polypharmacy may increase the risk for impaired cognition, fall-related injury, and death., Objective: To determine the extent of CNS-active polypharmacy among community-dwelling older adults with dementia in the US., Design, Setting, and Participants: Cross-sectional analysis of all community-dwelling older adults with dementia (identified by International Classification of Diseases, Ninth Revision, Clinical Modification or International Statistical Classification of Diseases and Related Health Problems, Tenth Revision diagnosis codes; N = 1 159 968) and traditional Medicare coverage from 2015 to 2017. Medication exposure was estimated using prescription fills between October 1, 2017, and December 31, 2018., Exposures: Part D coverage during the observation year (January 1-December 31, 2018)., Main Outcomes and Measures: The primary outcome was the prevalence of CNS-active polypharmacy in 2018, defined as exposure to 3 or more medications for longer than 30 days consecutively from the following classes: antidepressants, antipsychotics, antiepileptics, benzodiazepines, nonbenzodiazepine benzodiazepine receptor agonist hypnotics, and opioids. Among those who met the criterion for polypharmacy, duration of exposure, number of distinct medications and classes prescribed, common class combinations, and the most commonly used CNS-active medications also were determined., Results: The study included 1 159 968 older adults with dementia (median age, 83.0 years [interquartile range {IQR}, 77.0-88.6 years]; 65.2% were female), of whom 13.9% (n = 161 412) met the criterion for CNS-active polypharmacy (32 139 610 polypharmacy-days of exposure). Those with CNS-active polypharmacy had a median age of 79.4 years (IQR, 74.0-85.5 years) and 71.2% were female. Among those who met the criterion for CNS-active polypharmacy, the median number of polypharmacy-days was 193 (IQR, 88-315 polypharmacy-days). Of those with CNS-active polypharmacy, 57.8% were exposed for longer than 180 days and 6.8% for 365 days; 29.4% were exposed to 5 or more medications and 5.2% were exposed to 5 or more medication classes. Ninety-two percent of polypharmacy-days included an antidepressant, 47.1% included an antipsychotic, and 40.7% included a benzodiazepine. The most common medication class combination included an antidepressant, an antiepileptic, and an antipsychotic (12.9% of polypharmacy-days). Gabapentin was the most common medication and was associated with 33.0% of polypharmacy-days., Conclusions and Relevance: In this cross-sectional analysis of Medicare claims data, 13.9% of older adults with dementia in 2018 filled prescriptions consistent with CNS-active polypharmacy. The lack of information on prescribing indications limits judgments about clinical appropriateness of medication combinations for individual patients.

Research increasingly demonstrates the bidirectional communication between gut microbiota and the brain, enhancing the role of gut microbiota modulation in the treatment of central nervous system (CNS) disorders. The first five years of life are extremely important as it affects the development of gut microbiota, immune system and, consequently, the onset of psychometric alterations, particularly in genetically predisposed individuals. In this review, we focus on the link between specific microbial genera, gastrointestinal (GI) disorders, anxiety and depression and on the effects of different therapeutic strategies for mood disorders on gut microbiota., Competing Interests: Conflict of interest None declared., (Copyright © 2020 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

The novel coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The escalating number of SARS-CoV-2-infected individuals has conferred the viral spread with the status of global pandemic. However, there are no prophylactic or therapeutic drugs available on the market to treat COVID-19, although several drugs have been approved. Recently, two articles using the comparative viral-human protein-protein interaction map revealed that the sigma-1 receptor in the endoplasmic reticulum plays an important role in SARS-CoV-2 replication in cells. Knockout and knockdown of SIGMAR1 (sigma-1 receptor, encoded by SIGMAR1) caused robust reductions in SARS-CoV-2 replication, which indicates that the sigma-1 receptor is a key therapeutic target for SARS-CoV-2 replication. Interestingly, a recent clinical trial demonstrated that treatment with the antidepressant fluvoxamine, which has a high affinity at the sigma-1 receptor, could prevent clinical deterioration in adult outpatients infected with SARS-CoV-2. In this review, we discuss the brief history of the sigma-1 receptor and its role in SARS-CoV-2 replication in cells. Here, we propose repurposing of traditional central nervous system (CNS) drugs that have a high affinity at the sigma-1 receptor (i.e., fluvoxamine, donepezil, ifenprodil) for the treatment of SARS-CoV-2-infected patients. Finally, we discussed the potential of other CNS candidates such as cutamesine and arketamine.

Neuropsychiatric disorders are diseases of the central nervous system (CNS) which are characterised by complex pathomechanisms that including homeostatic failure, malfunction, atrophy, pathology remodelling and reactivity anomaly of the neuronal system where treatment options remain challenging. β-Carboline (βC) alkaloids are scaffolds of structurally diverse tricyclic pyrido[3,4-b]indole alkaloid with vast occurrence in nature. Their unique structural features which favour interactions with enzymes and protein receptor targets account for their potent neuropharmacological properties. However, our current understanding of their biological mechanisms for these beneficial effects, especially for neuropsychiatric disorders is sparse. Therefore, we present a comprehensive review of the scientific progress in the last two decades on the prospective pharmacology and physiology of the βC alkaloids in the treatment of some neuropsychiatric conditions such as depression, anxiety, Alzheimer's disease, Parkinson's disease, brain tumour, essential tremor, epilepsy and seizure, licking behaviour, dystonia, agnosia, spasm, positive ingestive response as demonstrated in non-clinical models. The current evidence supports that βC alkaloids offer potential therapeutic agents against most of these disorders and amenable for further drug design., (Copyright © 2020. Published by Elsevier B.V.)

