VIP, PACAP-38, BDNF and ADNP in NMDA-induced excitotoxicity in the rat retina

Abstract

ABSTRACT.Purpose: 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 ll 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. Conclusion: 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.

Protective Effects of PACAP in the Retina

“…A radioimmunoassay analysis showed that in contrast to VIP, retinal PACAP levels do not change after intravitreal NMDA injection, which might be caused by a compensatory upregulation [ 72 ]. A recent study has confi rmed that PACAP-mediated pathways are protective in NMDA-induced retinal lesion.…”

Neuroprotective effect of epigallocatechin‐3‐gallate against N‐methyl‐D‐aspartate‐induced excitotoxicity in the adult rat retina

“…Excessive stimulation of these glutamate receptors has been shown to play a role in the pathologic course of various neurodegenerative diseases, including retinal ischaemia (Louzada-Junior et al 1992), diabetic retinopathy (Kowluru et al 2001), optic nerve ischaemia (Kim et al 2000), and stroke and epilepsy (Lipton & Rosenberg 1994). In RGCs, glutamate toxicity is primarily mediated by NDMA receptors (Sun et al 2001;Calzada et al 2002;Holmgaard et al 2008;Teuchner et al Neuroprotective effect of epigallocatechin-3-gallate against N-methyl-d-aspartateinduced excitotoxicity in the adult rat retina (Sun et al 2001;Ju et al 2009). Epigallocatechin-3-gallate (EGCG) is a powerful antioxidant exhibiting multifunctional properties including anti-inflammatory and antiapoptotic effects and has shown neuroprotective effects in vivo and in vitro studies (Sutherland et al 2006;Zhang et al 2007Zhang et al , 2008Peng et al 2008;Osborne 2009;Xie et al 2010).…”

Transplanted Mouse Embryonic Stem Cell–Derived Retinal Ganglion Cells Integrate and Form Synapses in a Retinal Ganglion Cell-Depleted Mouse Model

“…In addition, another possibility for favorable graft RGC integration was the activation of endogenous neuroprotective responses after retinal injury. Several neurotrophic factors are expressed after NMDA intravitreal injection to promote neuroregeneration, such as brain-derived neurotrophic factor in the retina 22 , 23 and in the superior colliculus, 24 and CNTF in the retina. 25…”