|ognizant Communication Corporation|
The Regenerative Medicine Journal
VOLUME 16, NUMBER 3, 2007
Cell Transplantation, Vol. 16, pp. 187-195, 2007
0963-6897/07 $90.00 + 00
Copyright © 2007 Cognizant Comm. Corp.
Printed in the USA. All rights reserved.
Heparan Sulfate Mediates Neuroprotection From Degeneration in Experimental Glutaric Aciduria
Michelle C. Naylor,1 Mesfin Negia,1 Meredith Noetzel,1,2 Terry C. Burns,1,2,3 Zach L. Demorest,1 and Walter C. Low1,2,3
1Department of Neurosurgery, University of Minnesota, Minneapolis,
MN 55455, USA
2Graduate Program in Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA
3Stem Cell Institute, University of Minnesota, Minneapolis, MN 55455, USA
Glutaric aciduria type 1 (GA1) is a childhood metabolic disorder associated with crises that lead to striatal necrosis. Although the disorder can be controlled with diet, there is no current treatment to ameliorate the neurodegeneration following a metabolic crisis. We hypothesized that heparan sulfate (HS) administration would stimulate neural stem cell proliferation by dimerizing with FGF-2 and binding to the FGF-2 receptor on neural stem cells, thus enhancing the number of newly generated neurons to repair damage following a metabolic crisis. In addition, FGF-2 is known to exert neuroprotective effects independent of neurogenesis, so HS may also have neuroprotective activities. To test these hypotheses, ibotenic acid was injected into the striatum of adult mice, mimicking the metabolic crisis and damage caused by glutaric aciduria. Daily doses of HS and bromodeoxyuridine (BrdU) or BrdU alone were administered starting 1 day after the ibotenic acid lesion. BrdU was used to label dividing cells. Fluorescent immunohistochemistry was used to quantify the lesion size and evaluate the phenotype of BrdU-positive cells. Intrastriatal administration of ibotenic acid resulted in a substantial striatal lesion that occupied 18.5% of the ipsilateral brain hemisphere. In contrast, animals treated with HS exhibited a lesion volume representing <1% of the ipsilateral brain hemisphere (ANOVA; p < 0.0001). Increased neurogenesis, however, was not observed in this group. These results suggest that HS administration 2 days after a "metabolic crisis" can ameliorate brain injury in an animal model of GA1. The neuroprotective mechanisms of HS, however, remain to be elucidated but may exert their actions indirectly through binding with FGF-2.
Key words: Glutaric aciduria; Striatal necrosis; Heparan sulfate; FGF2; Bromodeoxyuridine
Address correspondence to Walter C. Low, Ph.D., Department of Neurosurgery, University of Minnesota, 2001 Sixth St., SE, Minneapolis, MN 55455, USA. Tel: 612-626-9200; E-mail: firstname.lastname@example.org
Galantamine Effects on Memory, Spatial Cue Utilization, and Neurotrophic Factors in Aged Female Rats
K. L. French,1 H. A. Bimonte-Nelson,2 and A.-Ch. Granholm3
1Department of Pharmacology, Medical University of South
Carolina, Charleston, SC, USA
2Department of Psychology, Behavioral Neuroscience Division, Arizona State University, Tempe, AZ, USA
3Department of Neurosciences and the Center on Aging, Medical University of South Carolina, Charleston, SC, USA
Galantamine is an acetylcholine esterase inhibitor that has been approved for use in Alzheimer's disease. However, even though clinical studies indicate efficacy in attenuating some of the symptoms associated with the disease, there are a paucity of studies evaluating the effects of galantamine administration on cognitive performance and brain parameters in aged rats. Further, because all previous animal studies using galantamine have been performed in male rats, there is no information on how females respond to galantamine treatment. Therefore, we studied the effects of 0.3, 0.6, and 1.2 mg/kg/day galantamine in 20-month-old female rats in terms of performance on the working and reference memory water radial arm maze task. Galantamine did not influence maze performance. Furthermore, a probe trial procedure to determine extramaze cue utilization while solving the water radial arm maze established that aged female rats utilized extramaze cues, and that they did not rely on a nonspatial chaining strategy to locate hidden platforms. Galantamine treatment had no effect on use of extramaze cues or chaining. In addition, there were no significant changes in neurotrophin levels in the frontal cortex, entorhinal cortex, hippocampus, or basal forebrain after galantamine administration. Therefore, the data reported here suggest that aged animals do utilize spatial strategies for solving a working memory task, but galantamine has no appreciable effects on this task, at least not at the doses tested.
