Neuroprotective and behavioral efficacy of nerve growth factor—transfected hippocampal progenitor cell transplants after experimental traumatic brain injury

2001 ◽  
Vol 94 (5) ◽  
pp. 765-774 ◽  
Author(s):  
Matthew F. Philips ◽  
Gustav Mattiasson ◽  
Tadeusz Wieloch ◽  
Anders Björklund ◽  
Barbro B. Johansson ◽  
...  
Keyword(s):  
Nerve Growth Factor ◽  
Brain Injury ◽  
Growth Factor ◽  
Sodium Pentobarbital ◽  
Nerve Growth ◽  
Content Type ◽  
Brain Injured ◽  
Hippocampal Ca3 ◽  
Neuromotor Function ◽  
Fine Print

Object. Immortalized neural progenitor cells derived from embryonic rat hippocampus (HiB5), were transduced ex vivo with the gene for mouse nerve growth factor (NGF) to secrete NGF (NGF-HiB5) at 2 ng/hr/105 cells in culture. Methods. Fifty-nine male Wistar rats weighing 300 to 370 g each were anesthetized with 60 mg/kg sodium pentobarbital and subjected to lateral fluid-percussion brain injury of moderate severity (2.3–2.4 atm, 34 rats) or sham injury (25 rats). At 24 hours postinjury, 2 µl (150,000 cells/µl) of [3H]thymidine-labeled NGF-HiB5 cells were transplanted stereotactically into three individual sites in the cerebral cortex adjacent to the injury site (14 rats). Separate groups of brain-injured rats received nontransfected (naive [n])-HiB5 cells (12 animals) or cell suspension vehicle (eight animals). One week postinjury, animals underwent neurological evaluation for motor function and cognition (Morris water maze) and were killed for histological, autoradiographic, and immunocytochemical analysis. Viable HiB5 cell grafts were identified in all animals, together with reactive microglia and macrophages located throughout the periinjured parenchyma and grafts (OX-42 immunohistochemistry). Brain-injured animals transplanted with either NGF-HiB5 or n-HiB5 cells displayed significantly improved neuromotor function (p < 0.05) and spatial learning behavior (p < 0.005) compared with brain-injured animals receiving microinjections of vehicle alone. A significant reduction in hippocampal CA3 cell death was observed in brain-injured animals receiving transplants of NGF-HiB5 cells compared with those receiving n-HiB5 cells or vehicle (p < 0.025). Conclusions. This study demonstrates that immortalized neural stem cells that have been retrovirally transduced to produce NGF can markedly improve cognitive and neuromotor function and rescue hippocampal CA3 neurons when transplanted into the injured brain during the acute posttraumatic period.

Intraventricular infusion of nerve growth factor as the cause of sympathetic fiber sprouting in sensory ganglia

1999 ◽  
Vol 91 (3) ◽  
pp. 447-453 ◽  
Author(s):  
Haring J. W. Nauta ◽  
Joseph C. Wehman ◽  
Vassilis E. Koliatsos ◽  
Marylee A. Terrell ◽  
Kyungsoon Chung
Keyword(s):  
Alzheimer’S Disease ◽  
Nerve Growth Factor ◽  
Growth Factor ◽  
Sensory Ganglia ◽  
Nerve Growth ◽  
Content Type ◽  
Sympathetic Fiber ◽  
Sympathetic Sprouting ◽  
Intraventricular Infusion ◽  
Fine Print

Object. The results of previous clinical trials have indicated that intraventricular infusion of nerve growth factor (NGF) in patients with Alzheimer's disease is frustrated by the appearance of weight loss and diffuse back pain. The present study tested whether NGF induces sympathetic sprouting in sensory ganglia. Such sprouting has been implicated in previous studies as a possible mechanism of sympathetically maintained pain in neuropathic animals.Methods. Nineteen Long—Evans rats underwent intraventricular infusion of either artificial cerebrospinal fluid (ACSF; seven animals) or NGF (12 animals). After 14 days of infusion, the sensory ganglia of the trigeminal nerve and the C-2, C-8, T-1, L-4, and L-5 dorsal roots were examined for sympathetic sprouting by using tyrosine hydroxylase immunohistochemical analysis.Conclusions. In the animals receiving NGF, 52 of 144 ganglia showed sympathetic fiber sprouting. In the control animals receiving ACSF, only two of 72 ganglia showed minor sympathetic fiber sprouting. A preferential sprouting of sympathetic fibers was demonstrated at lower lumbar ganglia compared with the cervical and thoracic ganglia. The data presented here demonstrate that in the rat intraventricular NGF infusion caused sympathetic sprouting in dorsal root ganglia (p < 0.01). These findings may have importance both for the treatment of Alzheimer's disease and the understanding of neuropathic pain.

