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

Philips, Matthew F.; Mattiasson, Gustav; Wieloch, Tadeusz; Björklund, Anders; Johansson, Barbro; Tomasevic, Gregor; Martínez‐Serrano, Alberto; Lenzlinger, Philipp M.; Sinson, Grant; Grady, M. Sean; McIntosh, Tracy K.

doi:10.3171/jns.2001.94.5.0765

Cited by 121 publications

(64 citation statements)

References 72 publications

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“…For example, C17.2 overexpressing GDNF (GDNF-C17.2) improved survival of transplanted cells, enhanced neuronal differentiation of these cells and promoted learning behavior of the TBI rats at 6 weeks after transplantation comparing to parental C17.2 cells (Bakshi et al, 2006). Similarly, HiB5 progenitor clone engineered to secrete NGF (NGF-HiB5), when transplanted peripheral to the TBI site, decreased apoptosis of the host hippocampal neurons and improved motor and cognitive function comparing to controls (Philips et al, 2001). …”

Section: Brain and Spinal Cord Injurymentioning

confidence: 99%

Neural Stem/Progenitor Cell Clones as Models for Neural Development and Transplantation

Li¹,

Zhao²,

Shu³

et al. 2012

Neural Stem Cells and Therapy

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Section: Brain and Spinal Cord Injurymentioning

confidence: 99%

Neural Stem/Progenitor Cell Clones as Models for Neural Development and Transplantation

Li¹,

Zhao²,

Shu³

et al. 2012

Neural Stem Cells and Therapy

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“…Although injury-induced cell death disrupts the circuit initially, our data call into question a causal relationship between protection of the CA3 neurons and postinjury performance in the MWM. Several groups have reported a treatment-related improvement in learning and/or memory after experimental TBI in conjunction with CA3 neuronal survival (Sanderson et al, 1999, Leoni et al, 2000, Kline et al, 2001, Philips et al, 2001, Floyd et al, 2002, Kline et al, 2002, Ozdemir et al, 2005, Statler et al, 2006. However, other reports have clearly documented learning deficits in brain-injured animals in the absence of discernable hippocampal damage (Lyeth et al, 1990) or the converse, an improvement in MWM performance after injury without CA3 neuroprotection (Dixon et al, 2003, Hoover et al, 2004.…”

Section: Discussionmentioning

confidence: 95%

Neurotrophin-mediated neuroprotection of hippocampal neurons following traumatic brain injury is not associated with acute recovery of hippocampal function

et al. 2007

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Traumatic brain injury (TBI) causes selective hippocampal cell death which is believed to be associated with the cognitive impairment observed in both clinical and experimental settings. The endogenous neurotrophin NT-4/5, a TrkB ligand, has been shown to be neuroprotective for vulnerable CA3 pyramidal neurons after experimental brain injury. In this study, infusion of recombinant NT-4/5 increased survival of CA2/3 pyramidal neurons to 71% after lateral fluid percussion injury in rats, compared to 55% in vehicle-treated controls. The functional outcome of this NT-4/5-mediated neuroprotection was examined using three hippocampal-dependent behavioral tests. Injury-induced impairment was evident in all three tests, but interestingly, there was no treatment-related improvement in any of these measures. Similarly, injury-induced decreased excitability in the Schaffer collaterals was not affected by NT-4/5 treatment. We propose that a deeper understanding of the factors that link neuronal survival to recovery of function will be important for future studies of potentially therapeutic agents.

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“…Therefore, grafting of exogenous stem cells may accelerate the natural regeneration process. Recent findings indicated that neural stem cell transplantation can be a viable approach for the treatment of brain trauma (4)(5)(6) or stroke (7)(8)(9)(10). However, it is still not completely understood how these cells, endogenous or exogenous, are involved in the brain repair process (11).…”

Section: Introductionmentioning

confidence: 99%

PARP inhibition improves the effectiveness of neural stem cell transplantation in experimental brain trauma

et al. 2003

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Abstract. Neural stem cell transplantation is a promising new treatment of ischemic or traumatic brain injury. We have now investigated the involvement of the peroxynitrite -poly(ADPribose) polymerase (ONOO --PARP) activation cascade in brain trauma and neural stem cell transplantation. The forelimb motor cortex of adult male rats was exposed to cold lesion (-60˚C) and motor function was monitored. Neural stem cells isolated from E14 rat embryos were labeled with brome deoxyuridine (BrDU) and injected into the injured cortex 6 days after the lesion. After another 6 days, the survival and differentiation of the grafted cells were investigated with immunohistochemistry. Increased production of ONOO -revealed by tyrosine nitration was seen in the lesion 2 days after transplantation. Animals treated with the ONOO -decomposition catalyst FP15 or the PARP inhibitor PJ34 had a significantly improved motor score, when compared to vehicle-treated controls. The neurological score further improved following stem cell grafting in the PJ34 treated, but not in the control animals. Six days after transplantation, differentiated BrDU positive cells were found in the cortical penumbra. The majority of these differentiated cells expressed an astrocyte marker and some of the cells expressed oligodendrocyte or neuronal markers. The number of surviving transplanted cells was significantly higher in the PJ34 treated group. Inhibition of the ONOO --PARP activation cascade significantly improves the effectiveness of neural stem cell transplantation and promotes rapid functional recovery. IntroductionStem cell transplantation is an emerging approach for the treatment of various diseases of the central nervous system. Naturally occurring stem cells can be found in the subventricular and hippocampal subgranular zones (1) and these cells respond to brain damage by proliferation and migration to the area of the injury (2,3). The number of these endogenous stem cells is very limited. Therefore, grafting of exogenous stem cells may accelerate the natural regeneration process. Recent findings indicated that neural stem cell transplantation can be a viable approach for the treatment of brain trauma (4-6) or stroke (7-10). However, it is still not completely understood how these cells, endogenous or exogenous, are involved in the brain repair process (11).Human trials with various neural stem cell transplantation strategies ended with both promising results and serious concerns (12-14). One major limitation of current approaches is the low number of surviving grafted cells (12,15). Thus, in most cases the survival rate of the cells is below 10% and this situation places severe constraints on ultimate beneficial results. Marginal improvements in cell survival can be achieved by limiting apoptosis (16,17), free radical production (18), or lipid peroxidation (19,20). Another approach for increasing the survival of grafted cells is the application of exogenous growth factors like GDNF (21,(22)(23)(24)(25). None of these methods can ensure the comple...

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

Abstract: 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.

Cited by 121 publications

References 72 publications

Neural Stem/Progenitor Cell Clones as Models for Neural Development and Transplantation

Neural Stem/Progenitor Cell Clones as Models for Neural Development and Transplantation

Neurotrophin-mediated neuroprotection of hippocampal neurons following traumatic brain injury is not associated with acute recovery of hippocampal function

PARP inhibition improves the effectiveness of neural stem cell transplantation in experimental brain trauma

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