Immune modulation and increased neurotrophic factor production in multiple sclerosis patients treated with testosterone

<p>Abstract</p> <p>Background</p> <p>Multiple sclerosis is a chronic inflammatory disease of the central nervous system with a pronounced neurodegenerative component. It has been suggested that novel treatment options are needed that target both aspects of the disease. Evidence from basic and clinical studies suggests that testosterone has an immunomodulatory as well as a potential neuroprotective effect that could be beneficial in MS.</p> <p>Methods</p> <p>Ten male MS patients were treated with 10 g of gel containing 100 mg of testosterone in a cross-over design (6 month observation period followed by 12 months of treatment). Blood samples were obtained at three-month intervals during the observation and the treatment period. Isolated blood peripheral mononuclear cells (PBMCs) were used to examine lymphocyte subpopulation composition by flow cytometry and <it>ex vivo </it>protein production of cytokines (IL-2, IFNγ, TNFα, IL-17, IL-10, IL-12p40, TGFβ1) and growth factors (brain-derived neurotrophic factor BDNF, platelet-derived growth factor PDGF-BB, nerve growth factor NGF, and ciliary neurotrophic factor CNTF). Delayed type hypersensitivity (DTH) skin recall tests were obtained before and during treatment as an <it>in vivo </it>functional immune measure.</p> <p>Results</p> <p>Testosterone treatment significantly reduced DTH recall responses and induced a shift in peripheral lymphocyte composition by decreasing CD4+ T cell percentage and increasing NK cells. In addition, PBMC production of IL-2 was significantly decreased while TGFβ1 production was increased. Furthermore, PBMCs obtained during the treatment period produced significantly more BDNF and PDGF-BB.</p> <p>Conclusion</p> <p>These results are consistent with an immunomodulatory effect of testosterone treatment in MS. In addition, increased production of BDNF and PDGF-BB suggests a potential neuroprotective effect.</p> <p>Trial Registration</p> <p>NCT00405353 <url>http://www.clinicaltrials.gov</url></p

Smaller cornu ammonis 2-3/dentate gyrus volumes and elevated cortisol in multiple sclerosis patients with depressive symptoms.

BACKGROUND: The hippocampus is likely involved in mood disorders, but in vivo evidence for the role of anatomically distinct hippocampal subregions is lacking. Multiple sclerosis, an inflammatory disease of the central nervous system, is linked to a high prevalence of depression as well as hippocampal damage and may thus provide important insight into the pathologic correlates of medical depression. We examined the role of subregional hippocampal volume for depression in relapsing-remitting multiple sclerosis.METHODS: Anatomically defined hippocampal subregional volumes (cornu ammonis 1-3 [CA1-CA3] and the dentate gyrus [CA23DG], subiculum, entorhinal cortex) were measured using a high-resolution T2-weighted magnetic resonance imaging sequence in 29 relapsing-remitting multiple sclerosis patients and 20 matched healthy control subjects. Diurnal salivary cortisol was assessed at awakening, 4 pm, and 9 pm on 2 consecutive days. Subjects also completed the Beck Depression Inventory.RESULTS: Multiple sclerosis patients showed smaller hippocampal volumes compared with control subjects, particularly in the CA1 and subiculum subregions. In addition, multiple sclerosis patients with depressive symptoms (Beck Depression Inventory score &gt;13) also showed smaller CA23DG volumes and higher cortisol levels. Within the multiple sclerosis group, CA23DG volume was correlated with depressive symptoms and cortisol levels. There were no associations with number of previous steroid treatments, global atrophy, or disease duration.CONCLUSIONS: This report provides in vivo evidence for selective association of smaller CA23DG subregional volumes in the hippocampus with cortisol hypersecretion and depressive symptoms in multiple sclerosis

Neuroprotective effects of testosterone treatment in men with multiple sclerosis.

Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease of the central nervous system. While current medication reduces relapses and inflammatory activity, it has only a modest effect on long-term disability and&nbsp;gray matter atrophy. Here, we have characterized the potential neuroprotective effects of testosterone on cerebral gray matter in a pilot clinical trial. Ten men with relapsing-remitting MS were included in this open-label phase II trial. Subjects were observed without treatment for 6&nbsp;months, followed by testosterone treatment for another 12&nbsp;months. Focal gray matter loss as a marker for neurodegeneration was assessed using voxel-based morphometry. During the non-treatment phase, significant voxel-wise gray matter decreases were widespread (p≤&nbsp;0.05 corrected). However, during testosterone treatment, gray matter loss was no longer evident. In fact, a significant gray matter increase in the right frontal cortex was observed (p≤&nbsp;0.05 corrected). These observations support the potential of testosterone treatment to stall (and perhaps even reverse) neurodegeneration associated with MS. Furthermore, they warrant the investigation of testosterone's neuroprotective effects in larger, placebo controlled MS trials as well as in other neurodegenerative diseases. This is the first report of gray matter increase as the result of treatment in MS

Phase 2 Trial of Ibudilast in Progressive Multiple Sclerosis.

