A cyclooxygenase-2 inhibitor ameliorates behavioral impairments induced by striatal administration of epidermal growth factor

Division of Molecular Neurobiology, Niigata University, Niahi-niigata, Niigata, Japan
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.75). 10/2007; 27(38):10116-27. DOI: 10.1523/JNEUROSCI.2368-07.2007
Source: PubMed

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.

  • [Show abstract] [Hide abstract]
    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 · 1.29 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: To test the hypothesis that short- and long-term celecoxib administration has no effect on orthodontic tooth movement. Male Wistar rats were submitted to short- (3 days) and long-term (14 days) celecoxib administration, while the respective control groups received equivolumetric saline intraperitoneal injections. The upper left first molars of all rats were moved mesially for 14 days by a fixed orthodontic appliance exerting 50 g force upon insertion. After the experimental period, tooth movement was quantified and tissues around the first molar were processed for tartrate-resistant acid phosphatase (TRAP) histochemistry. The amount of tooth movement and the number of TRAP-positive cells on the alveolar bone surface were evaluated. The amount of tooth movement was significantly reduced in rats submitted to short- and long-term celecoxib administration, while the number of osteoclasts on the alveolar bone did not differ between the four groups studied. The hypothesis is rejected. Although celecoxib administration did not affect the number of osteoclasts, the osteoclast activity might be reduced, which could explain the inhibition of tooth movement observed in the celecoxib-treated animals. These results indicate that orthodontists should be aware of patients under short- and long-term therapy with celecoxib.
    The Angle Orthodontist 10/2008; 78(5):860-5. DOI:10.2319/100207-474.1 · 1.28 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Epidermal growth factor (EGF) has a neurotrophic activity on developing midbrain dopaminergic neurons. We investigated developmental effects of peripheral EGF administration on dopaminergic neurons in midbrain slice preparations containing ventral tegmental area (VTA). Subcutaneous EGF administration to mouse neonates triggered phosphorylation of EGF receptors (ErbB1 and ErbB2) in the midbrain region, suggesting its penetration through the blood-brain barrier. We repeated EGF administration in postnatal mice and examined synaptic transmission in the VTA with electrophysiological recordings. Subchronic EGF treatment increased the amplitude of field excitatory postsynaptic potentials evoked by stimulation of the anterior VTA. To analyze the EGF effect at a single cell level, dopaminergic neurons were identified by their characteristic hyperpolarizing activated currents in whole cell recording. In these dopaminergic neurons, EGF effects the amplitude of spontaneous miniature excitatory postsynaptic currents (mEPSCs) without affecting their frequency. In agreement, EGF also enhanced the AMPA/NMDA ratio of evoked EPSCs in the dopaminergic neurons. In contrast, EGF effects on mEPSCs of neighboring neurons not exhibiting hyperpolarizing activated currents were modest or insignificant. Thus, these results suggest that circulating EGF substantially influences the physiological properties of developing midbrain dopaminergic neurons in perinatal and postnatal mice.
    Neuroscience 12/2008; 158(4):1731-41. DOI:10.1016/j.neuroscience.2008.10.057 · 3.33 Impact Factor