A cyclooxygenase-2 inhibitor ameliorates behavioral impairments induced by striatal administration of epidermal growth factor
ABSTRACT 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.
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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 · 2.71 Impact Factor
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ABSTRACT: Previous studies on a cytokine model for schizophrenia reveal that the hyperdopaminergic innervation and neurotransmission in the globus pallidus (GP) is involved in its behavioral impairments. Here, we further explored the physiological consequences of the GP abnormality in the indirect pathway, using the same schizophrenia model established by perinatal exposure to epidermal growth factor (EGF). Single-unit recordings revealed that the neural activity from the lateral GP was elevated in EGF-treated rats in vivo and in vitro (i.e., slice preparations), whereas the central area of the GP exhibited no significant differences. The increase in the pallidal activity was normalized by subchronic treatment with risperidone, which is known to ameliorate their behavioral deficits. We also monitored extracellular GABA concentrations in the substantia nigra, one of the targets of pallidal efferents. There was a significant increase in basal GABA levels in EGF-treated rats, whereas high potassium-evoked GABA effluxes and glutamate levels were not affected. A neurotoxic lesion in the GP of EGF-treated rats normalized GABA concentrations to control levels. Corroborating our in vivo results, GABA release from GP slices was elevated in EGF-treated animals. These findings suggest that the hyperactivity and enhanced GABA release of GP neurons represent the key pathophysiological features of this cytokine-exposure model for schizophrenia.Journal of Neurochemistry 08/2013; 126(4). DOI:10.1111/jnc.12223 · 4.24 Impact Factor
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ABSTRACT: Introduction: Higher levels of pro-inflammatory cytokines in schizophrenia have suggested that dysfunctions of the immune system may play a role in this disabling condition. The current study was performed to discover if low dose celecoxib combined with clozapine may improve symptoms of schizophrenia or not. Methods: In a double-blind randomized clinical trial, 40 patients with non- treatment resistance schizophrenia were allocated into two groups. The experimental group received flexible and low dose clozapine plus 200 mg/day of celecoxib for 4 weeks, while the control group received clozapine plus placebo. Experimental and control groups were similar in terms of age, gender, clozapine mean dosage and severity of schizophrenic symptoms at baseline. Main outcomes were severity of schizophrenia symptoms measured by the Positive and Negative Syndrome Scale (PANSS) at baseline followed by the second and fourth weeks. Results: Although both groups experienced significant improvement in all PANSS sub-scales in the second and fourth weeks (P<0.001), the differences between the two groups did not reach significance (P>0.05). Conclusion: Our findings did not support the findings of prior studies that report a significant effect for celecoxib combined with atypical antipsychotics. Such inconsistency may be due to statistical power, drug interactions between clozapine and celecoxib, and the low dose of celecoxib used in this study. Future research is needed on the role of anti-inflammatory medications as adds-on treatments for schizophrenia.Global Public Health 01/2015; 3(1):11-17. · 0.92 Impact Factor