piperidines and Multiple-Sclerosis

Fyn is a non-receptor tyrosine kinase belonging to the Src family of kinases (SFKs) which has been implicated in several integral functions throughout the central nervous system (CNS), including myelination and synaptic transmission. More recently, Fyn dysfunction has been associated with pathological processes observed in neurodegenerative diseases, such as multiple sclerosis (MS), Alzheimer's disease (AD) and Parkinson's disease (PD). Neurodegenerative diseases are amongst the leading cause of death and disability worldwide and, due to the ageing population, prevalence is predicted to rise in the coming years. Symptoms across neurodegenerative diseases are both debilitating and degenerative in nature and, concerningly, there are currently no disease-modifying therapies to prevent their progression. As such, it is important to identify potential new therapeutic targets. This review will outline the role of Fyn in normal/homeostatic processes, as well as degenerative/pathological mechanisms associated with neurodegenerative diseases, such as demyelination, pathological protein aggregation, neuroinflammation and cognitive dysfunction.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Benzamides; Central Nervous System; Dasatinib; Humans; Molecular Targeted Therapy; Multiple Sclerosis; Myelin Sheath; Nerve Tissue Proteins; Neurodegenerative Diseases; Oligodendroglia; Parkinson Disease; Piperidines; Proto-Oncogene Proteins c-fyn; PrPC Proteins; Pyridines; Receptors, N-Methyl-D-Aspartate; T-Cell Antigen Receptor Specificity; T-Lymphocyte Subsets; tau Proteins; Thiazoles

Topics: Adult; Donepezil; Ginkgo biloba; Humans; Indans; Memantine; Memory Disorders; Multiple Sclerosis; Neuroprotective Agents; Nootropic Agents; Phytotherapy; Piperidines; Randomized Controlled Trials as Topic; Rivastigmine

Multiple sclerosis (MS) is a heterogeneous, chronic, debilitating immune-mediated disease of the central nervous system (CNS). There are four types of MS according to their relapsing or progressive pattern that include relapsing-remitting (RRMS), secondary progressive (SPMS), primary progressive (PPMS), and progressive relapsing (PRMS). There is no definite cure for MS, thus medications typically focus on slowing the progression of the disease, managing symptoms and improving the quality of life. There is no specific medication for the management of PPMS and thus these patients are often neglected. New medicines in this phase of the disease are needed. On the other hand injectable immunomodulatory medicines, which dominated the MS market for over the past two decades, raise the issues of adherence and tolerance while oral therapies do offer a step forward in convenience. This systematic review article discusses the emerging synthetic small molecule that administered orally for MS treatment. We searched PubMed, Web of Science and Google Scholar to summaries the present knowledge on mechanism of action, and completed and current clinical trial of laquinimod, masitinib and siponimod. Data were collected from 1985 to January 2015. The development of effective medicines for MS is critically dependent upon understanding the biological basis of this complex multifactorial disease. The current pharmacotherapeuetic options for its treatment are mainly immunomodulators which were developed on the basis that MS is an autoimmune disease. The new synthetic small molecule agents such as laquinimod, masitinib and siponimod with different mechanism of actions can be administered orally rather than by injection.

Topics: Benzamides; Humans; Immunologic Factors; Multiple Sclerosis; Piperidines; Pyridines; Quinolones; Small Molecule Libraries; Thiazoles

This is an update of the Cochrane review "Pharmacologic treatment for memory disorder in multiple sclerosis" (first published in The Cochrane Library 2011, Issue 10).Multiple sclerosis (MS) is a chronic immune-mediated, inflammatory, demyelinating, neurodegenerative disorder of the central nervous system (CNS) and can cause both neurological and neuropsychological disability. Both demyelination and axonal and neuronal loss are believed to contribute to MS-related cognitive impairment. Memory disorder is one of the most frequent cognitive dysfunctions and presents a considerable burden to people with MS and to society due to the negative impact on function. A number of pharmacological agents have been evaluated in many existing randomised controlled trials for their efficacy on memory disorder in people with MS but the results were not consistent.. To assess the absolute and comparative efficacy, tolerability and safety of pharmacological treatments for memory disorder in adults with MS.. We searched the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group Trials Register (24 July 2013), PsycINFO (January 1980 to 26 June 2013) and CBMdisc (1978 to 24 June 2013), and checked reference lists of identified articles, searched some relevant journals manually, registers of clinical trials and published abstracts of conference proceedings.. All double-blind, randomised controlled parallel trials on pharmacological treatment versus placebo or one or more pharmacological treatments in adults with MS who had at least mild memory impairment (at 0.5 standard deviations below age- and sex-based normative data on a validated memory scale). We placed no restrictions regarding dose, route of administration and frequency; however, we only included trials with an administration duration of 12 weeks or greater.. Two review authors independently assessed trial quality and extracted data. We discussed disagreements and resolved them by consensus among review authors. We contacted principal investigators of included studies for additional data or confirmation.. We included seven randomised controlled trials (RCTs) involving 625 people mostly with relapsing-remitting, secondary-progressive and primary-progressive MS, evaluating the absolute efficacy of donepezil, ginkgo biloba, memantine and rivastigmine versus placebo in improving memory performance with diverse assessment scales. Overall, clinical and methodological heterogeneities existed across these studies. Moreover, most of them had methodological limitations on non-specific selections of targeted sample, non-matched variables at baseline or incomplete outcome data (high attrition bias). Only the two studies on donepezil had clinical and methodological homogeneity and relatively low risks for bias. One RCT evaluating estriol versus placebo is currently ongoing.We could not carry out a meta-analysis due to the heterogeneities across studies and the high attrition bias. A subgroup analysis for donepezil versus placebo showed no treatment effects on total recall on the Selective Reminding Test (mean difference (MD) 1.68; 95% confidence interval (CI) -2.21 to 5.58), total correct scores on the 10/36 Spatial Recall Test (MD -0.93; 95% CI -3.18 to 1.32), the Symbol Digit Modalities Test (MD -1.27; 95% CI -3.15 to 0.61) and the Paced Auditory Serial Addition Test (2+3 sec) (MD 2.23; 95% CI -1.87 to 6.33). Concerning safety, the main adverse events were: diarrhoea (risk ratio (RR) 3.88; 95% CI 1.66 to 9.05), nausea (RR 1.71; 95% CI 0.93 to 3.18) and abnormal dreams (RR 2.91; 95% CI 1.38 to 6.14). However, the results in both studies were subjected to a serious imprecision resulting from the small sample sizes and the low power of test (lower than 80%), which contributed to a moderate quality of the evidence. No serious adverse events were attributed to the treatments in all experimental groups.. We found no convincing evidence to support the efficacy of pharmacological symptomatic treatment for MS-associated memory disorder because most of available RCTs had a limited quality. Whether pharmacological treatment is effective for memory disorder in patients with MS remains inconclusive. However, there is moderate-quality evidence that donepezil 10 mg daily was not effective in improving memory in MS patients with mild memory impairment, but had a good tolerability. Adverse events such as nausea, diarrhoea and abnormal dreams were not frequent but were associated with treatment. Ginkgo biloba, memantine and rivastigmine were safe and well tolerated and no serious adverse effects were reported. Future large-scale RCTs with higher methodological quality are needed.