Key words: Acetylcholine esterase inhibitors; Aging; Learning and memory; Hippocampal tasks; Spatial strategy; Nonspatial strategy
Address correspondence to Ann-Charlotte Granholm, Director Center on Aging, Medical University of South Carolina, 26 Bee St., Charleston, SC 29425, USA. Tel: 843-297-0652; E-mail: email@example.com
Schwann Cell Transplantation Improves Reticulospinal Axon Growth and Forelimb Strength After Severe Cervical Spinal Cord Contusion
S. M. Schaal,12* B. M. Kitay,1,2* K. S. Cho,4 T. P. Lo, Jr.,1 D. J. Barakat,1 A. E. Marcillo,1 A. R. Sanchez,1 C. M. Andrade,1 and D. D. Pearse 1,2,3
1The Miami Project to Cure Paralysis, University of Miami
School of Medicine, Miami, FL, USA
2The Neuroscience Program, University of Miami School of Medicine, Miami, FL, USA
3Department of Neurological Surgery, University of Miami School of Medicine, Miami, FL, USA
4Department of Neurosurgery, Uijongbu St. Mary's Hospital, Catholic University Medical College, Seoul, South Korea
Schwann cell (SC) implantation alone has been shown to promote the growth of propriospinal and sensory axons, but not long-tract descending axons, after thoracic spinal cord injury (SCI). In the current study, we examined if an axotomy close to the cell body of origin (so as to enhance the intrinsic growth response) could permit supraspinal axons to grow onto SC grafts. Adult female Fischer rats received a severe (C5) cervical contusion (1.1 mm displacement, 3 KDyn). At 1 week postinjury, 2 million SCs ex vivo transduced with lentiviral vector encoding enhanced green fluorescent protein (EGFP) were implanted within media into the injury epicenter; injury-only animals served as controls. Animals were tested weekly using the BBB score for 7 weeks postimplantation and received at end point tests for upper body strength: self-supported forelimb hanging, forearm grip force, and the incline plane. Following behavioral assessment, animals were anterogradely traced bilaterally from the reticular formation using BDA-Texas Red. Stereological quantification revealed a twofold increase in the numbers of preserved NeuN+ neurons rostral and caudal to the injury/graft site in SC implanted animals, corroborating previous reports of their neuroprotective efficacy. Examination of labeled reticulospinal axon growth revealed that while rarely an axon was present within the lesion site of injury-only controls, numerous reticulospinal axons had penetrated the SC implant/lesion milieu. This has not been observed following implantation of SCs alone into the injured thoracic spinal cord. Significant behavioral improvements over injury-only controls in upper limb strength, including an enhanced grip strength (a 296% increase) and an increased self-supported forelimb hanging, accompanied SC-mediated neuroprotection and reticulospinal axon growth. The current study further supports the neuroprotective efficacy of SC implants after SCI and demonstrates that SCs alone are capable of supporting modest supraspinal axon growth when the site of axon injury is closer to the cell body of the axotomized neuron.
Key words: Axon regeneration; Axotomy; Cell body response; Intrinsic; Neuron; Neuroprotection; Supraspinal
Address correspondence to Dr. Damien D. Pearse, The Miami Project to Cure Paralysis, University of Miami School of Medicine, The Lois Pope Life Center, Locator code R-48, PO Box 016960, Miami, FL 33101, USA. Tel: 305-243-7139; Fax: 305-243-3923; E-mail D.Pearse@Miami.edu
*These authors contributed equally to the study.
