Effects of New P2X7R Antagonists on Retinal Inflammatory Degenerative Conditions

Purinergic P2X7 receptor (P2X7R), an adenosine triphosphate (ATP) gated
nonselective cation channel, is an emerging target for several
neurodegenerative conditions, including retinal degeneration. In particular,
P2X7R has an established role in multiple inflammatory and immune responses,
being implicated in the formation and activation of NLRP3 inflammasome leading
to inflammatory priming and release of immune cytokines. Despite several
efforts in P2X7R antagonist design, no drugs have reached the market yet. In
this perspective, through an integrated in silico and in vitro approach, we aimed
to repurpose FDA approved drugs in search of novel safe treatments for retinal
degenerative diseases, where P2X7R has been found to play a detrimental role.
Virtual screening of about 10000 FDA approved drugs identified 6 putative P2X7
antagonists. Three out of these six compounds inhibited hP2X7R, but not mouse
and rat receptors. Then, for these three P2X7R antagonists, namely
bazedoxifene, teniposide and tipranavir, we have evaluated the in vitro
tolerability by treating immortalized human Müller cells (MIO-M1), primary retinal
endothelial cells (HRECs), human umbilical vein endothelial cells (HUVECs) and
human retinal pigmented epithelial cells (hRPEs). Tipranavir and teniposide were well tolerated by the mentioned retinal cells, thereby they have been further
evaluated in in vitro models of glaucoma, diabetic retinopathy, and age-related macular degeneration. Tipranavir and teniposide showed retinal cell protection,
modulating the expression of HIF-1α, VEGF-A, and inflammatory cytokines.
Therefore, these compounds are worthy of further investigation to manage
retinal degenerative conditions.