Topics: Adult; Donepezil; Ginkgo biloba; Humans; Indans; Memantine; Memory Disorders; Middle Aged; Multiple Sclerosis; Neuroprotective Agents; Nootropic Agents; Phenylcarbamates; Phytotherapy; Piperidines; Randomized Controlled Trials as Topic; Rivastigmine

Memory disorder is one of the most frequent cognitive impairment and has a great negative impact on the quality of life in patients with multiple sclerosis (MS). A few pharmacologic agents appear to be effective to memory disorder in patients with MS in some existing randomised controlled trials.. To assess the absolute and comparative efficacy, tolerability and safety of pharmacologic treatments for memory disorder in adult patients with MS.. We searched the Cochrane Multiple Sclerosis Group's Trials Register (17 January 2011), PsycINFO (January 1980 - April Week 4 2011) and CBMdisc (January 1978 - 6 April 2011), and checked reference lists of identified articles, searched some relevant journals manually, registers of clinical trials and published abstracts of conference proceedings.. All double-blind, randomized controlled parallel trials on pharmacologic treatment versus placebo treatment or no treatment or one or more pharmacologic treatments, without restrictions regarding dose, route of administration and frequency, administration duration≥12 weeks for memory disorder in adult patients with MS who display at least mild memory impairment at 0.5 standard deviations below age -and-sex-based normative data on a validated memory scale. Adequately randomized or quasi-randomized trials were included.. Two review authors independently assessed trial quality and extracted data. Disagreements were discussed and resolved by consensus among review authors. Principal investigators of included studies were contacted for additional data or confirmation.. Four RCTs involving adult patients with all the types of MS and at least mild memory impairment were included, evaluating donepezil, Ginkgo biloba (GB), memantine and rivastigmine respectively vs placebo in treating memory disorder in MS.There were no serious adverse events in intervention groups.The quality of the included studies was overall low, some of important variables were not matched between groups at baseline, the samples of subjects were relatively small and the follow-up was short. Three RCTs which evaluate GB, memantine, rivastigmine respectively vs placebo are currently ongoing.. Until the results of ongoing studies are available, there is no convincing evidence to support pharmacologic intervention as an effective treatment for memory disorder in MS patients. However, donepezil, Ginkgo biloba, memantine and rivastigmine resulted to be safe and well tolerated as adverse events such as nausea, diarrhea, somnolence, and constipation were not frequent,  while no serious adverse effects were reported. Future high quality randomised controlled trials are needed.

Topics: Adult; Donepezil; Ginkgo biloba; Humans; Indans; Memantine; Memory Disorders; Middle Aged; Multiple Sclerosis; Neuroprotective Agents; Nootropic Agents; Phenylcarbamates; Phytotherapy; Piperidines; Randomized Controlled Trials as Topic; Rivastigmine

Chemokines belong to a large family of chemoattractant molecules involved in the directed migration of immune cells. They achieve their cellular effects by direct interaction with cell surface receptors. The chemokine receptor CCR1 appears to be involved in a variety of proinflammatory and autoimmune diseases and this makes it a very attractive therapeutic target. This review discusses the identification, chemistry, biology and therapeutic potential of BX 471 a potent CCR1 antagonist that is currently in the clinic for a variety of indications.

Topics: Animals; Anti-Inflammatory Agents; Arthritis, Rheumatoid; Humans; Multiple Sclerosis; Phenylurea Compounds; Piperidines; Protein Serine-Threonine Kinases; Psoriasis

Berlex and its parent company, Schering AG, are developing BX-471 (also known as ZK-811752), the lead in a series of non-peptide chemokine receptor 1 (CCR1) antagonists, for the potential treatment of autoimmune diseases, in particular multiple sclerosis (MS) [291682], [376290], [411184]. In March 2000, BX-471 was undergoing phase I trials for the potential treatment of autoimmune diseases [362022]; phase I trials in MS were ongoing in March 2002 [441989], [443941]. Positive results from these trials have been reported and Berlex was planning phase II trials in MS patients as of mid-March 2002 [444906]. In July 2001, Schering estimated filing in the US and EU in 2008 [411184], [416493]. WO-09856771 claims piperazinyl derivatives, pharmaceutical compositions comprising them and their use in the treatment of inflammatory conditions.

Topics: Animals; Autoimmune Diseases; Clinical Trials, Phase I as Topic; Drug Evaluation, Preclinical; Graft Rejection; Humans; Multiple Sclerosis; Phenylurea Compounds; Piperidines; Receptors, CCR1; Receptors, Chemokine; Structure-Activity Relationship; Treatment Outcome

Bruton's tyrosine kinase (BTK) regulates the functions of B cells and myeloid cells that are implicated in the pathogenesis of multiple sclerosis. Evobrutinib is a selective oral BTK inhibitor that has been shown to inhibit B-cell activation both in vitro and in vivo.. In this double-blind, randomized, phase 2 trial, we assigned patients with relapsing multiple sclerosis to one of five groups: placebo, evobrutinib (at a dose of 25 mg once daily, 75 mg once daily, or 75 mg twice daily), or open-label dimethyl fumarate (DMF) as a reference. The primary end point was the total (cumulative) number of gadolinium-enhancing lesions identified on T. A total of 267 patients were randomly assigned to a trial group. The mean (±SD) total number of gadolinium-enhancing lesions during weeks 12 through 24 was 3.85±5.44 in the placebo group, 4.06±8.02 in the evobrutinib 25-mg group, 1.69±4.69 in the evobrutinib 75-mg once-daily group, 1.15±3.70 in the evobrutinib 75-mg twice-daily group, and 4.78±22.05 in the DMF group. The baseline adjusted rate ratios for the total number of lesions over time as compared with placebo were 1.45 in the evobrutinib 25-mg group (P = 0.32), 0.30 in the evobrutinib 75-mg once-daily group (P = 0.005), and 0.44 in the evobrutinib 75-mg twice-daily group (P = 0.06). The unadjusted annualized relapse rate at week 24 was 0.37 in the placebo group, 0.57 in the evobrutinib 25-mg group, 0.13 in the evobrutinib 75-mg once-daily group, 0.08 in the evobrutinib 75-mg twice-daily group, and 0.20 in the DMF group. There was no significant effect of trial group on the change from baseline in the EDSS score. Elevations in liver aminotransferase values were observed with evobrutinib.. Patients with relapsing multiple sclerosis who received 75 mg of evobrutinib once daily had significantly fewer enhancing lesions during weeks 12 through 24 than those who received placebo. There was no significant difference with placebo for either the 25-mg once-daily or 75-mg twice-daily dose of evobrutinib, nor in the annualized relapse rate or disability progression at any dose. Longer and larger trials are required to determine the effect and risks of evobrutinib in patients with multiple sclerosis. (Funded by EMD Serono; ClinicalTrials.gov number, NCT02975349.).

