Apelin protects against NMDA-induced retinal neuronal death via an APJ receptor by activating Akt and ERK1/2, and suppressing TNF-α expression in mice

Abstract

Glutamate excitotoxicity mediated by N-methyl-d-aspartate (NMDA) receptors is an important cause of retinal ganglion cell death in glaucoma. To elucidate whether apelin protects against retinal neuronal cell death, we examined protective effects of exogenous and endogenous apelin on neuronal cell death induced by intravitreal injection of NMDA in the retinas of mice. An intravitreal injection of NMDA induced neuronal cell death in both the retinal ganglion cell layer and inner nuclear layer, and reduced the amplitudes of scotopic threshold response (STR) in electroretinography studies. Both cell death and STR amplitudes decrease induced by NMDA were prevented by a co-injection of [Pyr]-apelin-13, and were facilitated by apelin deficiency. The neuroprotective effects of [Pyr]-apelin-13 were blocked by an apelin receptor APJ antagonist, and by inhibitors of Akt and extracellular signal-regulated kinase 1/2 signaling pathways. Additionally, an intravitreal injection of tumor necrosis factor-α (TNF-α) neutralizing antibody prevented NMDA-induced retinal neuronal cell death, and exogenous and endogenous apelin suppressed NMDA-induced upregulation of TNF-α in the retina. These results suggest that apelin protects neuronal cells against NMDA-induced death via an APJ receptor in the retina, and that apelin may have beneficial effects in the treatment of glaucoma.

Deleterious Effect of NMDA Plus Kainate on the Inner Retinal Cells and Ganglion Cell Projection of the Mouse

“…Since the doses administered to induce retinal excitotoxicity injury vary according to the literature used [17,[36][37][38][39][40][41], a series of experiments were performed to determine the ideal dose of joint administration of KA and NMDA in our model. Initially, in a series of mice (n = 3-4), different individual concentrations of NMDA (10, 30 and 100 mM) and KA (5, 10 and 20 mM) were administered by intraocular injection (see above), and the density of surviving RGC was estimated.…”

The Susceptibility of Retinal Ganglion Cells to Optic Nerve Injury is Type Specific

“…For instance, it was proposed that glaucomatous damage is a result of elevated intraocular pressure (IOP) followed by ischemia, hypoxia of the optic nerve head, and consequently, RGC death due to glutamate-induced excitotoxicity, deprivation of energy and oxygen, an increase in levels of inflammation and alteration of the flow of trophic factors. These events lead to blockage of anterograde and retrograde axonal transport with ensuing axotomy and eventually blindness [20][21][22][23][24][25][26]. Similar to glaucoma, the precise mechanisms of RGC death in TON have not been elucidated, but the pathology appears to be multifactorial, and several mechanisms of RGC death have been postulated, such as axonal transport failure, neurotrophic factor deprivation, activation of apoptotic signals, mitochondrial dysfunction, excitotoxic damage, oxidative stress, misbehaving reactive glia and loss of synaptic connectivity [26][27][28][29].…”

Perinatal Hypoxic-Ischemic Encephalopathy and Neuroprotective Peptide Therapies: A Case for Cationic Arginine-Rich Peptides (CARPs)

“…The active apelin fragments are widely expressed in the body including the CNS [168]. Apelin peptides have been demonstrated to reduce neuronal excitotoxicity and activate extracellular signal-regulated kinase 1/2 ERK-1/2 and PI3K/Akt cell survival pathways in cultured neurons [169,170,171]. Apelin-36 (LVQPRGSRNGPGPWQGGRRKFRRQRPRLSHKGPMPF 42–77 ; net charge +10.1) has been assessed in a P7 rat model of HIE [172] with administration (1000 ng: IP) 1 h before hypoxia reduced infarct volume at 48 h post-HI, and improving neurological function up to 14 days post-HI.…”

“…Therefore, it is possible that CARPs, in addition to Apelin-36, may also be able to stimulate pro-cell survival ERK-1/2 and Akt pathways [180]. Although it should be mentioned that not surprisingly, Apelin-36 can also reduce excitotoxic calcium influx [169,170,171]. In the case of CARP-mediated immune modulation, mR18L (Ac-GFRRFLGSWARIYRAFVG-NH 2 ; net charge +4) is known to reduce LPS-induced systemic infection [181], dRK6 (RRKRRR; net charge +6) inhibits TNFα and IL-6 production by monocytes [182] and hBD3-3 (GKCSTRGRKCCRRKK; net charge +8) downregulates NF-κB induced inflammation [183].…”