A series of substituted imidazoline derivatives were synthesized and characterized. Compounds were tested in-vivo for their antihypertensive, analgesic, antiaggressive, depressant, antidepressant, and ALD 50 activities. The compounds 3a, 3c, 4c, 5a, and 6c showed cardiovascular as well as central nervous system activities and are potential candidate as drug among all fifteen compounds tested. All these compounds have shown better activity for antihypertensive, analgesic, antiaggressive, and depressant-antidepressant, properties than reference compounds clonidine, morphine, diazepam, and imipramine respectively. Most of the compounds have shown ALD 50  > 500 mg/kg with maximum in 4a and 5a (>1000 mg/kg)., (Copyright © 2020. Published by Elsevier Ltd.)

Ion channels are the third largest class of targets for therapeutic drugs. The pharmacology of ion channels is an important research area for identifying new treatment options for human diseases. The past decade or so has seen increasing interest in an ion channel protein belonging to the transient receptor potential (TRP) family, namely the melastatin subfamily member 7 (TRPM7), as an emerging drug target. TRPM7 is a bifunctional protein with a magnesium and calcium-conducting divalent ion channel fused with an active kinase domain. TRPM7 is ubiquitously expressed in human tissues, including the brain, and regulates various cell biology processes such as magnesium and calcium homeostasis, cell growth and proliferation, and embryonic development. TRPM7 provides a link between cellular metabolic status and intracellular calcium homeostasis in neurons due to TRPM7's unique sensitivity to fluctuating intracellular Mg·ATP levels. Thus, the protein plays a key role in ischemic and hypoxic neuronal cell death and brain injury, and is one of the key nonglutamate mechanisms in cerebral ischemia and stroke. Currently, the most potent and specific TRPM7 inhibitor is waixenicin A, a xenicane diterpenoid from the Hawaiian soft coral Sarcothelia edmondsoni. Using waixenicin A as a pharmacological tool, we demonstrated that TRPM7 is involved in promoting neurite outgrowth in vitro. Most recently, we found that waixenicin A reduced hypoxic-ischemic brain injury and preserved long-term behavioral outcomes in mouse neonates. We here suggest that TRPM7 is an emerging drug target for CNS diseases and disorders, and waixenicin A is a viable drug lead for these disorders.

The impact of the C-X-C receptor (CXCR) 7 and its close co-player CXCR4 in different physiological and pathophysiological processes has been extensively investigated within the last decades. Following activation by their shared ligand C-X-C ligand (CXCL) 12, both chemokine receptors can induce various routes of cell signaling and/or scavenge CXCL12 from the extracellular environment. This contributes to organ development and maintenance of homeostasis. Alterations of the CXCR4/CXCR7-CXCL12 axis have been detected in diseases such as cancer, central nervous system and cardiac disorders, and autoimmune diseases. These alterations include changes of the expression pattern, distribution, or downstream effects. The progression of the diseases can be regulated in preclinical models by the use of various modulators suggesting that this axis serves as a promising therapeutic target. It is therefore of great interest to investigate CXCR4/CXCR7/CXCL12 modulators in clinical development, with several CXCR4 and CXCL12 modulators such as plerixafor, ulocuplumab, balixafortide, and olaptesed pegol having already reached this stage. An overview is presented of the most important diseases whose outcomes can be positively or negatively regulated by the CXCR4/CXCR7-CXCL12 axis and summarizes preclinical and clinical data of modulators of that axis. Contrary to CXCR4 and CXCL12 modulators, CXCR7 modulators have, thus far, not been extensively studied. Therefore, more (pre)clinical investigations are needed., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The natural tridecapeptide neurotensin has been emerged as a promising therapeutic scaffold for the treatment of neurological diseases and cancer. In this work, we aimed to identify the top 100 most cited original research papers as well as recent key studies related to neurotensins. The Web of Science Core Collection database was searched and the retrieved research articles were analyzed by using the VOSviewer software. The most cited original articles were published between 1973 and 2013. The top-cited article was by Carraway and Leeman reporting the discovery of neurotensin in 1973. The highly cited terms were associated with hypotension and angiotensin-converting-enzyme. The conducted analysis reveals the therapeutic potentials of neurotensin, and further impactful research toward its clinical development is warrantied.

