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Chang-Ning Liu, Chris J. Somps, Chris Houle; Electroretinogram Is Not Altered by KAT II Inhibitor in Rats. Invest. Ophthalmol. Vis. Sci. 2012;53(14):5366.
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Selective inhibitors of kynurenine aminotransferase type II (KAT II) are being developed to treat cognitive impairment associated with schizophrenia. Reduced neurotransmission at the NMDA subtype of the glutamate receptor has been identified as a primary neurochemical deficit in schizophrenia. Since kynurenic acid (KYNA) is a negative NMDA receptor modulator in brain synapses, decreasing synaptic KYNA concentration by inhibiting its production in astrocytes should enhance NMDA signaling. However, KYNA and KAT II have also been detected in the inner retina of rodent, rabbit and human eyes. In addition, glycine, another positive NMDA modulator, has been found to be associated with visual and electroretinogram (ERG) disturbances. Thus, we conducted the current in vivo study in order to determine if a selective KAT II inhibitor causes changes in ERG responses in rats.
Male Sprague-Dawley (SD) rats (8/group) were administered PF-04859989 subcutaneously at 100 mg/kg (previously shown to decrease KYNA concentration in the prefrontal cortex) or vehicle two hours prior to ERG acquisition. Scotopic and photopic luminance responses, photopic adaptometry and flicker responses were measured following 1 hour of dark adaptation. Plasma and vitreous samples were obtained for determination of PF-04859989 concentrations at the end of the ERG session.
No significant differences were found between vehicle and PF-04859989 dosed SD rats in ERG parameters tested. PF-04859989 levels in vitreous humor were 0.93 fold the levels in plasma. The amplitude of the scotopic ERG oscillatory potentials was not correlated to the exposure of PF-04859989 in the vitreous humor (r = -0.17, P >0.05).
A single subcutaneous dose of 100 mg/kg PF-04859989, a KAT II inhibitor, did not result in changes in ERG in adult SD rats.
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