Intrastriatal implants of polymer encapsulated cells genetically modified to secrete human nerve growth factor: Trophic effects upon cholinergic and noncholinergic striatal neurons

doi:10.1016/0306-4522(95)00543-9

Neuroscience

Volume 72, Issue 1, May 1996, Pages 63-77

https://doi.org/10.1016/0306-4522(95)00543-9 Get rights and content

Abstract

Nerve growth factor selectively prevents the degeneration of cholinergic neurons following intrastriatal infusion but rescues both cholinergic and noncholinergic striatal neurons if the nerve growth factor is secreted from grafts of genetically modified fibroblasts. The present study evaluated whether grafted fibroblasts genetically modified to secrete human nerve growth factor could provide trophic influences upon intact cholinergic and noncholinergic striatal neurons. Unilateral striatal grafts of polymer-encapsulated cells genetically modified to secrete human nerve growth factor induced hypertrophy and significantly increased the optical density of choline acetyltransferase-immunoreactive striatal neurons one, two, and four weeks post-transplantation relative to rats receiving identical grafts missing only the human nerve growth factor construct. Nerve growth factor secreting grafts also induced a hypertrophy of noncholinergic neuropeptide Y-immunoreactive striatal neurons one, two, and four weeks post-transplantation. Glutamic acid decar☐ylase-immunoreactive neurons were unaffected by the human nerve growth factor secreting grafts. The effects upon choline acetyltransferase-immunoreactive and neuropeptide Y-immunoreactive striatal neurons dissipated following retrieval of the implants. Immunocytochemistry for nerve growth factor revealed intense graft-derived immunoreactivity for up to 1000 μm from the capsule extending along the dorsoventral axis of the striatum. Nerve growth factor-immunoreactivity was also observed within a subpopulation of striatal neurons and may represent nerve growth factor consumer neurons which retrogradely transported graft-derived nerve growth factor. When explanted, grafts produced 2–4 ng human nerve growth factor/24 h over the time course of this study indicating that this level of continuous human nerve growth factor secretion was sufficient to mediate the effects presently observed.

Reference (55)

BarkerP.A. et al.
Disruption of NGF binding to the low affinity neurotrophin receptor p75^LNTR reduces NGF binding to TrkA on PC 12 cells
Neuron
(1994)
ChengB. et al.
Glucose deprivation elicits enurofibrillary tangle-like antigenic changes in hippocampal neurons: prevention by NGF and βFGF
Exp. Neurol.
(1992)
ChengB. et al.
Modulation of calcium current, intracellular calcium levels and cell survival by glucose deprivation and growth factors in hippocampal neurons
Brain Res.
(1993)
DaviesS.W. et al.
Nerve growth factor selectively prevents excitotoxin induced degeneraton of striatal cholinergic neurons
Neurosci. Lett.
(1992)
DechantG. et al.
Neurotrophin receptors
Prog. Neurobiol.
(1994)
EmerichD.F. et al.
Implantation of polymer-encapsulated human nerve growth factor secreting fibroblasts attenuates the behavioral and neuropathological consequences of quinolinic acid injections into rodent striatum
Exp. Neurol.
(1994)
EngvallE.
Enzyme immunoassay ELISA and EMIT
Meth. Enzym.
(1980)
FerranteR.J. et al.
Sparing of acetylcholinesterase-containing striatal neurons in Huntington's disease
Brain Res.
(1987)
FrimD.M. et al.
Implanted NGF-producing fibroblasts induce catalase and ATP levels but do not affect glutamate receptor binding or NMDA receptor expression in the rat striatum
Exp. Neurol.
(1994)
FryerH.J.L. et al.
Lowry protein assay using an automatic microtiter plate spectrophotometer
Anal. Biochem.
(1986)

GageF.H. et al.

NGF receptor re-expression and NGF-mediated cholinergic neuronal hypertrophy in the damaged adult neostriatum

Neuron

(1989)

HantzopoulosP.A. et al.

