VIP, PACAP-38, BDNF and ADNP in NMDA-induced excitotoxicity in the rat retina.
OBJECTIVE
To evaluate the effect of intravitreal injection of N-methyl-D-aspartate (NMDA) on brain-derived neurotrophic factor (BDNF), pituitary adenylate cyclase-activating peptide-38 (PACAP-38), vasoactive intestinal peptide (VIP) and the VIP-associated glial protein activity-dependent neuroprotective protein (ADNP) in the rat retina. These elements have well-documented neuroprotective properties and may thus be integrated in endogenous neuroprotective mechanisms in the retina which break down in NMDA excitotoxicity.


METHODS
A volume of 2 μl of 100 nmol NMDA was intravitreally injected into one eye of rats, the untreated eye served as a control. Time-dependent effects of NMDA on VIP, PACAP-38 and BDNF were detected by radioimmunoassay and ELISA, and the effect on the expression of VIP, PACAP-38 and ADNP was evaluated by quantitative RT-PCR 20 days after NMDA injection. Topical flunarizine served to find out whether the effect of NMDA is counteracted.


RESULTS
Compared to PACAP-38, VIP levels significantly decreased on days 1, 7, 14, 28 and 56 after NMDA injection indicating that VIPergic cells are more vulnerable than PACAP-38-expressing cells. The expression of VIP and ADNP but not of PACAP-38 was found to be reduced, and application of topical flunarizine counteracted the decrease of VIP. BDNF levels significantly increased after days 1 and 3.


CONCLUSIONS
The early upregulation of BDNF seems to act neuroprotectively and leads to a delay of ganglion cell loss. Although there is no direct evidence, the decrease of VIP and ADNP - the consequence of the presence of NMDA receptors on these peptide-expressing cells - might contribute to the breakdown of endogenous neuroprotective mechanisms given that the decrease of the VIP-related ADNP runs in parallel with the decrease of VIP. Activating and maintaining these mechanisms must be the primary aim in the therapy of diseases with retinal neuronal degeneration.
Teuchner
Barbara
B
Department of Ophthalmology, Medical University of Innsbruck, Innsbruck, Austria.
Dimmer
Andreas
A
Humpel
Christian
C
Amberger
Albert
A
Fischer-Colbrie
Reiner
R
Nemeth
Jozsef
J
Waschek
James A
JA
Kieselbach
Gerhard
G
Kralinger
Martina
M
Schmid
Eduard
E
Bechrakis
Nikolaos
N
Troger
Josef
J
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D005444:Flunarizine / Q000008:administration & dosage; D058449:Intravitreal Injections; D008297:Male; D016202:N-Methylaspartate / Q000633:toxicity*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D009842:Oligopeptides; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000235:genetics / Q000378:metabolism*; D011863:Radioimmunoassay; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D012160:Retina / Q000187:drug effects* / Q000378:metabolism; D015854:Up-Regulation; D014660:Vasoactive Intestinal Peptide / Q000235:genetics / Q000378:metabolism*
D019208:Brain-Derived Neurotrophic Factor; D018690:Excitatory Amino Acid Agonists; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D009842:Oligopeptides; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; C410622:activity-dependent neurotrophic factor; D014660:Vasoactive Intestinal Peptide; D016202:N-Methylaspartate; D005444:Flunarizine