Differential Loss of Presynaptic Dopaminergic Markers in Parkinsonian Monkeys
Diane T. Stephenson,1 Mary Abigail Childs,1 Qiu Li,2 Santos Carvajal-Gonzalez,1 Alan Opsahl,1 Mark Tengowski,1 Martin D. Meglasson,3 Kalpana Merchant,4 and Marina E. Emborg5
1Pfizer Global Research and Development, Groton, CT 06340,
2Schering Plough Research Institute, Cardiovascular Metabolic Disease, Kenilworth, NJ 07022-1300, USA
3Ligand Pharmaceuticals, Discovery Research, San Diego, CA 92121, USA
4Eli Lilly, Neuroscience Division, Lilly Corporate Center, Indianapolis, IN 46285, USA
5Wisconsin National Primate Research Center, Department of Anatomy, University of Wisconsin, Madison, WI 53715, USA
Assessment of dopamine nerve terminal function and integrity is a strategy employed to monitor deficits in Parkinson's disease (PD) patients and in preclinical models of PD. Dopamine replacement therapies effectively replenish the diminished supply of endogenous dopamine and provide symptomatic benefit to patients. Tyrosine hydroxylase (TH), dopamine transporter (DAT), vesicular monoamine transporter 2 (VMAT2), and amino acid decarboxylase (AADC) are widely used markers of dopaminergic neurons and terminals. The present studies were initiated to: (a) assess alterations in all four markers in the MPTP primate model of dopaminergic degeneration and (b) to determine whether L-DOPA treatment may itself modulate the expression of these markers. MPTP treatment induced a significant decline of dopaminergic immunoreactive fiber and terminal density in the basal ganglia. The amount of reduction varied between markers. The rank order of presynaptic marker loss, from most to least profound reduction, was TH > VMAT2 > DAT > AADC. Semiquantitative image analysis of relative dopaminergic presynaptic fiber and terminal density illustrated region-specific reduction of all four markers. Double immunofluorescence colocalization of two presynaptic markers on the same tissue section confirmed there was a more dramatic loss of TH than of VMAT2 or of DAT following MPTP treatment. L-DOPA treatment was associated with a significantly higher level of AADC and VMAT2 immunoreactivity in the caudate nucleus compared to placebo. These results illustrate that neurotoxic injury of the dopamine system in primates leads to altered and differential expression of presynaptic dopaminergic markers in the basal ganglia and that expression of such markers may be modulated by L-DOPA therapy. These findings have implications for the use of biomarkers of disease progression as well as for the assessment of neurorestorative strategies, such as cell replacement, for the treatment of PD.
Key words: Parkinson's disease; Tyrosine hydroxylase (TH); Vesicular monoamine transporter 2 (VMAT2); Dopamine transporter (DAT); Amino acid decarboxylase (AADC); L-DOPA; MPTP; Immunohistochemistry
Address correspondence to Diane T. Stephenson, Ph.D., Pfizer Global Research and Development, Eastern Point Rd., Groton, CT 06340, USA. Tel: 860-686-6919; Fax: 860-686-0557; E-mail: Diane.t.Stephenson@pfizer.com
The Pivotal Role of RhoA GTPase in the Molecular Signaling of Axon Growth Inhibition After CNS Injury and Targeted Therapeutic Strategies
Robert E. Gross, Qi Mei, Claire-Anne Gutekunst, and Enrique Torre
Department of Neurosurgery, Center for Neurodegenerative Diseases, Emory University School of Medicine, Atlanta, GA, USA
The dogma that the adult central nervous system (CNS) is nonpermissive to axonal regeneration is beginning to fall in the face of increased understanding of the molecular and cellular biology of axon outgrowth. It is now appreciated that axon growth is regulated by a combination of extracellular factors related to the milieu of the developing or adult CNS and the presence of injury, and intracellular factors related to the "growth state" of the developing or regenerating neuron. Several critical points of convergence within the developing or regenerating neuron for mediating intracellular cell signaling effects on the growth cone cytoskeleton have been identified, and their modulation has produced marked increases in axon outgrowth within the "nonpermissive" milieu of the adult injured CNS. One such critical convergence point is the small GTPase RhoA, which integrates signaling events produced by both myelin-associated inhibitors (e.g., NogoA) and astroglial-derived inhibitors (chondroitin sulfate proteoglycans) and regulates the activity of downstream effectors that modulate cytoskeletal dynamics within the growth cone mediating axon outgrowth or retraction. Inhibition of RhoA has been associated with increased outgrowth on nonpermissive substrates in vitro and increased axon regeneration in vivo. We are developing lentiviral vectors that modulate RhoA activity, allowing more long-term expression than is possible with current approaches. These vectors may be useful in regenerative strategies for spinal cord injury, brain injury, and neurodegenerative diseases including Parkinson's disease, Alzheimer's disease, and Huntington's disease.