Topics: Administration, Oral; Adult; Agammaglobulinaemia Tyrosine Kinase; Brain; Dimethyl Fumarate; Disease Progression; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Immunosuppressive Agents; Magnetic Resonance Imaging; Male; Middle Aged; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Piperidines; Placebos; Protein Kinase Inhibitors; Pyrimidines; Transaminases; Treatment Outcome

The main objective of this study was to investigate the tolerability and safety of the monoaminergic stabilizer (-)-OSU6162 in patients with multiple sclerosis (MS). In addition, a potential therapeutic effect of (-)-OSU6162 with focus on MS-related fatigue was estimated by means of various self-assessment rating scales as well as a clinical investigator-rated scale.. In this open-label, single-arm study, 30 MS patients received treatment with the monoaminergic stabilizer (-)-OSU6162 during 12 weeks. The dose of (-)-OSU6162 was 15 mg twice daily during the first 4-week period, up to 30 mg twice daily during the second 4-week period and up to 45 mg twice daily during the third 4-week period, with follow-up visits after 16 and 20 weeks. MS-related fatigue was rated by the clinical investigator or by self-assessments, using mainly established rating scales. Twenty-five patients completed the study.. (-)-OSU6162 was well tolerated by all patients, and no serious adverse events were observed. Therapeutically, improvements were observed with respect to fatigue and mood, as judged by ratings on the Mental Fatigue Scale (MFS), Short Form-36 (SF-36) scale and Beck Depression Inventory (BDI). Furthermore, the large majority of patients were rated as globally improved in the medical observers' rating scale Clinical Global Impression of Change (CGI-C).. In view of its good tolerability, (-)-OSU6162 may offer a new treatment option for alleviating mental fatigue, as well as depression, in MS. Larger, randomized double-blind controlled trials are warranted to confirm the present preliminary observations.

Topics: Adult; Depression; Fatigue; Female; Humans; Male; Middle Aged; Multiple Sclerosis; Piperidines; Psychiatric Status Rating Scales; Treatment Outcome

Treatment options for patients suffering from progressive forms of multiple sclerosis (MS) remain inadequate. Mast cells actively participate in the pathogenesis of MS, in part because they release large amounts of various mediators that sustain the inflammatory network. Masitinib, a selective oral tyrosine kinase inhibitor, effectively inhibits the survival, migration and activity of mast cells. This exploratory study assessed the safety and clinical benefit of masitinib in the treatment of primary progressive MS (PPMS) or relapse-free secondary progressive MS (rfSPMS).. Multicenter, randomized, placebo-controlled, proof-of-concept trial. Masitinib was administered orally at 3 to 6 mg/kg/day for at least 12 months, with dose adjustment permitted in event of insufficient response with no toxicity. The primary response endpoint was the change relative to baseline in the multiple sclerosis functional composite score (MSFC). Clinical response was defined as an increase in MSFC score relative to baseline of > 100%.. Thirty-five patients were randomized to receive masitinib (N = 27) or placebo (N = 8). Masitinib was relatively well tolerated with the most common adverse events being asthenia, rash, nausea, edema, and diarrhea. The overall frequency of adverse events was similar to the placebo group, however, a higher incidence of severe and serious events was associated with masitinib treatment. Masitinib appeared to have a positive effect on MS-related impairment for PPMS and rfSPMS patients, as evidenced by an improvement in MSFC scores relative to baseline, compared with a worsening MSFC score in patients receiving placebo; +103% ± 189 versus -60% ± 190 at month-12, respectively. This positive, albeit non-statistically significant response was observed as early as month-3 and sustained through to month-18, with similar trends seen in the PPMS and rfSPMS subpopulations. A total of 7/22 (32%) assessable masitinib patients reported clinical response following 12 months of treatment (according to the modified intent-to-treat population, observed cases) compared with none in the placebo group. The Expanded Disability Status Scale remained stable for both treatment groups.. These data suggest that masitinib is of therapeutic benefit to PPMS and rfSPMS patients and could therefore represent an innovative avenue of treatment for this disease. This exploratory trial provides evidence that may support a larger placebo-controlled investigation.

Topics: Administration, Oral; Benzamides; Female; France; Humans; Male; Middle Aged; Multiple Sclerosis; Pilot Projects; Piperidines; Placebo Effect; Pyridines; Thiazoles; Treatment Outcome

The goal of this study was to determine if memory would be improved by donepezil as compared to placebo in a multicenter, double-blind, randomized clinical trial (RCT).. Donepezil 10 mg daily was compared to placebo to treat memory impairment. Eligibility criteria included the following: age 18-59 years, clinically definite multiple sclerosis (MS), and performance ≤ ½ SD below published norms on the Rey Auditory Verbal Learning Test (RAVLT). Neuropsychological assessments were performed at baseline and 24 weeks. Primary outcomes were change on the Selective Reminding Test (SRT) of verbal memory and the participant's impression of memory change. Secondary outcomes included changes on other neuropsychological tests and the evaluating clinician's impression of memory change.. A total of 120 participants were enrolled and randomized to either donepezil or placebo. No significant treatment effects were found between groups on either primary outcome of memory or any secondary cognitive outcomes. A trend was noted for the clinician's impression of memory change in favor of donepezil (37.7%) vs placebo (23.7%) (p = 0.097). No serious or unanticipated adverse events attributed to study medication developed.. Donepezil did not improve memory as compared to placebo on either of the primary outcomes in this study.. This study provides Class I evidence which does not support the hypothesis that 10 mg of donepezil daily for 24 weeks is superior to placebo in improving cognition as measured by the SRT in people with MS whose baseline RAVLT score was 0.5 SD or more below average.

Topics: Adolescent; Adult; Cholinesterase Inhibitors; Donepezil; Double-Blind Method; Female; Humans; Indans; Male; Memory Disorders; Middle Aged; Multiple Sclerosis; Neuropsychological Tests; Piperidines; Treatment Outcome; Verbal Learning; Young Adult

Topics: Adolescent; Adult; Aged; Cognition Disorders; Disability Evaluation; Donepezil; Double-Blind Method; Executive Function; Female; Humans; Indans; Male; Middle Aged; Multiple Sclerosis; Neuropsychological Tests; Nootropic Agents; Piperidines; Retrospective Studies; Treatment Outcome; Verbal Learning; Young Adult

Acetylcholinesterase inhibitors are used to treat dementia associated with Alzheimer's disease, but their cognitive benefits may extend to additional disorders such as multiple sclerosis (MS). A single-center double-blind placebo-controlled randomized clinical trial evaluated the effectiveness of donepezil in a sample of 69 MS persons selected for initial memory difficulties. Subjects received neuropsychological assessment at baseline and after 24 weeks of treatment. The primary outcome was change in total recall on the Selective Reminding Test, a measure of verbal learning and memory. Secondary outcomes included other neuropsychological tests from the Brief Repeatable Battery, patient-reported change in memory, and physician-reported impression of cognitive change. Donepezil improved memory performance on the SRT compared to placebo. This benefit remained significant after controlling for various covariates including Expanded Disability Status Scale (EDSS), MS subtype, interferon beta use, treatment group beliefs, gender, baseline selected reminding test (SRT) score, and reading ability. Subjects on donepezil were more likely to report memory improvement (65.7%) than those on placebo (32.4%). The clinician also reported cognitive improvement in more donepezil (54.3%) than placebo (29.4%) subjects. No serious adverse events related to study medication occurred. However, more donepezil (34.3%) than placebo (8.8%) subjects reported unusual/abnormal dreams. Donepezil improved learning and memory in MS patients with initial cognitive difficulties in a single-center clinical trial. Replication of results in a larger multi-center investigation is warranted in order to more definitively assess the efficacy of this intervention.