The low affinity NGF receptor, p75, can collaborate with each to the trks to potentiate functional responses to the neurotrophins

Neuron

(1994)

HigginsG.A. et al.

NGF induction of NGF receptor gene expression and cholinergic neuronal hypertrophy within the basal forebrain of the adult rat

Neuron

(1989)

HoltzmanD.M. et al.

p140trk mRNA marks NGF-responsive forebrain neurons: evidence that trk gene expression is induced by NGF

Neuron

(1992)

HoyleG.W. et al.

Expression of NGF in sympathetic neurons leads to excessive axon outgrowth from ganglia but decreased terminal innervation within tissues

Neuron

(1993)

KordowerJ.H. et al.

Encapsulated PC12 cell transplants into hemiparkinsonian monkeys: a behavioral, neuroanatomical and neurochemical analysis

Cell Transplantation.

(1995)

KowallN.W. et al.

Pattern of cell loss in Huntington's disease

Trends Neurosci.

(1987)

MattsonM.P. et al.

Mechanisms of neurotrophic protection against calcium-and free radical-mediated excitotoxic injury: implications from treating neurodegenerative disorders

Exp. Neurol.

(1993)

MillerF.D. et al.

Nerve growth factor derived from terminals selectively increases the ratio of p75 to trkA NGF receptors on mature sympathetic neurons

Devl Biol.

(1994)

SchumacherJ.M. et al.

Intracerebral implantation of nerve growth factor-producing fibroblasts protects striatum against neurotoxic levels of excitatory amino acids

Neuroscience

(1991)

SteiningerT.L. et al.

High-affinity nerve growth factor receptor (Trk) immunoreactivity is localized in cholinergic neurons of the basal forebrain and striatum in the adult rat brain

Brain Res.

(1993)

VeneroJ.L. et al.

Intrastriatal infusion of nerve growth factor after quinolinic acid prevents reduction of cellular expression of choline acetyltransferase messenger RNA and trkA messenger RNA, but not glutamate decar☐ylase messenger RNA

Neuroscience

(1994)

AshizawaT. et al.

CAG repeat size and clinical presentation in Huntington's disease

Neurology

(1994)

BaetgeE.E. et al.

Complete nucleotide and deduced amino acid sequence o bovine phenylethanolamineN-methyltransferase: partial homology with rat tyrosine hydroxylase

CabassoI.

Hollow fiber membranes

ConnerJ.M. et al.

The localization of nerve growth factor-like immunoreactivity in the adult rat basal forebrain and hippocampal formation

J. comp. Neurol.

(1992)

ConnerJ.M. et al.

Distribution of nerve growth factor-like immunoreactive in the adult rat brain following colchicine treatment

J. comp. Neurol.

(1992)

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Intrastriatal implants of polymer encapsulated cells genetically modified to secrete human nerve growth factor: Trophic effects upon cholinergic and noncholinergic striatal neurons

Abstract

Neuron

Exp. Neurol.

Brain Res.

Neurosci. Lett.

Prog. Neurobiol.

Exp. Neurol.

Meth. Enzym.

Brain Res.

Exp. Neurol.

Anal. Biochem.

Neuron

Neuron

Neuron

Neuron

Neuron

Cell Transplantation.

Trends Neurosci.

Exp. Neurol.

Devl Biol.

Neuroscience

Brain Res.

Neuroscience

CAG repeat size and clinical presentation in Huntington's disease

Neurology

Complete nucleotide and deduced amino acid sequence o bovine phenylethanolamineN-methyltransferase: partial homology with rat tyrosine hydroxylase

Hollow fiber membranes

The localization of nerve growth factor-like immunoreactivity in the adult rat basal forebrain and hippocampal formation

J. comp. Neurol.

Distribution of nerve growth factor-like immunoreactive in the adult rat brain following colchicine treatment

J. comp. Neurol.