A Showcase of Bench-to-Bedside Regenerative Medicine at the 2010 ASNTR

Insight into the expanding themes of regenerative medicine is provided by the American Society for Neural Therapy and Repair's annual meeting. The 17th meeting covered a wide range of neurodegenerative disorders, exploring methods to elucidate the currently unknown mechanisms behind the disorders, as well as possible treatments ranging from the use of growth factors, gene therapy to cell transplantation. The importance of growth factors, both as a contributing factor to a disease and as a possible treatment either solo, or as a consequence of, or in conjunction with, stem cell therapy, was highlighted. The potential for viral vectors was also explored either for cells prior to transplantation or as a direct treatment regime into the brain itself. Identification of biomarkers that would allow early detection of a disease is an important factor in our fight against disease. The ability to now perform whole genome analysis and biomolecular profiling provides hope that such markers could be identified which not only could identify this likely to suffer from a disorder but also could allow its progress to be monitored. A few preclinical and clinical cell transplantation trials were also introduced as potential areas of followup in the years to come

Translating amniotic fluid-derived stem cells for transplantation in stroke

This article discusses possible applications of cells derived from human amniotic fluid in regenerative medicine, specifically in stroke therapy. Recent studies have evaluated amniotic fluid as a viable source for mesenchymal stem cells in the expansion of cell-based transplantation. Laboratory data have demonstrated the ability of amniotic fluid stem cells (AFSC) to act as biobridges or subdural patch-like networks when treating traumatic brain injury (TBI). Also AFSCs have been shown to differentiate along the neuronal lineage following transplantation in animal models of brain disorders. In addition to the cells' many clinical applications, AFSCs can be harvested without raising any ethical concern. This paper evaluates the characteristics of AFSCs, along with the functional benefits of using the cells in animal stroke models, reinforcing the potential advantages of deriving stem cells from amniotic fluid, for stroke treatment

A Step-up Approach for Cell Therapy in Stroke: Translational Hurdles of Bone Marrow-Derived Stem Cells

Stroke remains a significant unmet condition in the USA and throughout the world. To date, only approximately 3% of the population suffering an ischemic stroke benefit from the thrombolytic drug tissue plasminogen activator, largely due to the drug’s narrow therapeutic window. The last decade has witnessed extensive laboratory studies suggesting the therapeutic potential of cell-based therapy for stroke. Limited clinical trials of cell therapy in stroke patients are currently being pursued. Bone marrow-derived stem cells are an attractive, novel transplantable cell source for stroke. There remain many unanswered questions in the laboratory before cell therapy can be optimized for transplantation in the clinical setting. Here, we discuss the various translational hurdles encountered in bringing cell therapy from the laboratory to the clinic, using stem cell therapeutics as an emerging paradigm for stroke as a guiding principle. In particular, we focus on the preclinical studies of cell transplantation in experimental stroke with emphasis on a better understanding of mechanisms of action in an effort to optimize efficacy and to build a safety profile for advancing cell therapy to the clinic. A forward looking strategy of combination therapy involving stem cell transplantation and pharmacologic treatment is also discussed

The Truth Is Out There: Biological Features and Clinical Indications of Extracellular Vesicles from Human Perinatal Stem Cells

The potential of perinatal tissues to provide cellular populations to be used in different applications of regenerative medicine is well established. Recently, the efforts of researchers are being addressed regarding the evaluation of cell products (secreted molecules or extracellular vesicles, EVs) to be used as an alternative to cellular infusion. The data regarding the effective recapitulation of most perinatal cells' properties by their secreted complement point in this direction. EVs secreted from perinatal cells exhibit key therapeutic effects such as tissue repair and regeneration, the suppression of inflammatory responses, immune system modulation, and a variety of other functions. Although the properties of EVs from perinatal derivatives and their significant potential for therapeutic success are amply recognized, several challenges still remain that need to be addressed. In the present review, we provide an up-to-date analysis of the most recent results in the field, which can be addressed in future research in order to overcome the challenges that are still present in the characterization and utilization of the secreted complement of perinatal cells and, in particular, mesenchymal stromal cells

Therapeutic targets and limits of minocycline neuroprotection in experimental ischemic stroke