Topics: Adult; Analysis of Variance; Cognition; Donepezil; Double-Blind Method; Female; Follow-Up Studies; Humans; Indans; Male; Memory; Middle Aged; Multiple Sclerosis; Neuropsychological Tests; Nootropic Agents; Piperidines; Retrospective Studies; Task Performance and Analysis; Time Factors

We assessed the safety and efficacy of orally administered CC chemokine receptor 1 (CCR1) antagonist in 105 patients with relapsing/remitting MS (RRMS) in a 16-week, randomized, double-blind, placebo-controlled trial. The primary endpoint was the cumulative number of newly active lesions on serial MRI scans. Other MRI, immunologic, and clinical outcomes were also explored. No significant treatment difference was observed for any tested MRI variable. CCR1 does not contribute to initial leukocyte infiltration in RRMS.

Topics: Central Nervous System; Chemokines; Chemotaxis, Leukocyte; Disease Progression; Double-Blind Method; Drug Administration Schedule; Humans; Immunosuppressive Agents; Magnetic Resonance Imaging; Multiple Sclerosis; Phenylurea Compounds; Piperidines; Placebos; Receptors, CCR1; Receptors, Chemokine; Signal Transduction; Treatment Outcome

To determine the effect of donepezil in treating memory and cognitive dysfunction in multiple sclerosis (MS).. This single-center double-blind placebo-controlled clinical trial evaluated 69 MS patients with cognitive impairment who were randomly assigned to receive a 24-week treatment course of either donepezil (10 mg daily) or placebo. Patients underwent neuropsychological assessment at baseline and after 24 weeks of treatment. The primary outcome was change in verbal learning and memory on the Selective Reminding Test (SRT). Secondary outcomes included other tests of cognitive function, patient-reported change in memory, and clinician-reported impression of cognitive change.. Donepezil-treated patients showed significant improvement in memory performance on the SRT compared to placebo (p = 0.043). The benefit of donepezil remained significant after controlling for various covariates including age, Expanded Disability Status Scale, baseline SRT score, reading ability, MS subtype, and sex. Donepezil-treated patients did not show significant improvements on other cognitive tests, but were more than twice as likely to report memory improvement than those in the placebo group (p = 0.006). The clinician also reported cognitive improvement in almost twice as many donepezil vs placebo patients (p = 0.036). No serious adverse events related to study medication occurred, although more donepezil (34.3%) than placebo (8.8%) subjects reported unusual/abnormal dreams (p = 0.010).. Donepezil improved memory in MS patients with initial cognitive impairment in a single center clinical trial. A larger multicenter investigation of donepezil in MS is warranted in order to more definitively assess the efficacy of this intervention.

Topics: Adolescent; Adult; Cholinesterase Inhibitors; Donepezil; Double-Blind Method; Female; Follow-Up Studies; Humans; Indans; Male; Memory; Middle Aged; Multiple Sclerosis; Nootropic Agents; Piperidines; Treatment Outcome

Cognitive dysfunction occurs in up to 65% of patients with multiple sclerosis (MS), but there is no effective treatment for the symptoms. The authors conducted a 12-week, open-pilot study to assess the efficacy and tolerability of donepezil HCl administered in patients with MS and cognitive impairment. Seventeen patients at a long-term care facility with Mini-Mental State Examination scores of < or = 25 received 5 mg of donepezil HCl for a 4-week period, followed by 8 weeks of 10 mg of donepezil HCl. Cognitive, neurologic, functional, and behavioral assessments were conducted at baseline and at 4 and 12 weeks. Statistically significant improvement was observed in several cognitive domains including attention, memory, and executive functioning, as well as different aspects of behavior. These data suggest that donepezil HCl merits further study as a potentially viable treatment option for patients with cognitive impairment associated with MS.

Topics: Adult; Aged; Attention; Cognition Disorders; Donepezil; Female; Humans; Indans; Male; Middle Aged; Multiple Sclerosis; Nootropic Agents; Piperidines; Psychiatric Status Rating Scales; Verbal Learning

Topics: Alopecia Areata; Humans; Multiple Sclerosis; Piperidines; Protein Kinase Inhibitors; Pyrimidines

Recent clinical trials have shown promising results for the next-generation Bruton's tyrosine kinase (BTK) inhibitor evobrutinib in the treatment of multiple sclerosis (MS). BTK has a central role in signaling pathways that govern the development of B cells. Whether and how BTK activity shapes B cells as key drivers of MS is currently unclear. Compared with levels of BTK protein, we found higher levels of phospho-BTK in ex vivo blood memory B cells from patients with relapsing-remitting MS and secondary progressive MS compared with controls. In these MS groups, BTK activity was induced to a lesser extent after anti-IgM stimulation. BTK positively correlated with CXCR3 expression, both of which were increased in blood B cells from clinical responders to natalizumab (anti-VLA-4 antibody) treatment. Under in vitro T follicular helper-like conditions, BTK phosphorylation was enhanced by T-bet-inducing stimuli, IFN-γ and CpG-ODN, while the expression of T-bet and T-bet-associated molecules CXCR3, CD21, and CD11c was affected by evobrutinib. Furthermore, evobrutinib interfered with in vitro class switching, as well as memory recall responses, and disturbed CXCL10-mediated migration of CXCR3+ switched B cells through human brain endothelial monolayers. These findings demonstrate a functional link between BTK activity and disease-relevant B cells and offer valuable insights into how next-generation BTK inhibitors could modulate the clinical course of patients with MS.

Topics: Agammaglobulinaemia Tyrosine Kinase; Humans; Multiple Sclerosis; Phosphorylation; Piperidines; Pyrimidines; T-Box Domain Proteins

Topics: Agammaglobulinaemia Tyrosine Kinase; Autoimmunity; Clinical Trials as Topic; Drug Industry; Humans; Imidazoles; Indoles; Multiple Sclerosis; Piperazines; Piperidines; Protein Kinase Inhibitors; Pyridones; Pyrimidines

Multiple sclerosis (MS) is a disease of the autoimmune-mediated disorder in the central nervous system, for which no effective therapeutic agent is currently available. The regulation of macrophage polarization toward M2 is a general benefit for treating MS. The gene biomarker-based phenotypic screening approach was developed, and 3,4-disubstituted piperidine derivative S-28 was identified as a lead compound modulating macrophage M2 polarization. Further SAR studies resulted in the discovery of the most potent modulator D11 that showed good oral bioavailability and significant in vivo therapeutic effects. Mechanistic studies demonstrated that the M2 polarization macrophages modulated by D11 mainly functioned through inhibiting the proliferation of T-cells and activating the phosphorylation of Stat3 and Akt. Therefore, the gene biomarker-based phenotypic screening was demonstrated as a promising tool for the discovery of novel macrophage M2 polarization modulators. Compound D11 may serve as a promising starting point for the development of therapeutics to treat MS.

