Abstract
BackgroundZK 200775 is an antagonist at the α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor and had earned attention as a possible neuroprotective agent in cerebral ischemia. Probands receiving the agent within phase I trials reported on an alteration of visual perception. In this trial, the effects of ZK 200775 on the visual system were analyzed in detail.MethodologyIn a randomised controlled trial we examined eyes and vision before and after the intravenous administration of two different doses of ZK 200775 and placebo. There were 3 groups of 6 probands each: Group 1 recieved 0.03 mg/kg/h, group 2 0.75 mg/kg/h of ZK 200775, the control group received 0.9% sodium chloride solution. Probands were healthy males aged between 57 and 69 years. The following methods were applied: clinical examination, visual acuity, ophthalmoscopy, colour vision, rod absolute threshold, central visual field, pattern-reversal visual evoked potentials (pVEP), ON-OFF and full-field electroretinogram (ERG).Principal FindingsNo effect of ZK 200775 was seen on eye position or motility, stereopsis, pupillary function or central visual field testing. Visual acuity and dark vision deteriorated significantly in both treated groups. Color vision was most remarkably impaired. The dark-adapted ERG revealed a reduction of oscillatory potentials (OP) and partly of the a- and b-wave, furthermore an alteration of b-wave morphology and an insignificantly elevated b/a-ratio. Cone-ERG modalities showed decreased amplitudes and delayed implicit times. In the ON-OFF ERG the ON-answer amplitudes increased whereas the peak times of the OFF-answer were reduced. The pattern VEP exhibited lower amplitudes and prolonged peak times.ConclusionsThe AMPA receptor blockade led to a strong impairment of typical OFF-pathway functions like color vision and the cone ERG. On the other hand the ON-pathway as measured by dark vision and the scotopic ERG was affected as well. This further elucidates the interdependence of both pathways.Trial RegistrationClinicalTrials.gov NCT00999284
Highlights
Glutamate is an important excitatory neurotransmitter of the retina [1,2,3]
The AMPA receptor blockade led to a strong impairment of typical OFF-pathway functions like color vision and the cone ERG
The administration of ZK 200775 had no effect on eye position (Table S2) and motility (Table S3), stereopsis as tested with the Titmus test, pupillary afference and efference (Table S4), central visual field testing with the Amsler grid (Table S5) and anterior and posterior segment morphology
Summary
Glutamate is an important excitatory neurotransmitter of the retina [1,2,3]. Its activity is mediated by metabotropic and ionotropic glutamate receptors (mGluRs and iGluRs). The latter are subdivided into N-methyl-D-aspartate (NMDA) and non-NMDA receptors. The latter again are classified as a-Amino3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA, composed of the subunits iGluR1-4) and kainate (composed of the subunits iGluR6-7) receptors (see Figure S1). Probands receiving the agent within phase I trials reported on an alteration of visual perception. In this trial, the effects of ZK 200775 on the visual system were analyzed in detail
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