Protective effects of PF‐4708671 against N‐methyl‐d‐aspartic acid‐induced retinal damage in rats

Abstract

We previously demonstrated that rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR), protects against N-methyl-d-aspartic acid (NMDA)-induced retinal damage in rats. Rapamycin inhibits mTOR activity, thereby preventing the phosphorylation of ribosomal protein S6, which is a downstream target of S6 kinase. Therefore, we aimed to determine whether PF-4708671, an inhibitor of S6 kinase, protects against NMDA-induced retinal injury. Intravitreal injection of NMDA (200 nmol/eye) caused cell loss in the ganglion cell layer and neuroinflammatory responses, such as an increase in the number of CD45-positive leukocytes and Iba1-positive microglia. Surprisingly, simultaneous injection of PF-4708671 (50 nmol/eye) with NMDA significantly attenuated these responses without affecting phosphorylated S6 levels. These results suggest that PF-4708671 and rapamycin likely protect against NMDA-induced retinal damage via distinct pathways. The neuroprotective effect of PF-4708671 is unlikely to be associated with inhibition of the S6 kinase, even though PF-4708671 is reported to be a S6 kinase inhibitor.

Inhibition of p70 Ribosomal S6 Kinase (S6K1) Reduces Cortical Blood Flow in a Rat Model of Autism-Tuberous Sclerosis

“…Inhibition of specific downstream targets of mTOR signaling may offer a more selective approach, potentially making it more beneficial for ASD therapy. We used PF-4708671, which is a highly specific inhibitor of S6K1 and of benefit in several neurological disorders, to conduct the current study (Hayashi et al, 2016 ; Pearce et al, 2010 ; Srivastava et al, 2016 ). The decreased cerebral blood flow resulting from the blockade of the S6K1 branch of mTOR signaling could potentially offer therapeutic benefits in the treatment of tuberous sclerosis-ASD in humans (Gkogkas et al, 2013 ; Kelleher & Bear, 2008 ; Sharma & Mehan, 2021 ; Winden et al, 2018 ).…”

Metformin Protects against NMDA-Induced Retinal Injury through the MEK/ERK Signaling Pathway in Rats

“…We previously demonstrated that leukocyte infiltration and microglial activation in the retina occurred one day after intravitreal injection of NMDA in rats [ 26 , 38 , 39 , 40 ]. Infiltrating leukocytes and activated microglia promote retinal inflammation and exacerbate neuronal damage [ 19 , 20 ].…”

“…Histological evaluation was performed according to the methods described in our previous studies [ 25 , 26 , 37 , 38 , 40 ]. Briefly, seven days after injection, rats were deeply anesthetized with pentobarbital sodium.…”

“…Immunohistochemical staining of retinal cross-sections was performed according to the methods described in our previous studies [ 26 , 38 , 39 , 40 ]. Briefly, the eyecups without the cornea and lens were fixed in 1% PFA in PBS overnight at 4 °C and rinsed several times with PBS.…”