[Show abstract][Hide abstract] ABSTRACT: Dimiracetam, a bicyclic 2-pyrrolidinone derivative originally developed as cognition enhancer, is a member of the nootropic family for which anedoctal efficacy in models of neuropathic pain has been reported. Its antineuropathic activity was evaluated in established models of neuropathic pain induced by nerve injury, chemotherapy or MIA-induced osteoarthritis. Acutely, dimiracetam was very effective in models of antiretroviral drug induced painful neuropathy, oxaliplatin-induced hyperalgesia and in the MIA-osteoarthritis. Chronic dimiracetam dosing in the MIA and ART- induced models completely reverted hyperalgesia back to the level of healthy controls. Once reached, the maximal effect was maintained despite dose diminution and increased inter-dose interval. The effect of the last dose outlasted dimiracetam half-life longer than 12 times. In synaptosomal preparations, dimiracetam counteracted the NMDA-induced release of glutamate with highest potency in the spinal cord, possibly via NMDA receptor isoforms containing pH-sensitive GluN1 and GluN2A subunits. Dimiracetam appears to be a promising and safe treatment for neuropathic pain conditions for which there are very limited therapeutic options.
[Show abstract][Hide abstract] ABSTRACT: Treatment of neuromuscular diseases is still an unsolved problem. Evidence over the last years strongly indicates the involvement of malformation and dysfunction of neuromuscular junctions in the development of such medical conditions. Stabilization of NMJs thus seems to be a promising approach to attenuate the disease progression of muscle wasting diseases. An important pathway for the formation and maintenance of NMJs is the agrin/Lrp4/MuSK pathway. Here we demonstrate that the agrin biologic NT-1654 is capable of activating the agrin/Lrp4/MuSK system in vivo, leading to an almost full reversal of the sarcopenia-like phenotype in neurotrypsin-overexpressing (SARCO) mice. We also show that injection of NT-1654 accelerates muscle re-innervation after nerve crush. This report demonstrates that a systemically administered agrin fragment has the potential to counteract the symptoms of neuromuscular disorders.
PLoS ONE 01/2014; 9(2):e88739. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: An international task force of academic and industry leaders in sarcopenia research met on December 5, 2012 in Orlando, Florida to develop guidelines for designing and executing randomized clinical trials of sarcopenia treatments. The Task Force reviewed results from previous trials in related disease areas to extract lessons relevant to future sarcopenia trials, including practical issues regarding the design and conduct of trials in elderly populations, the definition of appropriate target populations, and the selection of screening tools, outcome measures, and biomarkers. They discussed regulatory issues, the challenges posed by trials of different types of interventions, and the need for standardization and harmonization. The Task Force concluded with recommendations for advancing the field toward better clinical trials.
The Journal of Nutrition Health and Aging 01/2013; 17(7):612-8. · 2.39 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: INTRODUCTION: Sarcopenia is considered to be an enormous burden for both the individuals affected and for society at large. A multifactorial aetiology of this geriatric syndrome has been discussed. Amongst other pathomechanisms, the degeneration of the neuromuscular junction (NMJ) may be of major relevance. The intact balance between the pro-synaptic agent agrin and the anti-synaptic agent neurotrypsin ensures a structurally and functionally intact NMJ. Excessive cleavage of the native motoneuron-derived agrin by neurotrypsin into a C-terminal Agrin Fragment (CAF) leads to functional disintegration at the NMJ and may consecutively cause sarcopenia. The present study evaluates the hypothesis that CAF serum concentration is a potential marker for the loss of appendicular lean mass in older adults. It also explores how CAF concentration is influenced by vitamin D supplementation and physical exercise. METHOD: Serum was taken from 69 (47 female) prefrail community-dwelling older adults participating in a training intervention study to measure the CAF concentration using the Western blot technique. All participants were supplemented orally with vitamin D3 before the training intervention period commenced. Appendicular lean mass (aLM) was evaluated by dual energy X-ray absorptiometry. Multiple linear regression models were used to identify factors significantly associated with CAF concentration. RESULTS: Appendicular lean mass, age and sex were identified as significant explanatory factors for CAF concentration. Gait speed and hand grip strength were not associated with CAF concentration. Male participants showed a strong correlation (r=-0.524) between CAF serum concentration and aLM, whereas this was not the case (r=-0.219) in females. Vitamin D supplementation and physical exercise were significantly associated with a reduction in CAF concentration, especially in participants with initially high CAF concentrations. CONCLUSIONS: C-terminal Agrin Fragment could be a potential marker for identifying sarcopenia in a subgroup of affected individuals in the future. The decline of muscle mass seems to be a CAF-associated process in males, whereas the situation in females may be more complex and multifactorial. CAF concentration is reduced by vitamin D supplementation and physical exercise and therefore suggests a potentially positive effect on NMJs. Further prospective studies of sarcopenic patients in addition to muscle biopsy and electromyographical investigations are planned to verify the external validity of the CAF concept.