Prevention of apoptotic but not necrotic cell death following neuronal injury by neurotrophins signaling through the tyrosine kinase receptor

2004 ◽  
Vol 100 (1) ◽  
pp. 79-87 ◽  
Author(s):  
Dong H. Kim ◽  
Xiurong Zhao ◽  
Christina H. Tu ◽  
Patrizia Casaccia-Bonnefil ◽  
Moses V. Chao
Keyword(s):  
Cell Death ◽  
Nerve Growth Factor ◽  
Growth Factor ◽  
Tyrosine Kinase ◽  
Dna Fragmentation ◽  
Cortical Neurons ◽  
Nerve Growth ◽  
Content Type ◽  
Neurotrophin 3 ◽  
Fine Print

Object. Neurotrophins prevent the death of neurons during embryonal development and have potential as therapeutic agents. During development, neuronal death occurs only by apoptosis and not by necrosis. Following injury, however, neurons can die by both processes. Data from prior studies have not clearly indicated whether neurotrophins can decrease apoptosis compared with necrosis. The goal of this study was to determine the effect of neurotrophin treatment on each of these processes following injury and to characterize the receptor(s) required. Methods. The authors used an in vitro model of injury with the aid of primary cortical neurons obtained from rat embryos. After 9 days in culture and the elimination of glia, homogeneous and mature neurons were available for experimentation. Noxious stimuli were applied, including radiation, hypoxia, and ischemia. Subsequent cell death by apoptosis or necrosis was noted based on morphological and enzymatic assessments (such as lactate dehydrogenase [LDH] release) and assays for DNA fragmentation. The effect of treatment with nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 was determined. Finally, Western blot analyses were performed to note the neurotrophin receptor status in the neurons (tyrosine kinase receptors [Trks] and p75). The authors studied different stimuli-induced cell death by using different processes. With the application of radiation, cells died primarily by apoptosis, as evidenced by cell shrinkage, the presence of apoptotic bodies, and specific DNA fragmentation. This was a delayed process (> 6 hours) that could be reduced by gene transcription or protein synthesis inhibitors. With ischemia, cells died immediately by necrosis, showing cell enlargement and rupture. Ischemic cell death was not affected by the inhibition of macromolecular synthesis. Hypoxia produced a mixture of the two cell death processes. Both BDNF and neurotrophin-3 demonstrated protection against apoptotic cell death only. Statistically significant decreases of both LDH release and apoptosis-specific DNA fragmentation were noted following radiation and hypoxia, but not for ischemia. Nerve growth factor, unlike the other neurotrophins, did not affect apoptosis because a functional receptor, Trk A, was not expressed by the cortical neurons. There was expression of both Trk B and Trk C, which bind BDNF and neurotrophin-3. Conclusions. These findings have significant clinical implications. Neurotrophins may only be effective in disorders in which apoptosis, and not necrosis, is the major process. Furthermore, the Trk signaling cascade must be activated for this response to occur. Because the expression of these receptors diminishes in adulthood, neurotrophin application may be most appropriate in the pediatric population.

Hypothermia Attenuates the Normal Increase in Interleukin 1β RNA and Nerve Growth Factor Following Traumatic Brain Injury in the Rat

1995 ◽  
Vol 12 (2) ◽  
pp. 159-167 ◽  
Author(s):  
JAMES R. GOSS ◽  
SCOT D. STYREN ◽  
PETER D. MILLER ◽  
PATRICK M. KOCHANEK ◽  
ALAN M. PALMER ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Nerve Growth Factor ◽  
Brain Injury ◽  
Growth Factor ◽  
Interleukin 1Β ◽  
Nerve Growth ◽  
Normal Increase

scholarly journals Nerve growth factor expression correlates with severity and outcome of traumatic brain injury in children