Key words: Myelin; CSPG; Semaphorin; Spinal cord injury; Gene therapy; Lentivirus
Address correspondence to Robert E. Gross, M.D., Ph.D., Department of Neurosurgery, 1365 Clifton Road, N.E., Suite 6200, Atlanta, GA 30322, USA. Tel: 404-778-3091; Fax: 404-778-4472; E-mail: Robert.firstname.lastname@example.org
Plasticity of the Central Nervous System and Formation of "Auxiliary Niches" After Stem Cell Grafting: An Essay
Václav Ourednik and Jitka Ourednik
Department of Biomedical Sciences, Iowa State University, Ames, IA 50011, USA
It is hoped that stem cell biology will play a major role in the treatment of a number of so far incurable diseases via transplantation therapy. Today, we know that neural stem cell grafts not only represent a valuable source of missing cells and molecules for the host nervous system, but they also bring with them biological principles and processes assuring tissue plasticity and homeostasis found in early development and in postnatal neurogenic areas. In this review, we discuss the potential of grafted neural stem/progenitor cells to induce plasticity in the adult diseased brain by mimicking the cellular and molecular processes governing the biology of endogenous stem cell niches. If confirmed, such anlagen of "auxiliary niches" could help us to optimize intercellular communication in donor cell-initiated networks of graft-host interactions and to "rejuvenate" the adult nervous system in its response to disease and injury.
Key words: Progenitor; Homeostasis; Development; Neurotransplantation; Neurogenesis; Rescue; Neuroprotection; Neurodegeneration
Address correspondence to Václav Ourednik, Ph.D., Department of Biomedical Sciences, CVM 2048, Iowa State University, Ames, IA 50011, USA. Tel: 515-294-3719; Fax: 515-294-2315; E-mail: email@example.com
The Role of Endothelial Progenitor Cells in Ischemic Cerebral and Heart Diseases
Dah-Ching Ding,1,2* Woei-Cherng Shyu,2* Shinn-Zong Lin,2 and Hung Li3
1Graduate Institute of Medical Science, School of Medicine,
Tzu-Chi University, Hualien, Taiwan
2Neuro-Medical Scientific Center, Tzu-Chi Buddhist General Hospital, Tzu-Chi University, Hualien, Taiwan
3Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan
Ischemic heart and cerebral diseases are complex clinical syndromes. Endothelial dysfunction caused by dysfunctional endothelial progenitor cells (EPCs) is thought to play a major role in pathophysiology of both types of disease. Healthy EPCs may be able to replace the dysfunctional endothelium through endogenous repair mechanisms. EPC levels are changed in patients with ischemic cerebrovascular and cardiovascular disease and EPCs may play a role in the pathophysiology of these diseases. EPCs are also a marker for preventive and therapeutic interventions. Homing of EPCs to ischemic sites is a mechanism of ischemic tissue repair, and molecules such as stromal-derived factor-1 and integrin may play a role in EPC homing in ischemic disease. Potentiation of the function and numbers of EPCs as well as combining EPCs with other pharmaceutical agents may improve the condition of ischemia patients. However, the precise role of EPCs in ischemic heart and cerebral disease and their therapeutic potential still remain to be explored. Here, we discuss the identification, mobilization, and clinical implications of EPCs in ischemic diseases.
