Dendritic Cells Loaded With FK506 Kill T Cells in an Antigen-Specific Manner and Prevent Autoimmunity in Vivo.
Dendritic cells loaded with FK506 kill T cells in an antigen-specific manner and prevent autoimmunity in vivo.
Filed under: Drug and Alcohol Rehabilitation
elife. 2013; 2: e00105
Orange DE, Blachere NE, Fak J, Parveen S, Frank MO, Herre M, Tian S, Monette S, Darnell RB
FK506 (Tacrolimus) is a potent inhibitor of calcineurin that blocks IL2 production and is widely used to prevent transplant rejection and treat autoimmunity. FK506 treatment of dendritic cells (FKDC) limits their capacity to stimulate T cell responses. FK506 does not prevent DC survival, maturation, or costimulatory molecule expression, suggesting that the limited capacity of FKDC to stimulate T cells may be due to inhibition of calcineurin signaling in the DC. Instead, we demonstrate that DC inhibit T cells by sequestering FK506 and continuously releasing the drug over several days. T cells encountering FKDC proliferate but fail to upregulate the survival factor bcl-xl and die, and IL2 restores both bcl-xl and survival. In mice, FKDC act in an antigen-specific manner to inhibit T-cell mediated autoimmune arthritis. This establishes that DCs can act as a cellular drug delivery system to target antigen specific T cells.DOI:http://dx.doi.org/10.7554/eLife.00105.001.
HubMed – drug
Post-natal treatment by a blood-brain-barrier permeable calpain inhibitor, SNJ1945 rescued defective function in lissencephaly.
Filed under: Drug and Alcohol Rehabilitation
Sci Rep. 2013; 3: 1224
Toba S, Tamura Y, Kumamoto K, Yamada M, Takao K, Hattori S, Miyakawa T, Kataoka Y, Azuma M, Hayasaka K, Amamoto M, Tominaga K, Wynshaw-Boris A, Wanibuchi H, Oka Y, Sato M, Kato M, Hirotsune S
Toward a therapeutic intervention of lissencephaly, we applied a novel calpain inhibitor, SNJ1945. Peri-natal or post-natal treatment with SNJ1945 rescued defective neuronal migration in Lis1(+/-) mice, impaired behavioral performance and improvement of (18)F-FDG uptake. Furthermore, SNJ1945 improved the neural circuit formation and retrograde transport of NFG in Lis1(+/-) mice. Thus, SNJ1945 is a potential drug for the treatment of human lissencephaly patients.
HubMed – drug
Evaluation of a candidate anti-arthritic drug using the mouse collagen antibody induced arthritis model and clinically relevant biomarkers.
Filed under: Drug and Alcohol Rehabilitation
Am J Transl Res. 2013; 5(1): 92-102
Bender AT, Spyvee M, Satoh T, Gershman B, Teceno T, Burgess L, Kumar V, Wu Y, Yang H, Ding Y, Akare S, Chen Q
The most rigorous scenario for testing a candidate rheumatoid arthritis therapeutic would be to use clinically relevant biomarkers and readouts to monitor disease development in an animal model that has a mechanism of disease that reflects the human condition. Treatment should begin when the full spectrum of arthritic processes, including bone damage, is present. We have tried to take this approach to evaluate a novel EP4 receptor antagonist (ER-886046) for its anti-arthritic potential. This work aimed not only to test a potential drug, but to also demonstrate a strategy for performing a more clinically relevant evaluation of future candidate arthritis treatments. A variety of biomarkers including: radiographic evaluation, clinical scoring, histology analysis, F4/80 macrophage immunohistochemistry, luminol bioluminescent imaging and (99m)Tc-MDP-SPECT imaging were evaluated as disease readouts in the mouse anti-collagen antibody induced arthritis model (CAIA). CAIA mice were treated either prophylactically or therapeutically with ER-886046 and the compound’s efficacy was probed using the various biomarkers and compared to the reference drugs prednisolone and celecoxib. The various biomarkers effectively measured different aspects of arthritis pathology and consistently demonstrated the efficacy of ER-886046. The compound was found to be effective even when dosed therapeutically after bone damaging processes had initiated. The results presented herein demonstrate how biomarkers and a clinically relevant experimental design can be used to evaluate a candidate therapeutic. Utilization of clinically relevant biomarkers may provide a means for more translatable pre-clinical testing of candidate therapeutics and may provide information on their mechanism of action.