2008 ◽  
Vol 12 (3) ◽  
pp. 195-204 ◽  
Author(s):  
Antonio Chiaretti ◽  
Alessia Antonelli ◽  
Riccardo Riccardi ◽  
Orazio Genovese ◽  
Patrizio Pezzotti ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Nerve Growth Factor ◽  
Brain Injury ◽  
Growth Factor ◽  
Nerve Growth ◽  
Nerve Growth Factor Expression ◽  
Factor Expression ◽  
Growth Factor Expression

Interleukin-6 and Nerve Growth Factor Upregulation Correlates with Improved Outcome in Children with Severe Traumatic Brain Injury

2008 ◽  
Vol 25 (3) ◽  
pp. 225-234 ◽  
Author(s):  
Antonio Chiaretti ◽  
Alessia Antonelli ◽  
Antonio Mastrangelo ◽  
Patrizio Pezzotti ◽  
Luca Tortorolo ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Nerve Growth Factor ◽  
Brain Injury ◽  
Growth Factor ◽  
Severe Traumatic Brain Injury ◽  
Interleukin 6 ◽  
Nerve Growth ◽  
Improved Outcome

Nerve Growth Factor Attenuates Cholinergic Deficits Following Traumatic Brain Injury in Rats

1997 ◽  
Vol 146 (2) ◽  
pp. 479-490 ◽  
Author(s):  
C.Edward Dixon ◽  
Paul Flinn ◽  
Juliang Bao ◽  
Richard Venya ◽  
Ronald L. Hayes
Keyword(s):  
Traumatic Brain Injury ◽  
Nerve Growth Factor ◽  
Brain Injury ◽  
Growth Factor ◽  
Nerve Growth

Expression of the basic fibroblast growth factor gene in mild and more severe head injury in the rat

1998 ◽  
Vol 89 (2) ◽  
pp. 297-302 ◽  
Author(s):  
Shu-Yuan Yang ◽  
Jian-Zhong Cui
Keyword(s):  
Brain Injury ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Basic Fibroblast Growth Factor ◽  
Severe Injury ◽  
Fibroblast Growth ◽  
Content Type ◽  
Injury Group ◽  
Fine Print

Object. The goal of this study was to investigate the relationship between basic fibroblast growth factor (bFGF) gene expression and neuropathological changes in the hippocampus after varying degrees of brain injury. Methods. Mild and severe brain injury in rats was produced by using Marmarou's method. There were 25 animals in each brain injury group and 25 additional animals served as controls. Basic fibroblast growth factor gene expression was investigated by means of RNA hybridization, in situ hybridization, immunohistochemical analysis, and histological analysis using hematoxylin and eosin staining. A 3.7-kb bFGF messenger (m)RNA was detected in the rat hippocampus in both control and injured rats. In the mild injury group its expression was increased at 12 hours after injury and peaked on the 3rd day. Neuronal degeneration in the hippocampal CA2 and CA3 sectors was maximum on that day. In the severe injury group, the expression of the bFGF gene was the same as that in the mild injury group at corresponding times, but the number of surviving neurons in the CA2 and CA3 sectors was much lower than in the mild injury group. In situ hybridization showed that the main cells that expressed bFGF mRNA were pyramidal and granulocytic neurons in all three experimental groups. The number of neurons expressing bFGF mRNA in the severe injury group was less than that in the mild injury group, but the intensity of expression was greater. Immunohistochemical staining showed that the number of neurons expressing the bFGF protein was less in the severe injury group than in the mild injury group. Conclusions. It is concluded that after mild injury there is a close relationship between the expression of the bFGF gene and the degree of histological change in the hippocampus; this indicates that as one of the growth factors, bFGF may participate in the protection and repair processes of neurons following brain injury. In severe injury there is a reduced expression of bFGF. The reason for this appears to be that more of the cells that have the potential to express bFGF have died, reducing the ability to express the bFGF gene. Conversely, it is possible that there may be an intrinsic insufficiency of expression of the gene, compatible with the known vulnerability of the hippocampus to many pathological conditions. Consideration should be given to supplying exogenous bFGF to protect the brain, particularly the hippocampus, after injury.

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