<p>Abstract</p> <p>Background</p> <p>Minocycline, a second-generation tetracycline with anti-inflammatory and anti-apoptotic properties, has been shown to promote therapeutic benefits in experimental stroke. However, equally compelling evidence demonstrates that the drug exerts variable and even detrimental effects in many neurological disease models. Assessment of the mechanism underlying minocycline neuroprotection should clarify the drug's clinical value in acute stroke setting.</p> <p>Results</p> <p>Here, we demonstrate that minocycline attenuates both <it>in vitro </it>(oxygen glucose deprivation) and <it>in vivo </it>(middle cerebral artery occlusion) experimentally induced ischemic deficits by direct inhibition of apoptotic-like neuronal cell death involving the anti-apoptotic Bcl-2/cytochrome c pathway. Such anti-apoptotic effect of minocycline is seen in neurons, but not apparent in astrocytes. Our data further indicate that the neuroprotection is dose-dependent, in that only low dose minocycline inhibits neuronal cell death cascades at the acute stroke phase, whereas the high dose exacerbates the ischemic injury.</p> <p>Conclusion</p> <p>The present study advises our community to proceed with caution to use the minimally invasive intravenous delivery of low dose minocycline in order to afford neuroprotection that is safe for stroke.</p

Low dose intravenous minocycline is neuroprotective after middle cerebral artery occlusion-reperfusion in rats

BACKGROUND: Minocycline, a semi-synthetic tetracycline antibiotic, is an effective neuroprotective agent in animal models of cerebral ischemia when given in high doses intraperitoneally. The aim of this study was to determine if minocycline was effective at reducing infarct size in a Temporary Middle Cerebral Artery Occlusion model (TMCAO) when given at lower intravenous (IV) doses that correspond to human clinical exposure regimens. METHODS: Rats underwent 90 minutes of TMCAO. Minocycline or saline placebo was administered IV starting at 4, 5, or 6 hours post TMCAO. Infarct volume and neurofunctional tests were carried out at 24 hr after TMCAO using 2,3,5-triphenyltetrazolium chloride (TTC) brain staining and Neurological Score evaluation. Pharmacokinetic studies and hemodynamic monitoring were performed on minocycline-treated rats. RESULTS: Minocycline at doses of 3 mg/kg and 10 mg/kg IV was effective at reducing infarct size when administered at 4 hours post TMCAO. At doses of 3 mg/kg, minocycline reduced infarct size by 42% while 10 mg/kg reduced infarct size by 56%. Minocycline at a dose of 10 mg/kg significantly reduced infarct size at 5 hours by 40% and the 3 mg/kg dose significantly reduced infarct size by 34%. With a 6 hour time window there was a non-significant trend in infarct reduction. There was a significant difference in neurological scores favoring minocycline in both the 3 mg/kg and 10 mg/kg doses at 4 hours and at the 10 mg/kg dose at 5 hours. Minocycline did not significantly affect hemodynamic and physiological variables. A 3 mg/kg IV dose of minocycline resulted in serum levels similar to that achieved in humans after a standard 200 mg dose. CONCLUSIONS: The neuroprotective action of minocycline at clinically suitable dosing regimens and at a therapeutic time window of at least 4–5 hours merits consideration of phase I trials in humans in view of developing this drug for treatment of stroke

Object location and object recognition memory impairments, motivation deficits and depression in a model of Gulf War illness

doi: 10.3389/fnbeh.2014.00078 Object location and object recognition memory impairments, motivation deficits and depressio

Hibernation-like state induced by an opioid peptide protects against experimental stroke

BACKGROUND: Delta opioid peptide [D-ala2,D-leU5]enkephalin (DADLE) induces hibernation in summer ground squirrels, and enhances preservation and survival of isolated or transplanted lungs and hearts. In the present study, we investigated the protective effect of DADLE in the central nervous system. RESULTS: Adult Sprague-Dawley rats were pretreated with DADLE (4 mg/kg every 2 h x 4 injections, i.p.) or saline prior to unilateral occlusion of the middle cerebral artery (MCA). Daily behavioral tests revealed that ischemic animals treated with DADLE did not show any significant behavioral dysfunctions compared with saline-treated ischemic animals. Opioid antagonists only transiently inhibited the protective effect of DADLE, indicating the participation of non-opioid mechanisms in DADLE neuroprotection. Histological examination using triphenyltetrazolium chloride (TTC) revealed that brains from ischemic animals treated with DADLE, either alone or with adjuvant opioid blockers, exhibited almost completely intact striata. In contrast, brains from ischemic animals that received saline showed significant infarction in the lateral striatum. Analyses of apoptotic cell death revealed a significant increase in the p-53 mRNA expression in the striatum of ischemic animals that received saline, while those that received DADLE exhibited near normal striatal p-53 expression. This protective effect was accompanied by significant increments in protein levels of glial cell line-derived neurotrophic factor in the striatum of DADLE-treated ischemic animals. CONCLUSION: These results indicate that DADLE protected against necrotic and apoptotic cell death processes associated with ischemia-reperfusion injury. The present study demonstrates that delta opioids are crucially involved in stroke, suggesting that the opioid system is important in the study of brain injury and protection