Topics: Animals; Biological Availability; CD4-Positive T-Lymphocytes; Cell Proliferation; Encephalomyelitis, Autoimmune, Experimental; Genetic Markers; High-Throughput Screening Assays; Humans; Macrophages; Mice; Multiple Sclerosis; Phenotype; Phosphorylation; Piperidines; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; RAW 264.7 Cells; STAT3 Transcription Factor; Structure-Activity Relationship

The neurodegenerative disease multiple sclerosis (MS) is pathologically characterized by the massive influx of immune cells into the central nervous system. This contributes to demyelination and axonal damage which causes symptoms such as motor and cognitive dysfunctions. The migration of leukocytes from the blood vessel is orchestrated by a multitude of factors whose determination is essential in reducing cellular influx in MS patients and the experimental autoimmune encephalomyelitis (EAE) animal model. The here studied enzyme tissue Transglutaminase (TG2) is present intracellularly, on the cell surface and extracellularly. There it contributes to cellular adhesion and migration via its transamidation activity and possibly by facilitating cellular interaction with the extracellular matrix. Previous data from our group showed reduced motor symptoms and cellular infiltration after using a pharmacological TG2 transamidation activity inhibitor in a rat EAE model. However, it remained elusive if the cross-linking activity of the enzyme resulted in the observed effects. To follow-up, we now characterized two new small molecule TG2 activity inhibitors, BJJF078 and ERW1041E. Both compounds are potent inhibitor of recombinant human and mouse Transglutaminase enzyme activity, mainly TG2 and the close related enzyme TG1. In addition they did not affect the binding of TG2 to the extracellular matrix substrate fibronectin, a process via which TG2 promotes cellular adhesion and migration. We found, that ERW1041E but not BJJF078 resulted in reduced EAE disease motor-symptoms while neither caused apparent changes in pathology (cellular influx), Transglutaminase activity or expression of inflammation related markers in the spinal cord, compared to vehicle treated controls. Although we cannot exclude issues on bioavailability and in vivo efficacy of the used compounds, we hypothesize that extracellular TG1/TG2 activity is of greater importance than (intra-)cellular activity in mouse EAE pathology.

Topics: Animals; Anti-Inflammatory Agents; Benzamides; Cells, Cultured; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Enzyme Inhibitors; Fibronectins; GTP-Binding Proteins; Humans; Isoxazoles; Mice; Mice, Inbred C57BL; Monocytes; Multiple Sclerosis; Naphthalenes; Piperidines; Protein Binding; Protein Glutamine gamma Glutamyltransferase 2; Pyrrolidines; Quinolines; Spinal Cord; Transglutaminases

Effective therapies for multiple sclerosis (MS) are still missing. This neurological disease affects more than 2.5 million people worldwide. To date, biological immunomodulatory drugs are effective and safe during short-term treatment, but they are suitable only for parenteral administration and they are expensive. Accordingly, academic and industrial environments are still focusing their efforts toward the development of new MS drugs. Considering that neurodegeneration is a contributory factor in the onset of MS, herein we will focus on the crucial role played by sigma 1 receptors (S1Rs) in MS. A pilot study was performed, evaluating the effect of the S1R agonist (R)-RC33 on rat dorsal root ganglia experimental model. The encouraging results support the potential of S1R agonists for MS treatment.

Topics: Animals; Biphenyl Compounds; Disease Models, Animal; Immunomodulation; Models, Molecular; Molecular Conformation; Multiple Sclerosis; Neuroprotective Agents; Piperidines; Rats; Receptors, sigma; Sigma-1 Receptor

It is well known that dendritic cells (DCs) play a pivotal role in triggering self-specific responses. Conversely, tolerogenic DCs (tolDCs), a specialized subset, induce tolerance and negatively regulate autoreactive responses. Tofacitinib, a Janus kinase inhibitor developed by Pfizer for treatment of rheumatoid arthritis, is probable to be a promising candidate for inducing tolDCs. The aims of this study were to evaluate the effectiveness of tolDCs induced by tofacitinib in a myelin oligodendrocyte glycoprotein- (MOG-) specific experimental autoimmune encephalomyelitis (EAE) model and to investigate their effects on Th17/Treg balance in the animal model of multiple sclerosis (MS). Our results revealed that tofacitinib-treated DCs maintained a steady semimature phenotype with a low level of proinflammatory cytokines and costimulatory molecules. DCs treated by tofacitinib also induced antigen-specific T cells hyporesponsiveness in a concentration-dependent manner. Upon intravenous injection into EAE mice, MOG pulsed tolDCs significantly dampened disease activity, and adoptive cell therapy (ACT) disturbed Th17/Treg balance with a remarkable decrease of Th1/Th17 cells and an increase in regulatory T cells (Tregs). Overall, DCs modified by tofacitinib exhibited a typical tolerogenic phenotype, and the antigen-specific tolDCs may represent a new avenue of research for the development of future clinical treatments for MS.

Topics: Animals; CD4 Lymphocyte Count; Cells, Cultured; Dendritic Cells; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Female; Immune Tolerance; Immunotherapy, Adoptive; Mice; Mice, Inbred C57BL; Multiple Sclerosis; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; T-Lymphocytes, Regulatory; Th1 Cells; Th17 Cells

The endocannabinoids 2-araquidonoylglycerol (2-AG) and anandamide (AEA) are bioactive lipids crucially involved in the regulation of brain function in basal and pathological conditions. Blockade of endocannabinoid metabolism has emerged as a promising therapeutic strategy for inflammatory diseases of the central nervous system, including myelin disorders such as multiple sclerosis. Nevertheless, the biological actions of endocannabinoid degradation inhibitors in oligodendrocytes and white matter tracts are still ill defined. Here we show that the selective monoacylglycerol lipase (MAGL) inhibitor JZL184 suppressed cell death by mild activation of AMPA receptors in oligodendrocytes in vitro, an effect that was mimicked by MAGL substrate 2-AG and by the second major endocannabinoid AEA, in a concentration-dependent manner, whereas inhibition of the AEA metabolizing enzyme fatty acid amide hydrolase with URB597 was devoid of effect. Pharmacological experiments suggested that oligodendrocyte protection from excitotoxicity resulting from MAGL blockade involved the activation of cannabinoid CB1 receptors and the reduction of AMPA-induced cytosolic calcium overload, mitochondrial membrane depolarization, and production of reactive oxygen species. Administration of JZL184 under a therapeutic regimen decreased clinical severity, prevented demyelination, and reduced inflammation in chronic experimental autoimmune encephalomyelitis. Furthermore, MAGL inactivation robustly preserved myelin integrity and suppressed microglial activation in the cuprizone-induced model of T-cell-independent demyelination. These findings suggest that MAGL blockade may be a useful strategy for the treatment of immune-dependent and -independent damage to the white matter.