[Show abstract][Hide abstract] ABSTRACT: Sarcopenia is a recently defined medical condition described as age-associated loss of skeletal muscle mass and function. Recently, a transgenic mouse model was described linking dispersal of the neuromuscular junction caused by elevated agrin degradation to the rapid onset of sarcopenia. These mice show a significant elevation of serum levels of a C-terminal agrin fragment (CAF) compared to wild-type littermates. A series of experiments was designed to ascertain the significance of elevated agrin degradation in the development of human sarcopenia. A quantitative Western blot method was devised to detect CAF in sera of humans. A first trial on consenting blood donors (n=169; age 19-74years) detected CAF in the limited range of 2.76±0.95ng/ml. In sarcopenia patients (diagnosed according to clinical and instrumental standards) mean CAF levels were significantly elevated (p=9.8E10-9; n=73; age 65-87years) compared to aged matched controls. Of all sarcopenia patients, 40% had elevated, non-overlapping CAF levels compared to controls. Evidence is presented for a pathogenic role of the agrin/neurotrypsin system in a substantial subset of sarcopenia patients. These patients are characterized by elevated CAF blood levels compared to aged-matched healthy volunteers suggesting the identification of an agrin-dependent form of sarcopenia. Elevated CAF levels in a large subpopulation of sarcopenic patients suggest the existence of a specific form of sarcopenia for which CAF could become a biomarker and a new target for therapeutic interventions. The feasibility of this approach was demonstrated by the development of a small molecule capable of inhibiting neurotrypsin in vitro and in vivo.
[Show abstract][Hide abstract] ABSTRACT: A first Task Force on Sarcopenia was organized in Castres, near Toulouse, in 2008, with a series of papers on Sarcopenia published in the JNHAin 2009. Folowing this work a second international task force on Sarcopenia was organized in Rome in 2009 and the consensus paper was published in the JAMDA. Our third international Task Force was hosted in Albuquerque on Designing sarcopenia trials. We are happy to present now the abstract presented at our 4° International Task Force on Sarcopenia biomarkers just before the International Conference on Sacopenia research in 2011. Recommendations for imaging biomarkers in sarcopenia therapeutic trials; Defining Sarcopenia; Use of MRI and CT in Clinical Trials of Sarcopenia; Muscle quality and function: Implications for sarcopenia definitions and therapeutic targets; Modifiable risk factors for sarcopenia and mobility disability, which could be targeted in multicomponent interventions trials; Electrical Impedance Myography:A New Tool for the Assessment of Sarcopenia; Challenges in assessment of muscle strength and function - Lessons from als clinical trials; Novel Imaging Methods for Early Drug Development;Qualification of novel methodologies at the European Medicines Agency; Agrin-dependent sarcopenia. The consensus paper from this symposium will be submitted for publication shortly.
The Journal of Nutrition Health and Aging 01/2011; 15(10):834-46. · 2.39 Impact Factor