Astrocytes play important roles in numerous central nervous system disorders including autoimmune inflammatory, hypoxic, and degenerative diseases such as Multiple Sclerosis, ischemic stroke, and Alzheimer's disease. Depending on the spatial and temporal context, activated astrocytes may contribute to the pathogenesis, progression, and recovery of disease. Recent progress in the dissection of transcriptional responses to varying forms of central nervous system insult has shed light on the mechanisms that govern the complexity of reactive astrocyte functions. While a large body of research focuses on the pathogenic effects of reactive astrocytes, little is known about how they limit inflammation and contribute to tissue regeneration. However, these protective astrocyte pathways might be of relevance for the understanding of the underlying pathology in disease and may lead to novel targeted approaches to treat autoimmune inflammatory and degenerative disorders of the central nervous system. In this review article, we have revisited the emerging concept of protective astrocyte functions and discuss their role in the recovery from inflammatory and ischemic disease as well as their role in degenerative disorders. Focusing on soluble astrocyte derived mediators, we aggregate the existing knowledge on astrocyte functions in the maintenance of homeostasis as well as their reparative and tissue-protective function after acute lesions and in neurodegenerative disorders. Finally, we give an outlook of how these mediators may guide future therapeutic strategies to tackle yet untreatable disorders of the central nervous system., (Copyright © 2020 Linnerbauer and Rothhammer.)

Effective drug delivery to the CNS to achieve the desired therapeutic response is a significant challenge in the field of drug delivery. In central nervous system (CNS), blood brain barrier (BBB) restricts the desired therapeutic responses due to inefficient targeting, release kinetics, and failure to reach therapeutic concentrations in the brain. Therefore, most potentially beneficial diagnostic and therapeutic agents are not able to reach to the brain upon systemic administration. Despite the existence of many invasive techniques to promote drug deliveries across BBB, novel strategies of drug delivery system which can cross BBB effectively are required, otherwise translation of novel neurotherapeutics from bench to bedside will be difficult to achieve. In this review, we briefly outline the existing and emerging strategies for CNS drug deliveries with a focus on potential and challenges of using extracellular vesicles (EVs) in CNS drug delivery system. EVs are emerging as a promising tool for therapeutic delivery owing to its favorable intrinsic features of biocompatibility, stability, stealth capacity, ability to overcome natural barriers and inherent homing capability. EVs are nanovesicles that allow cell-cell communication. The EVs-cargo reflects the physiological as well as the pathophysiological state of a cell. EVs are shown to play a role in human immunodeficiency virus (HIV) infection and dissemination, which contributes to acquired immune deficiency syndrome (AIDS). In the context of HIV-1 infection, this review also outlines the role of EVs in dissemination, challenges faced in EVs research in HIV-1 co-morbid conditions and potential of nanotechnologies, especially EVs in Neuro-AIDS. Graphical Abstract EVs are used for the delivery of small molecule drugs, protein, and nucleic acid to the CNS as well as imaging molecules for in vivo tracking. For the purpose of delivery, EVs may or may not be subjected to membrane modification. The advantages of EVs, including its biocompatibility, low immunogenicity, and low toxicity profiles, can be exploited to potentially devise novel therapeutic delivery system for CNS drug targeting. This article outlines the challenges in potential EV-based therapeutic delivery.

Central nervous system (CNS) disorders like Alzheimer's disease (AD), Parkinson disease (PD), stroke, epilepsy, depression, and bipolar disorder have a high impact on both medical and social problems due to the surge in their prevalence. All of these neuronal disorders share some common etiologies including disruption of Ca 2+ homeostasis and accumulation of misfolded proteins. These misfolded proteins further disrupt the intracellular Ca 2+ homeostasis by disrupting the activity of several ion channels including transient receptor potential (TRP) channels. TRP channel families include non-selective Ca 2+ permeable channels, which act as cellular sensors activated by various physio-chemical stimuli, exogenous, and endogenous ligands responsible for maintaining the intracellular Ca 2+ homeostasis. TRP channels are abundantly expressed in the neuronal cells and disturbance in their activity leads to various neuronal diseases. Under the pathological conditions when the activity of TRP channels is perturbed, there is a disruption of the neuronal homeostasis through increased inflammatory response, generation of reactive oxygen species, and mitochondrial dysfunction. Therefore, there is a potential of pharmacological interventions targeting TRP channels in CNS disorders. This review focuses on the role of TRP channels in neurological diseases; also, we have highlighted the current insights into the pharmacological modulators targeting TRP channels., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objective: The authors assessed central nervous system (CNS) polypharmacy among low-income, racially diverse homebound older adults with depression (N=277) and its associations with the participants' ratings of depressive symptoms and pain., Methods: CNS-active and other psychotropic and analgesic medications intake was collected from patients' medication containers. Depressive symptoms were assessed with the 24-item Hamilton Depression Rating Scale, and pain intensity was measured on an 11-point numerical rating scale. Covariates were disability (World Health Organization Disability Assessment Schedule 2.0) and perceived social support (Multidimensional Scale of Perceived Social Support)., Results: Of the patients, 16% engaged in CNS polypharmacy, taking three or more CNS-active medications. Of these, 69%, 69%, and 89% were using selective serotonin reuptake inhibitors, benzodiazepines, and opioids, respectively. Higher pain intensity ratings were associated with CNS polypharmacy. Benzodiazepine users were more likely than nonusers to use opioids., Conclusions: Medication reviews and improved access to evidence-based psychotherapeutic treatments are needed for these older individuals with depression.