Topics: Amidohydrolases; Animals; Benzamides; Benzodioxoles; Cannabinoid Receptor Modulators; Carbamates; Demyelinating Diseases; Monoacylglycerol Lipases; Multiple Sclerosis; Oligodendroglia; Piperidines; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1

Oligodendrocytes are the myelin-forming cells of the central nervous system (CNS). Failure of myelin development and oligodendrocyte loss results in serious human disorders, including multiple sclerosis. Here, we show that donepezil, an acetlycholinesterase inhibitor developed for the treatment of Alzheimer's disease, can stimulate oligodendrocyte differentiation and maturation of neural stem cell-derived oligodendrocyte progenitor cells without affecting proliferation or cell viability. Transcripts for essential myelin-associated genes, such as PLP, MAG, MBP, CNPase, and MOG, in addition to transcription factors that regulate oligodendrocyte differentiation and myelination, were rapidly increased after treatment with donepezil. Furthermore, luciferase assays confirmed that both MAG and MBP promoters display increased activity upon donepezil-induced oligodendrocytes differentiation, suggesting that donepezil increases myelin gene expression mainly through enhanced transcription. We also found that the increase in the number of oligodendrocytes observed following donepezil treatment was significantly inhibited by the nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine, but not by the muscarinic acetylcholine receptor antagonist scopolamine. Moreover, donepezil-induced myelin-related gene expression was suppressed by mecamylamine at both the mRNA and protein level. These results suggest that donepezil stimulates oligodendrocyte differentiation and myelin-related gene expression via nAChRs in neural stem cell-derived oligodendrocyte progenitor cells. We show that donepezil, a drug for the treatment of Alzheimer disease, can stimulate oligodendrocyte differentiation and maturation of oligodendrocyte progenitor cells. Transcripts for essential myelin-associated genes, such as PLP, MAG, MBP, CNPase and MOG in addition to transcripton factors that regulate oligodendrocyte differentiation and myelination were rapidly increased after treatment with donepezil. These effects were partly dependent on nicotinic acetylcholine receptor (nAChR).

Topics: Animals; Cell Differentiation; Cells, Cultured; Central Nervous System; Donepezil; Female; Gene Expression; Indans; Mice; Multiple Sclerosis; Myelin Basic Protein; Neurogenesis; Oligodendroglia; Piperidines; Receptors, Nicotinic; Stem Cells

The occurrence of cognitive disturbances upon CNS inflammation or infection has been correlated with increased levels of the cytokine tumor necrosis factor-α (TNFα). To date, however, no specific mechanism via which this cytokine could alter cognitive circuits has been demonstrated. Here, we show that local increase of TNFα in the hippocampal dentate gyrus activates astrocyte TNF receptor type 1 (TNFR1), which in turn triggers an astrocyte-neuron signaling cascade that results in persistent functional modification of hippocampal excitatory synapses. Astrocytic TNFR1 signaling is necessary for the hippocampal synaptic alteration and contextual learning-memory impairment observed in experimental autoimmune encephalitis (EAE), an animal model of multiple sclerosis (MS). This process may contribute to the pathogenesis of cognitive disturbances in MS, as well as in other CNS conditions accompanied by inflammatory states or infections.

Topics: Animals; Astrocytes; Dentate Gyrus; Encephalomyelitis, Autoimmune, Experimental; Humans; Learning; Memory; Mice; Multiple Sclerosis; Piperidines; Receptors, N-Methyl-D-Aspartate; Receptors, Tumor Necrosis Factor, Type I; Signal Transduction; Tumor Necrosis Factor-alpha

Topics: Abatacept; Adult; Anticoagulants; Antidiarrheals; Antitubercular Agents; Benzazepines; Canagliflozin; Dimethyl Fumarate; Dipeptidyl-Peptidase IV Inhibitors; Drug Approval; Dyspareunia; Humans; Hypoglycemic Agents; Multiple Sclerosis; Obesity; Oligonucleotides; Piperidines; Proanthocyanidins; Tamoxifen; Uracil

Topics: 4-Aminopyridine; Donepezil; Follow-Up Studies; Humans; Indans; Middle Aged; Multiple Sclerosis; Piperidines; Potassium Channel Blockers; Risk Assessment; Seizures; Severity of Illness Index

Multiple sclerosis (MS) is the leading cause of neurological disability among young and middle-aged adults. One of the most devastating consequences of MS in this relatively young population group is unemployment. Although certain demographic and disease factors have been associated with employment, few studies have examined the contribution of person-specific factors, such as personality.. The goal of this study was to determine the extent to which personality, demographics, and clinical measures contribute to unemployment in MS.. A total of 101 individuals with MS who were enrolled in a clinical trial on cognition underwent a brief neuropsychological battery and completed questionnaires related to vocation, mood, fatigue, and personality. Neurological impairment was measured with the Expanded Disability Status Scale (EDSS).. Employment status was related with disease duration, MS subtype, level of neurological impairment, fatigue, performance on measures assessing information processing speed (Symbol Digit Modalities Test (SDMT)), learning and memory (Selective Reminding Test), and the personality characteristic of persistence. Based on a forward logistic regression analysis, EDSS, SDMT, and persistence were the strongest predictors of employment status.. These findings underscore the importance of personality on outcomes in MS and point to the need for more clinical attention and research in this area.

Topics: Adult; Affect; Chi-Square Distribution; Cognition; Cognition Disorders; Cost of Illness; Cross-Sectional Studies; Disability Evaluation; Donepezil; Fatigue; Female; Humans; Indans; Learning; Logistic Models; Male; Memory; Middle Aged; Multiple Sclerosis; Neuropsychological Tests; New York; Nootropic Agents; Personality; Piperidines; Predictive Value of Tests; Randomized Controlled Trials as Topic; Retrospective Studies; Risk Assessment; Risk Factors; Severity of Illness Index; Surveys and Questionnaires; Time Factors; Unemployment

Cognitive dysfunction affects approximately half of the patients with multiple sclerosis (MS). Cholinesterase inhibitor drugs are approved to treat cognitive dysfunction associated with degenerative dementia.. To critically assess current evidence regarding the efficacy of the cholinesterase inhibitor, donepezil in the treatment of MS-associated cognitive impairment.. The objective was addressed through the development of a structured critically appraised topic. This included a clinical scenario, structured question, literature search strategy, critical appraisal, results, evidence summary, commentary, and bottom line conclusions. Participants included consultant and resident neurologists, a medical librarian, clinical epidemiologists, and content experts in the fields of behavioral neurology and MS.. A randomized control trial was selected for critical appraisal. This trial randomized MS patients to receive donepezil 10 mg daily or placebo for treatment of MS-related cognitive dysfunction. There was no significant treatment effect found between the 2 groups on either the primary outcome of memory or any of the secondary cognitive measures. Post hoc analyses suggested a trend favoring donepezil in subjects with greater baseline cognitive dysfunction.. Donepezil 10 mg daily for 24 weeks is not superior to placebo in improving MS-related cognitive dysfunction.

