A Cyclooxygenase-2 Inhibitor Ameliorates Behavioral Impairments Induced by Striatal Administration of Epidermal Growth Factor
Consistent with the hypothesis that neuroinflammatory processes contribute to the neuropathology of schizophrenia, the protein levels of epidermal growth factor (EGF) and its receptor ErbB1 are abnormal in patients with schizophrenia. To evaluate neuropathological significance of this abnormality, we established an animal model for behavioral deficits by administering EGF into the striatum and evaluated the effects of cyclooxygenase-2 (Cox-2) inhibitor celecoxib. Intracranial infusion of EGF into the striatum of adult male rats activated ErbB1 and induced neurobehavioral impairments observed in several schizophrenia models. Unilateral EGF infusion to the striatum lowered prepulse inhibition (PPI) in a dose-dependent manner and impaired latent learning of active shock avoidance without affecting basal learning ability. Bilateral EGF infusion similarly affected PPI. In contrast, EGF infusion to the nucleus accumbens did not induce a behavioral deficit. Intrastriatal EGF infusion also increased Cox-2 expression, elevated tyrosine hydroxylase activity, and upregulated the levels of dopamine and its metabolites. Subchronic administration of celecoxib (10 mg/kg, p.o.) ameliorated the abnormalities in PPI and latent learning as well as normalized dopamine metabolism. We conclude that this EGF-triggered neuroinflammatory process is mediated in part by Cox-2 activity and perturbs dopamine metabolism to generate neurobehavioral abnormalities.
Available from: PubMed Central
- "We tested the first hypothesis that the penetration of the blood-brain barrier would be critical for the effectiveness of EGF injection. If it is the case, the direct EGF supply to the brain of adult rats should mimic neonatal EGF injection . Indeed when EGF was subchronically infused into the striatum of adult rats from an osmotic minipump, EGF induced the deficits of prepulse inhibition and impaired latent inhibition of fear learning as was observed in the neonatal injection model. "
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ABSTRACT: Neuregulin-1 and epidermal growth factor (EGF) are implicated in the pathogenesis of schizophrenia. To test the developmental hypothesis for schizophrenia, we administered these factors to rodent pups, juveniles, and adults and characterized neurobiological and behavioral consequences. These factors were also provided from their transgenes or infused into the adult brain. Here we summarize previous results from these experiments and discuss those from neuropathological aspects. In the neonatal stage but not the juvenile and adult stages, subcutaneously injected factors penetrated the blood-brain barrier and acted on brain neurons, which later resulted in persistent behavioral and dopaminergic impairments associated with schizophrenia. Neonatally EGF-treated animals exhibited persistent hyperdopaminergic abnormalities in the nigro-pallido-striatal system while neuregulin-1 treatment resulted in dopaminergic deficits in the corticolimbic dopamine system. Effects on GABAergic and glutamatergic systems were transient or limited. Even in the adult stage, intracerebral administration and transgenic expression of these factors produced similar but not identical behavioral impairments, although the effects of intracerebral administration were reversible. These findings suggest that dopaminergic development is highly vulnerable to circulating ErbB ligands in the pre- and perinatal stages. Once maldevelopment of the dopaminergic system is established during early development, dopamine-associating behavioral deficits become irreversible and manifest at postpubertal stages.
BioMed Research International 05/2014; 2014:697935. DOI:10.1155/2014/697935 · 1.58 Impact Factor
Available from: Norihito Shintani
- "We measured the tissue contents of dopamine, DOPAC and HVA as described previously . The prefrontal cortex, hippocampus, and striatum were dissected and frozen on dry ice. "
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ABSTRACT: Neuregulin-1 (NRG1) is one of the susceptibility genes for schizophrenia and implicated in the neurotrophic regulation of GABAergic and dopaminergic neurons, myelination, and NMDA receptor function. Postmortem studies often indicate a pathologic association of increased NRG1 expression or signaling with this illness. However, the psychobehavioral implication of NRG1 signaling has mainly been investigated using hypomorphic mutant mice for individual NRG1 splice variants.
To assess the behavioral impact of hyper NRG1 signaling, we generated and analyzed two independent mouse transgenic (Tg) lines carrying the transgene of green fluorescent protein (GFP)-tagged type-1 NRG1 cDNA. The promoter of elongation-factor 1α gene drove ubiquitous expression of GFP-tagged NRG1 in the whole brain. As compared to control littermates, both heterozygous NRG1-Tg lines showed increased locomotor activity, a nonsignificant trend toward decreasing prepulse inhibition, and decreased context-dependent fear learning but exhibited normal levels of tone-dependent learning. In addition, social interaction scores in both Tg lines were reduced in an isolation-induced resident-intruder test. There were also phenotypic increases in a GABAergic marker (parvalbumin) as well as in myelination markers (myelin basic protein and 2',3'-cyclic nucleotide 3'-phosphodiesterase) in their frontal cortex, indicating the authenticity of NRG1 hyper-signaling, although there were marked decreases in tyrosine hydroxylase levels and dopamine content in the hippocampus.
These findings suggest that aberrant hyper-signals of NRG1 also disrupt various cognitive and behavioral processes. Thus, neuropathological implication of hyper NRG1 signaling in psychiatric diseases should be evaluated with further experimentation.
PLoS ONE 12/2010; 5(12):e14185. DOI:10.1371/journal.pone.0014185 · 3.23 Impact Factor
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ABSTRACT: It has been reported that anti-inflammatory drugs used for treatment of pain and discomfort related to orthodontic treatment could slow down tooth movement. However, the effect of these drugs on orthodontic root resorption is not well understood.
The aim of this study was to investigate whether the COX-2 inhibitor celecoxib offers some protection against orthodontically induced root resorption.
Male Wistar rats were divided into four groups: Groups I and II were treated with saline and celecoxib (10 mg / kg), respectively for 3 days. Groups III and IV were treated with saline and celecoxib for 14 days. The upper left first molars of all rats were moved mesially for 14 days with 50 g of force. An area including the disto-apical aspect of the mesial root of the first molar was processed for histological and histochemical techniques with tartarate-resistant acid phosphatase (TRAP).
The degree of root resorption was measured using an image analysis system with a grid-sheet superimposed in the root were resorption lacunae were counted. The number of TRAP-positive cells on the tooth root surface defined as odontoclasts were also evaluated.
The results revealed that there were no significant differences in the degree of root resorption and in the number of odontoclasts on the root between the four groups studied.
The short and long-term celecoxib administration did not suppress the root resorption in case of experimental orthodontic force application.
Orthodontics and Craniofacial Research 09/2008; 11(3):156-61. DOI:10.1111/j.1601-6343.2008.00424.x · 1.06 Impact Factor
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