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The Challenges for Drug Development: Cytokines, Genes, and Stem Cells.
MedLine Citation:
PMID:  23030554     Owner:  NLM     Status:  Publisher    
The development of new treatment strategies can offer exciting possibilities for individuals with neurodegenerative disorders, especially if destructive disabilities can be eliminated. However, drug development is an intricate process and can have multiple components that range from assessing an agent's role upon targeted cellular pathways to assessing a drug's ability to prevent or reverse the progression of a particular disease. Along this drug development course one must consider not only the efficacy of a drug, but also the toxicity profile of the agent. Examination of novel agents for the nervous system, such as erythropoietin (EPO), can be illustrative for the considerations that unfold during drug development. As a cytokine and growth factor, EPO is produced and secreted in several organs throughout the body that include the brain, liver, and uterus and is present in the breath of individuals. Although EPO is currently approved by the Food and Drug Administration for the treatment of anemia, the presence of EPO and its receptor in the nervous system has generated an immense amount of interest to target EPO and its downstream pathways for novel therapeutic strategies against neurodegenerative disorders. EPO can protect neurons during acute injury from oxidative stress, stroke, spinal cord ischemia, retinal disease, and demyelinating disease. During chronic neurodegenerative disorders such as cognitive loss and Alzheimer's disease, EPO can prevent cell toxicity, reduce β-amyloid burden, and lead to memory improvements. In models of Parkinson's disease, EPO represses expression of the pro-apoptotic protein p53 up-regulated modulator of apoptosis (PUMA) and prevents L-3, 4-dihydroxyphenylalanine (L-DOPA) toxicity through reductions in caspase 3 activity. EPO also has been shown in animal models to have increased expression during electroconvulsive therapy and reduce depressive behavior. In studies with seizures, EPO reduces seizure duration and protects against hippocampal cell loss. At the cellular level, EPO can modulate a number of components in the apoptotic cascade to avert cell death. EPO prevents mitochondrial depolarization and the subsequent release of cytochrome c. EPO can control mitochondrial signaling through Bad, Bax, Puma and blocks Apaf-1 activation. EPO also prevents the early activation of several caspases such as caspase 1, caspase 3, and caspase 9. New work has revealed that EPO also relies upon mammalian target of rapamycin (mTOR) signaling for the neuronal differentiation of post-mortem neural precursors. Retinal progenitor cells have been shown to be resistant to hypoxia when exposed to EPO that leads to mTOR activation. EPO through wingless (Wnt1) signaling can activate mTOR to block apoptotic cell death in inflammatory cells. In cell models of Alzheimer's disease, amyloid degeneration of microglia is limited by EPO through activation of mTOR pathways. Yet, EPO can have clinical limitations. Excessive over-expression of EPO may abolish any protective effects and lead to thrombotic injury. EPO may be contraindicated during severe hypertension since EPO may raise mean arterial blood pressure. As a result, in an effort to limit some of these disadvantages of EPO, analogues of EPO are also under consideration that are absent of erythrogenic properties. In this issue of Current Neurovascular Research, we prevent novel studies that are highly relevant for drug development, and in particular for EPO. Lagarto et al. examine the toxicology profile of EPO with a nasal formulation. The authors show that this formulation may have a high potential for clinical applications since the nasal formulation was without erythrogenic properties, hematological side effects, antibody formation, or weight loss after a fourteen-day treatment. Given the role that EPO may have in governing the wingless and mTOR pathways to promote neuroprotection, the article by Shang et al. provides us with new insight upon the downstream wingless pathway involving Wnt1 inducible signaling pathway protein 1 (WISP1) and mTOR signaling. These investigators show that in a cellular model of Alzheimer's disease WISP1 is protective against amyloid toxicity, activates mTOR, and controls the regulatory mTOR component proline rich Akt substrate 40 kDa (PRAS40), identifying these novel targets for new strategies directed against Alzheimer's disease and related disorders. The article by Lu et al. brings us to the potential role of stem cell therapy for neuromyelitis optica. The authors demonstrate that transplanted human umbilical cord-derived mesenchymal stem cells, known to secrete growth factors and cytokines such as EPO, in a small group of patients with neuromyelitis optica lead to clinical improvement that may be secondary to modulation of B-cell and T-cell activities. The work by Sharma et al. compliments this study by examining the role of the vascular endothelial growth factor 2 (VEGF2) gene in the pathogenesis of age-related macular degeneration. Articles by Ciancarelli et al., Fassbender et al., Lahoti et al., and Kimura et al. extend the work of these studies to examine for us the role of oxidative stress and antibody formation in clinical studies with neuro-rehabilitation and in experimental studies with spinal cord injury and apoptotic signaling. Our review articles by Bhutani and Anad, and by Zheng et al. provide further analysis for drug development in relation to the role of biomarkers and the treatment of subarachnoid hemorrhage. The studies presented in this issue of Current Neurovascular Research provide an enticing perspective for the varied parameters that can encompass drug development as well as help us comprehend the need to effectively translate basic cellular mechanisms into useful and safe clinical treatments, a challenge never to be under estimated or assumed until properly powered clinical trials are undertaken.
Kenneth Maiese
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-9-27
Journal Detail:
Title:  Current neurovascular research     Volume:  -     ISSN:  1875-5739     ISO Abbreviation:  Curr Neurovasc Res     Publication Date:  2012 Sep 
Date Detail:
Created Date:  2012-10-3     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101208439     Medline TA:  Curr Neurovasc Res     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Laboratory of Cellular and Molecular Signaling Cancer Center, F 1220, New Jersey Health Sciences University 205 South Orange Avenue, Newark, NJ 07101, USA.
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