BACKGROUND: There are limited treatments for progressive multiple sclerosis. Ibudilast inhibits several cyclic nucleotide phosphodiesterases, macrophage migration inhibitory factor, and toll-like receptor 4 and can cross the blood-brain barrier, with potential salutary effects in progressive multiple sclerosis. METHODS: We enrolled patients with primary or secondary progressive multiple sclerosis in a phase 2 randomized trial of oral ibudilast (≤100 mg daily) or placebo for 96 weeks. The primary efficacy end point was the rate of brain atrophy, as measured by the brain parenchymal fraction (brain size relative to the volume of the outer surface contour of the brain). Major secondary end points included the change in the pyramidal tracts on diffusion tensor imaging, the magnetization transfer ratio in normal-appearing brain tissue, the thickness of the retinal nerve-fiber layer, and cortical atrophy, all measures of tissue damage in multiple sclerosis. RESULTS: Of 255 patients who underwent randomization, 129 were assigned to ibudilast and 126 to placebo. A total of 53% of the patients in the ibudilast group and 52% of those in the placebo group had primary progressive disease; the others had secondary progressive disease. The rate of change in the brain parenchymal fraction was -0.0010 per year with ibudilast and -0.0019 per year with placebo (difference, 0.0009; 95% confidence interval, 0.00004 to 0.0017; P=0.04), which represents approximately 2.5 ml less brain-tissue loss with ibudilast over a period of 96 weeks. Adverse events with ibudilast included gastrointestinal symptoms, headache, and depression. CONCLUSIONS: In a phase 2 trial involving patients with progressive multiple sclerosis, ibudilast was associated with slower progression of brain atrophy than placebo but was associated with higher rates of gastrointestinal side effects, headache, and depression. (Funded by the National Institute of Neurological Disorders and Stroke and others; NN102/SPRINT-MS ClinicalTrials.gov number, NCT01982942 .)

Phase 2 Trial of Ibudilast in Progressive Multiple Sclerosis

BackgroundThere are limited treatments for progressive multiple sclerosis. Ibudilast inhibits several cyclic nucleotide phosphodiesterases, macrophage migration inhibitory factor, and toll-like receptor 4 and can cross the blood-brain barrier, with potential salutary effects in progressive multiple sclerosis.MethodsWe enrolled patients with primary or secondary progressive multiple sclerosis in a phase 2 randomized trial of oral ibudilast (≤100 mg daily) or placebo for 96 weeks. The primary efficacy end point was the rate of brain atrophy, as measured by the brain parenchymal fraction (brain size relative to the volume of the outer surface contour of the brain). Major secondary end points included the change in the pyramidal tracts on diffusion tensor imaging, the magnetization transfer ratio in normal-appearing brain tissue, the thickness of the retinal nerve-fiber layer, and cortical atrophy, all measures of tissue damage in multiple sclerosis.ResultsOf 255 patients who underwent randomization, 129 were assigned to ibudilast and 126 to placebo. A total of 53% of the patients in the ibudilast group and 52% of those in the placebo group had primary progressive disease; the others had secondary progressive disease. The rate of change in the brain parenchymal fraction was -0.0010 per year with ibudilast and -0.0019 per year with placebo (difference, 0.0009; 95% confidence interval, 0.00004 to 0.0017; P=0.04), which represents approximately 2.5 ml less brain-tissue loss with ibudilast over a period of 96 weeks. Adverse events with ibudilast included gastrointestinal symptoms, headache, and depression.ConclusionsIn a phase 2 trial involving patients with progressive multiple sclerosis, ibudilast was associated with slower progression of brain atrophy than placebo but was associated with higher rates of gastrointestinal side effects, headache, and depression. (Funded by the National Institute of Neurological Disorders and Stroke and others; NN102/SPRINT-MS ClinicalTrials.gov number, NCT01982942 .)

Design, rationale, and baseline characteristics of the randomized double-blind phase II clinical trial of ibudilast in progressive multiple sclerosis

BACKGROUND: Primary and secondary progressive multiple sclerosis (MS), collectively called progressive multiple sclerosis (PMS), is characterized by gradual progression of disability. The current anti-inflammatory treatments for MS have little or no efficacy in PMS in the absence of obvious active inflammation. Optimal biomarkers for phase II PMS trials is unknown. Ibudilast is an inhibitor of macrophage migration inhibitor factor and phosphodiesterases-4 and -10 and exhibits possible neuroprotective properties. The goals of SPRINT-MS study are to evaluate the safety and efficacy of ibudilast in PMS and to directly compare several imaging metrics for utility in PMS trials. METHODS: SPRINT-MS is a randomized, placebo-controlled, phase II trial of ibudilast in patients with PMS. Eligible subjects were randomized 1:1 to receive either ibudilast (100 mg/day) or placebo for 96 weeks. Imaging is conducted every 24 weeks for whole brain atrophy, magnetization transfer ratio, diffusion tensor imaging, cortical brain atrophy, and retinal nerve fiber layer thickness. Clinical outcomes include neurologic disability and patient reported quality of life. Safety assessments include laboratory testing, electrocardiography, and suicidality screening. RESULTS: A total of 331 subjects were enrolled, of which 255 were randomized onto active study treatment. Randomized subjects were 53.7% female and mean age 55.7 (SD 7.3) years. The last subject is projected to complete the study in May 2017. CONCLUSION: SPRINT-MS is designed to evaluate the safety and efficacy of ibudilast as a treatment for PMS while simultaneously validating five different imaging biomarkers as outcome metrics for use in future phase II proof-of-concept PMS trials