Key words: Endothelial progenitor cells; Stroke; Ischemic heart disease; Therapy
Address correspondence to Hung Li, Ph.D., Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan. Tel: 886-2-27880460; Fax: 886-2-27826085; E-mail: firstname.lastname@example.org
*These two authors contributed equally to this article.
Blood-Brain Barrier Pathology in Alzheimer's and Parkinson's Disease: Implications for Drug Therapy
Brinda S. Desai,1 Angela J. Monahan,1 Paul M. Carvey,1,2 and Bill Hendey1
1Department of Pharmacology, Rush University Medical Center,
Chicago IL, USA
2Department of Neurological Sciences, Rush University Medical Center, Chicago IL, USA
The blood-brain barrier (BBB) is a tightly regulated barrier in the central nervous system. Though the BBB is thought to be intact during neurodegenerative diseases such as Alzheimer's (AD) and Parkinson's disease (PD), recent evidence argues otherwise. Dysfunction of the BBB may be involved in disease progression, eliciting of peripheral immune response, and, most importantly, altered drug efficacy. In this review, we will give a brief overview of the BBB, its components, and their functions. We will critically evaluate the current literature in AD and PD BBB pathology resulting from insult, neuroinflammation, and neurodegeneration. Specifically, we will discuss alterations in tight junction, transport and endothelial cell surface proteins, and vascular density changes, all of which result in altered permeability. Finally, we will discuss the implications of BBB dysfunction in current and future therapeutics. Developing a better appreciation of BBB dysfunction in AD and PD may not only provide novel strategies in treatment, but will prove an interesting milestone in understanding neurodegenerative disease etiology and progression.
Key words: Permeability; Therapeutics; Tight junction; Progression
Address correspondence to Brinda S. Desai, Rush University Medical Center, Cohn Research Building, 1735 W Harrison Suite 453, Chicago, IL 60612, USA. Tel: (312) 563-2747; Fax: (312) 563-3552; E-mail: Brinda_Desai@rush.edu
Huntington's Disease: Pathological Mechanisms and Therapeutic Strategies
Shilpa Ramaswamy,1 Kathleen M. Shannon,2 and Jeffrey H. Kordower1
1Department of Neuroscience, Rush University Medical Center,
Chicago, IL, USA
2Department of Neurology, Section of Movement Disorders, Rush University Medical Center, Chicago, IL, USA
Huntington's disease (HD) is a devastating neurodegenerative disorder that occurs in patients with a mutation in the huntingtin or IT15 gene. Patients are plagued by early cognitive signs, motor deficits, and psychiatric disturbances. Symptoms are attributed to cell death in the striatum and disruption of cortical-striatal circuitry. Mechanisms of cell death are unclear, but processes involving mitochondrial abnormalities, excitotoxicity, and abnormal protein degradation have been implicated. Many factors likely contribute to neuron death and dysfunction, and this has made it difficult to systematically address the pathology in HD. Pharmaceutical therapies are commonly used in patients to treat disease symptoms. These have limited benefit and do not address the inexorable disease progression. Several neuroprotective therapies are being evaluated in animal models of HD as well as in clinical trials. Similarly, cell replacement strategies such as fetal transplantation have been used in the clinic with minimal success, making future cell replacement strategies such as stem cell therapy uncertain. This review describes the disease pathology in HD and addresses many of the past and emerging therapeutic strategies.
Key words: Huntington's disease; Therapies; Cell death; Symptoms
Address correspondence to Jeffrey H. Kordower, Ph.D., The Jean Schweppe-Armour
Professor of Neurological Science, Director, Research Center for Brain
Repair, Section Head, Department of Neuroscience, Rush University Medical
Center, 1735 W. Harrison Street, Suite 300, Chicago, IL 60612, USA. Tel:
312-563-3585; Fax: 312-563-3571; E-mail: email@example.com