A nerve growth factor peptide retards seizure development and inhibits neuronal sprouting in a rat model of epilepsy.

Rashid, Kashif; Zee, Catharina E.E.M. Van der; Ross, Gregory M.; Chapman, C. Andrew; Stanisz, Jolanta; Riopelle, R. J.; Racine, R.; Fahnestock, Margaret

doi:10.1073/pnas.92.21.9495

Cited by 70 publications

(16 citation statements)

References 39 publications

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“…Our findings that NGF administration accelerates kindling rates and enhances mossy fiber sprouting are compatible with those of Van der Zee et al (1995) and Rashid et al (1995), who demonstrated that intraventricular infusion of NGF inhibitors retards kindling rates and reduces mossy fiber sprouting. Taken together, these findings indicate that NGF plays an important role in regulating the development of kindling and kindling-induced neural growth.…”

Section: Potential Mechanism For Increased Kindling Rates and Enhancesupporting

confidence: 81%

Nerve Growth Factor Accelerates Seizure Development, Enhances Mossy Fiber Sprouting, and Attenuates Seizure-Induced Decreases in Neuronal Density in the Kindling Model of Epilepsy

Adams¹,

et al. 1997

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Recurrent seizure activity induced during kindling has been reported to produce a functional synaptic reorganization of the mossy fibers in the hippocampus. To date, it is unclear whether this kindling-induced growth is secondary to decreases in hilar neuron density, which are presumed to reflect hilar neuronal cell loss, or whether it is related specifically to an activationdependent plasticity. We recently demonstrated that blocking nerve growth factor (NGF) biological activity retards seizure development and inhibits the sprouting of mossy fibers. We now demonstrate that intraventricular administration of NGF itself accelerates the progression of kindling epileptogenesis, increases mossy fiber sprouting in the CA3 region and in the inner molecular layer (IML), but reduces seizure-induced decreases in hilar cell density. These findings provide support for a role of NGF in kindling and kindling-induced mossy fiber sprouting. In addition, the results dissociate this form of epileptogenesis from hilar cell loss or decreases in hilar cell density attributable to increases in hilar area, thereby supporting seizure-induced mossy fiber sprouting as being primarily attributable to the combined effects of neuronal activation and the activation-induced upregulation of growth factors.

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Section: Potential Mechanism For Increased Kindling Rates and Enhancesupporting

confidence: 81%

Nerve Growth Factor Accelerates Seizure Development, Enhances Mossy Fiber Sprouting, and Attenuates Seizure-Induced Decreases in Neuronal Density in the Kindling Model of Epilepsy

Adams¹,

et al. 1997

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“…These abnormal connections may be responsible for the development of chronic hyperexcitability in the hippocampus and for chronic seizures (Sutula et al 1988;Davenport et al 1990;Houser et al 1990;Meberg et al 1993b;Bendotti et al 1994;Elmer et al 1996). The trigger for this abnormal axonal plasticity could be the death of some hilar neurons and the trophic stimulation of granule cells after seizures (Holtzman and Lowenstein 1995;Rashid et al 1995). As discussed above, loss of hilar neurons and increased trophic factor expression also occurs in granule cells after ischemia, but the present studies in rat indicated only moderate increases in expression of GAP-43 in granule cells.…”

Section: Discussionmentioning

confidence: 96%

Transient expression of GAP-43 within the hippocampus after global brain ischemia in rat

Schmidt‐Kastner

Bedard

Hakim

1997

Cell and Tissue Research

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Neuroanatomical methods have been used to study selective vulnerability after global brain ischemia. A consistent pattern of ischemic neuronal damage is found in the rodent hippocampus with loss of CA1 neurons and of some cells in the hilus of the dentate gyrus. Very little is known about plastic changes that would be expected in ischemia-resistant areas such as CA3 neurons and granule cells. Neuronal plasticity after lesions may be indicated by changes in labeling with antibodies to the growth-associated protein 43 (GAP-43). Expression of GAP-43 as a marker for neuronal plasticity was studied here in the hippocampus after global brain ischemia. Halothane-anesthetized rats were subjected to 20 min of transient forebrain ischemia using four-vessel occlusion. In situ hybridization was used to study GAP-43 mRNA at 1, 3, 6, and 12 h and at 1, 3, and 7 days after ischemia. Immunostaining was carried out with two different antibodies to GAP-43 in brains which were perfusion-fixed after 1, 2, 4, and 7/8 days. In the control hippocampus, GAP-43 mRNA was localized to CA1-CA3 and the hilus. Moderate increases in cellular signals were seen in hilar cells and granule cells early after ischemia, and some changes occurred in CA3 at late stages. Hybridization was lost in CA1 due to cell death. With immunostaining, GAP-43 was not seen in the cytoplasm of neurons, whereas dense labeling occurred in a differentiated pattern in the axonal and dendritic layers. At 1 day after ischemia, neurons in the hilus of the dentate gyrus and in the stratum pyramidale and lucidum of CA3 showed strong cytoplasmic labeling for GAP-43. Few cells were labeled in these regions at 2 days, and none at later stages. Pyramidal cells in CA1 and CA3 areas and granule cells were never labeled. These studies demonstrate a transient expression of GAP-43 mRNA and protein in a subset of vulnerable neurons after transient brain ischemia. The cytoplasmic localization in hilar neurons could be due to increased synthesis of GAP-43 or to changes in axoplasmic transport. It is suggested that axonal damage occurs in hilar cells which stimulates GAP-43 expression. The increased production of trophic factors after ischemia in granule cells could also cause plastic changes in hilar cells. Since hilar neurons are in a strategic position to control the excitability of the dentate area, increased expression of GAP-43 may indicate an important pathophysiological process. In seizure experiments, strong expression of GAP-43 mRNA in granule cells was associated with abnormal mossy fiber sprouting and development of chronic epilepsy. The relevance of the minor GAP-43 mRNA upregulation after ischemia must be considered. The changes in CA3 neurons at several days after ischemia might represent a plastic response to a loss of CA1 neurons.

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“…We recently developed a highly potent small peptide that allosterically inhibits TrkB signaling in neurons and that is active in vivo after systemic delivery (20). Our in vivo study, together with others' studies (21)(22)(23), demonstrates the feasibility of developing heterocyclic ligands that can modulate TrkB activity in living animals. However, peptide-derived ligands have the problem of being proteolytically unstable, which potentially decreases their efficiency under therapeutic conditions.…”

Section: Introductionmentioning

confidence: 97%

Identification of a low–molecular weight TrkB antagonist with anxiolytic and antidepressant activity in mice

Cazorla

Prémont²,

Mann³

et al. 2011

J. Clin. Invest.

341

315

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A nerve growth factor peptide retards seizure development and inhibits neuronal sprouting in a rat model of epilepsy.

Cited by 70 publications

References 39 publications

Nerve Growth Factor Accelerates Seizure Development, Enhances Mossy Fiber Sprouting, and Attenuates Seizure-Induced Decreases in Neuronal Density in the Kindling Model of Epilepsy

Nerve Growth Factor Accelerates Seizure Development, Enhances Mossy Fiber Sprouting, and Attenuates Seizure-Induced Decreases in Neuronal Density in the Kindling Model of Epilepsy

Transient expression of GAP-43 within the hippocampus after global brain ischemia in rat

Identification of a low–molecular weight TrkB antagonist with anxiolytic and antidepressant activity in mice

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