Topics: Cognition Disorders; Donepezil; Humans; Indans; Memory; Multiple Sclerosis; Nootropic Agents; Piperidines; Treatment Outcome

Topics: Anticoagulants; Antineoplastic Agents; Benzimidazoles; beta-Alanine; Carcinoma, Neuroendocrine; Clinical Trials as Topic; Dabigatran; Drug Approval; Efficiency, Organizational; Fingolimod Hydrochloride; Humans; Immunosuppressive Agents; Multiple Sclerosis; Patient Safety; Piperidines; Propylene Glycols; Quinazolines; Risk; Sphingosine; Stroke; Thyroid Neoplasms; Time Factors; United States; United States Food and Drug Administration

Topics: Amino Acids; Animals; Autoimmunity; Cell Differentiation; Eukaryotic Initiation Factor-2; Evolution, Molecular; Gene Expression Regulation; Humans; Interleukin-17; Lymphopoiesis; Mice; Multiple Sclerosis; Phosphorylation; Piperidines; Protein Biosynthesis; Protein Serine-Threonine Kinases; Quinazolinones; Signal Transduction; T-Lymphocyte Subsets; T-Lymphocytes, Helper-Inducer

Cannabinoids may exhibit symptom control in multiple sclerosis (MS). We show here that cannabinoid receptor (CBR) agonists can also be immunosuppressive and neuroprotective in models of MS. Immunosuppression was associated with reduced: myelin-specific T cell responses; central nervous system infiltration and reduced clinical disease. This was found to be largely CB(1)R-dependent and only occurred at doses that induced significant cannabimimetic effects that would not be achieved clinically. Lower, non-immunosuppressive doses of cannabinoids however, slowed the accumulation of nerve loss and disability, despite failing to inhibit relapses. This further highlights the neuroprotective potential of cannabinoids to slow the progression of MS.

Topics: Animals; Benzoxazines; Cannabinoids; Encephalomyelitis, Autoimmune, Experimental; Immunosuppressive Agents; Mice; Mice, Inbred C57BL; Morpholines; Multiple Sclerosis; Naphthalenes; Neuroprotective Agents; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Rimonabant; T-Lymphocytes

Topics: Adrenergic beta-Agonists; Albuterol; Amantadine; Analgesics, Non-Narcotic; Androstadienes; Aromatase Inhibitors; Asthma; Bronchodilator Agents; Donepezil; Drug Therapy, Combination; Female; Fluticasone; Food Hypersensitivity; Humans; Indans; Interferons; Latex Hypersensitivity; Letrozole; Mandelic Acids; Middle Aged; Multiple Sclerosis; Nebulizers and Vaporizers; Nitriles; Nootropic Agents; Parasympatholytics; Paresthesia; Piperidines; Respiratory Function Tests; Salmeterol Xinafoate; Thyroxine; Triazoles

Topics: Adult; Analgesia, Obstetrical; Analgesia, Patient-Controlled; Delivery, Obstetric; Female; Humans; Infant, Newborn; Infusions, Intravenous; Labor Pain; Male; Multiple Sclerosis; Narcotics; Piperidines; Pregnancy; Pregnancy Complications; Remifentanil

Topics: Cholinesterase Inhibitors; Donepezil; Humans; Indans; Memory Disorders; Multiple Sclerosis; Piperidines; Randomized Controlled Trials as Topic

Laboratory research including animal models of human disease suggests that cannabinoids might have therapeutic potential in multiple sclerosis (MS). We have recently seen a 46-year-old woman who developed MS after starting treatment with a cannabinoid receptor antagonist for obesity. The occurrence of MS several months after starting a cannabinoid receptor antagonist suggests that the cannabinoid system might indeed be relevant to disease pathogenesis in MS.

Topics: Appetite Depressants; Cannabinoid Receptor Antagonists; Female; Humans; Magnetic Resonance Imaging; Middle Aged; Multiple Sclerosis; Obesity; Piperidines; Pyrazoles; Receptors, Cannabinoid; Rimonabant

Topics: Cholinesterase Inhibitors; Cognition Disorders; Donepezil; Humans; Indans; Memory; Multiple Sclerosis; Nootropic Agents; Piperidines

Activation of cannabinoid receptors causes inhibition of spasticity, in a mouse model of multiple sclerosis, and of persistent pain, in the rat formalin test. The endocannabinoid anandamide inhibits spasticity and persistent pain. It not only binds to cannabinoid receptors but is also a full agonist at vanilloid receptors of type 1 (VR1). We found here that vanilloid VR1 receptor agonists (capsaicin and N-N'-(3-methoxy-4-aminoethoxy-benzyl)-(4-tert-butyl-benzyl)-urea [SDZ-249-665]) exhibit a small, albeit significant, inhibition of spasticity that can be attenuated by the vanilloid VR1 receptor antagonist, capsazepine. Arvanil, a structural "hybrid" between capsaicin and anandamide, was a potent inhibitor of spasticity at doses (e.g. 0.01 mg/kg i.v.) where capsaicin and cannabinoid CB(1) receptor agonists were ineffective. The anti-spastic effect of arvanil was unchanged in cannabinoid CB(1) receptor gene-deficient mice or in wildtype mice in the presence of both cannabinoid and vanilloid receptor antagonists. Likewise, arvanil (0.1-0.25 mg/kg) exhibited a potent analgesic effect in the formalin test, which was not reversed by cannabinoid and vanilloid receptor antagonists. These findings suggest that activation by arvanil of sites of action different from cannabinoid CB(1)/CB(2) receptors and vanilloid VR1 receptors leads to anti-spastic/analgesic effects that might be exploited therapeutically.

Topics: Animals; Arachidonic Acids; Benzoxazines; Camphanes; Cannabinoid Receptor Modulators; Capsaicin; Disease Models, Animal; Dose-Response Relationship, Drug; Genotype; Mice; Mice, Inbred Strains; Mice, Knockout; Morpholines; Multiple Sclerosis; Muscle Spasticity; Naphthalenes; Pain; Pain Measurement; Piperidines; Pyrazoles; Receptors, Cannabinoid; Receptors, Drug; Rimonabant

Spasticity is a complicating sign in multiple sclerosis that also develops in a model of chronic relapsing experimental autoimmune encephalomyelitis (CREAE) in mice. In areas associated with nerve damage, increased levels of the endocannabinoids, anandamide (arachidonoylethanolamide, AEA) and 2-arachidonoyl glycerol (2-AG), and of the AEA congener, palmitoylethanolamide (PEA), were detected here, whereas comparable levels of these compounds were found in normal and non-spastic CREAE mice. While exogenously administered endocannabinoids and PEA ameliorate spasticity, selective inhibitors of endocannabinoid re-uptake and hydrolysis-probably through the enhancement of endogenous levels of AEA, and, possibly, 2-arachidonoyl glycerol-significantly ameliorated spasticity to an extent comparable with that observed previously with potent cannabinoid receptor agonists. These studies provide definitive evidence for the tonic control of spasticity by the endocannabinoid system and open new horizons to therapy of multiple sclerosis, and other neuromuscular diseases, based on agents modulating endocannabinoid levels and action, which exhibit little psychotropic activity.

