Neuroprotective Effect of DHEA-derivative BNN27 against N-Methyl-D-Aspartate-induced Retinal Excitotoxicity in Mice

Abstract

Purpose: To investigate the neuroprotective role of a novel synthetic analogue (BNN27) of Dehydroepiandrosterone in an experimental model of N-methyl-D-aspartate induced (NMDA) retinal excitotoxicity in mice after intraperitoneal submission. BNN27 passes through the blood-brain barrier and interact with nerve growth factor (NGF) receptors, TrkA and p75.

Methods: Six to eight week old C57BL/6 mice were used. NMDA 100mg/ml (2 μl) was injected intravitreal with a 33g Hamilton syringe in deeply anesthetized animals. Animals were treated daily with IP injections of BNN27 (40mg/kg or 100mg/kg) or ethanol vehicle. Mice were sacrificed 24 and 72 hours later. TUNEL staining was performed in order to evaluate cellular death. Six animals per group and time point were evaluated.

Results: NMDA induced apoptotic cell death was similar 24 and 72 hours after intravitreal administration (36±4 and 42±6 TUNEL positive cells/section respectively. (mean ± SD). Treatment resulted in a dose dependent reduction in TUNEL positive cells in the ganglion cell layer both in 24 and 72 hours after NMDA induced retinal excitotoxicity. Treatment with 40mg/kg of BNN27 reduced TUNEL positive cells to 22±4 and 25±4 TUNEL positive cells/section, while BNN27 at 100mg/kg significantly reduced TUNEL positive cells to 13±2 cells/section and 8±2 cells/section at 24 and 72 hours after NMDA intravitreal injection respectively.

Conclusions: BNN27 appears to exert anti-apoptotic effects in NMDA retinal excitotoxicity induced apoptosis, possibly through its interaction with NGF receptors, representing a potential lead molecule to develop new neuroprotective agents for retina degeneration.

Keywords: 615 neuroprotection • 426 apoptosis/cell death • 517 excitatory amino acid receptors