HubMed – drug
Long-Lasting Antidepressant Action of Ketamine, but Not Glycogen Synthase Kinase-3 Inhibitor SB216763, in the Chronic Mild Stress Model of Mice.
Filed under: Drug and Alcohol Rehabilitation
PLoS One. 2013; 8(2): e56053
Ma XC, Dang YH, Jia M, Ma R, Wang F, Wu J, Gao CG, Hashimoto K
Clinical studies demonstrate that the N-methyl-D-aspartate (NMDA) receptor antagonist, ketamine, induces rapid antidepressant effects in patients with refractive major depressive disorder and bipolar depression. This rapid onset of action makes ketamine a highly attractive drug for patients, particularly those who do not typically respond to therapy. A recent study suggested that glycogen synthase kinase (GSK)-3 may underlie the rapid antidepressant action of ketamine, although the precise mechanisms are unclear. In this study, we examined the effects of ketamine and GSK-3 inhibitor SB216763 in the unpredictable, chronic mild stress (CMS) mouse model of mice.Adult C57/B6 male mice were divided into 2 groups, a non-stressed control group and the unpredictable CMS (35 days) group. Then, either vehicle, ketamine (10 mg/kg), or the established GSK-3 inhibitor, SB216763 (10 mg/kg), were administered into mice in the CMS group, while vehicle was administered to controls. In the open field test, there was no difference between the four groups (control+vehicle, CMS+vehicle, CMS+ketamine, CMS+SB216763). In the sucrose intake test, a 1% sucrose intake drop, seen in CMS mice, was significantly attenuated after a single dose of ketamine, but not SB216763. In the tail suspension test (TST) and forced swimming test (FST), the increased immobility time seen in CMS mice was significantly attenuated by a single dose of ketamine, but not SB216763. Interestingly, the ketamine-induced increase in the sucrose intake test persisted for 8 days after a single dose of ketamine. Furthermore, a single administration of ketamine, but not SB216763, significantly attenuated the immobility time of the TST and FST in the control (non-stressed) mice.These findings suggest that a single administration of ketamine, but not GSK-3 inhibitor SB216763, produces a long-lasting antidepressant action in CMS model mice.
HubMed – drug
Structural and functional imaging studies in chronic cannabis users: a systematic review of adolescent and adult findings.
Filed under: Drug and Alcohol Rehabilitation
PLoS One. 2013; 8(2): e55821
Batalla A, Bhattacharyya S, Yücel M, Fusar-Poli P, Crippa JA, Nogué S, Torrens M, Pujol J, Farré M, Martin-Santos R
The growing concern about cannabis use, the most commonly used illicit drug worldwide, has led to a significant increase in the number of human studies using neuroimaging techniques to determine the effect of cannabis on brain structure and function. We conducted a systematic review to assess the evidence of the impact of chronic cannabis use on brain structure and function in adults and adolescents.Papers published until August 2012 were included from EMBASE, Medline, PubMed and LILACS databases following a comprehensive search strategy and pre-determined set of criteria for article selection. Only neuroimaging studies involving chronic cannabis users with a matched control group were considered.One hundred and forty-two studies were identified, of which 43 met the established criteria. Eight studies were in adolescent population. Neuroimaging studies provide evidence of morphological brain alterations in both population groups, particularly in the medial temporal and frontal cortices, as well as the cerebellum. These effects may be related to the amount of cannabis exposure. Functional neuroimaging studies suggest different patterns of resting global and brain activity during the performance of several cognitive tasks both in adolescents and adults, which may indicate compensatory effects in response to chronic cannabis exposure.However, the results pointed out methodological limitations of the work conducted to date and considerable heterogeneity in the findings.Chronic cannabis use may alter brain structure and function in adult and adolescent population. Further studies should consider the use of convergent methodology, prospective large samples involving adolescent to adulthood subjects, and data-sharing initiatives.
HubMed – drug
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