Topics: Amides; Animals; Arachidonic Acids; Brain; Cannabinoid Receptor Modulators; Cannabinoids; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Endocannabinoids; Ethanolamines; Glycerides; Humans; Mice; Mice, Inbred Strains; Multiple Sclerosis; Palmitic Acids; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Receptors, Cannabinoid; Receptors, Drug; Rimonabant; Spasm; Spinal Cord

Chronic relapsing experimental allergic encephalomyelitis (CREAE) is an autoimmune model of multiple sclerosis. Although both these diseases are typified by relapsing-remitting paralytic episodes, after CREAE induction by sensitization to myelin antigens Biozzi ABH mice also develop spasticity and tremor. These symptoms also occur during multiple sclerosis and are difficult to control. This has prompted some patients to find alternative medicines, and to perceive benefit from cannabis use. Although this benefit has been backed up by small clinical studies, mainly with non-quantifiable outcomes, the value of cannabis use in multiple sclerosis remains anecdotal. Here we show that cannabinoid (CB) receptor agonism using R(+)-WIN 55,212, delta9-tetrahydrocannabinol, methanandamide and JWH-133 (ref. 8) quantitatively ameliorated both tremor and spasticity in diseased mice. The exacerbation of these signs after antagonism of the CB1 and CB2 receptors, notably the CB1 receptor, using SR141716A and SR144528 (ref. 8) indicate that the endogenous cannabinoid system may be tonically active in the control of tremor and spasticity. This provides a rationale for patients' indications of the therapeutic potential of cannabis in the control of the symptoms of multiple sclerosis, and provides a means of evaluating more selective cannabinoids in the future.

Topics: Animals; Camphanes; Cannabinoids; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Mice; Multiple Sclerosis; Piperidines; Pyrazoles; Receptors, Cannabinoid; Receptors, Drug; Rimonabant; Spasm; Tremor

To examine the potential of eliprodil-a neuroprotective agent with a high affinity for sigma-receptors-to promote myelination in neuron-oligodendrocytes cocultures.. Remyelination is one of the major therapeutic issues in MS. Because neuronal integrity is required for CNS myelination, the authors postulated that neuroprotective molecules might favor myelination.. Two experimental culture conditions were compared: standard medium Bottenstein and Sato ([B-S] medium) and a medium depleted of both thyroid hormones and progesterone (depleted [D] medium). Myelination was quantified by counting the number of myelinated internodes, identified immunocytochemically with an antimyelin basic protein (anti-MBP) antibody.. The authors first confirmed that in D medium myelination was reduced by a factor of 3.5 compared with cultures maintained in B-S medium. Under both culture conditions, addition of 10(-6) M eliprodil did not modify significantly the total number of either microtubule associated protein-2-positive neurons or MBP-positive oligodendrocytes. However, eliprodil induced a twofold (p < 0.01) increase in myelination when added to B-S medium, and a 4.7-fold (p < 0.0001) increase when added to D medium.. Although the molecular mechanism mediating the effect of the sigma-receptor agonist on myelination remains to be elucidated, these results strongly suggest that neuroprotective molecules may be of therapeutic interest in demyelinating diseases such as MS.

Topics: Animals; Axons; Central Nervous System; Coculture Techniques; Drug Evaluation, Preclinical; Forecasting; Mice; Multiple Sclerosis; Myelin Sheath; Neurons; Neuroprotective Agents; Oligodendroglia; Piperidines; Receptors, sigma; Stimulation, Chemical; Triiodothyronine

The CC chemokines macrophage inflammatory protein-1alpha (MIP-1alpha) and RANTES (regulated on activation normal T cell expressed) have been implicated in rheumatoid arthritis and multiple sclerosis. Since their effects are mediated through the CCR1 chemokine receptor, we set up a small molecule CCR1 antagonist program to search for inhibitors. Through high capacity screening we discovered a number of 4-hydroxypiperidine compounds with CCR1 antagonist activity and report their synthesis and in vitro pharmacology here. Scatchard analysis of the competition binding data revealed that the compounds had Ki values ranging from 40 to 4000 nM. The pharmacological profile of the most potent member of this series, compound 1 (2-2-diphenyl-5-(4-chlorophenyl)piperidin-lyl)valeronitri te), was further evaluated. Compound 1 showed concentration-dependent inhibition of MIP-1alpha-induced extracellular acidification and Ca2+ mobilization demonstrating functional antagonism. When given alone, the compound did not elicit any responses, indicating the absence of intrinsic agonist activity. Compound 1 inhibited MIP-1alpha- and RANTES-induced migration in peripheral blood mononuclear cells in a dose-responsive manner. Selectivity testing against a panel of seven transmembrane domain receptors indicated that compound 1 is inactive on a number of receptors at concentrations up to 10 microM. This is the first description of CCR1 receptor antagonists that may be useful in the treatment of chronic inflammatory diseases involving MIP-1alpha, RANTES, and CCR1.

Topics: Arthritis, Rheumatoid; Cell Line; Chemokine CCL3; Chemokine CCL4; Chemokine CCL5; Chemotaxis, Leukocyte; Humans; Hydroxylation; Kinetics; Ligands; Macrophage Inflammatory Proteins; Multiple Sclerosis; Piperidines; Receptors, CCR1; Receptors, Chemokine

Topics: Cisapride; Female; Gastric Emptying; Gastroparesis; Humans; Middle Aged; Multiple Sclerosis; Parasympathomimetics; Piperidines

Electron spin resonance (ESR) was used in a search for a possible generalized membrane defect underlying myelin instability in multiple sclerosis (MS). In contrast to most ESR studies of biological membranes, a small, nonelectrolyte spin label, TEMPO, was chosen; its partition coefficient was determined in extracted erythrocyte lipids from MS patients and normal controls. No differences were observed the advantages and limitations of TEMPO in comparison with lipid spin labels as probes for the study of biological membranes are discussed.

Topics: Cyclic N-Oxides; Electron Spin Resonance Spectroscopy; Erythrocyte Membrane; Erythrocytes; Humans; Membrane Lipids; Multiple Sclerosis; Piperidines; Spin Labels; Temperature

Topics: Adolescent; Adrenocorticotropic Hormone; Anticonvulsants; Carisoprodol; Czechoslovakia; Humans; Male; Multiple Sclerosis; Muscle Relaxants, Central; Piperidines; Propiophenones; Rest; Vasodilator Agents; Vitamin B 12; Vitamin B Complex

Topics: Biometry; Humans; Multiple Sclerosis; Piperidines