Non-amyloidogenic effects of [alpha]2 adrenergic agonists: implications for brimonidine-mediated neuroprotection

The amyloid beta (A) pathway is strongly implicated in neurodegenerative conditions such as Alzheimers disease and more recently, glaucoma. Here, we identify the 2 adrenergic receptor agonists (2ARA) used to lower intraocular pressure can prevent retinal ganglion cell (RGC) death via the non-amyloidogenic A-pathway. Neuroprotective effects were confirmed in vivo and in vitro in different glaucoma-related models using 2ARAs brimonidine (BMD), clonidine (Clo) and dexmedetomidine. 2ARA treatment significantly reduced RGC apoptosis in experimental-glaucoma models by 97.7% and 92.8% (BMD, Po0.01) and 98% and 92.3% (Clo, Po0.01)) at 3 and 8 weeks, respectively. A reduction was seen in an experimental A-induced neurotoxicity model (67% BMD and 88.6% Clo, both Po0.01, respectively), and in vitro, where 2ARAs significantly (Po0.05) prevented cell death, under both hypoxic (CoCl2) and stress (UV) conditions. In experimental-glaucoma, BMD induced ninefold and 25-fold and 36-fold and fourfold reductions in A and amyloid precursor protein (APP) levels at 3 and 8 weeks, respectively, in the RGC layer, with similar results with Clo, and in vitro with all three 2ARAs. BMD significantly increased soluble APP (sAPP) levels at 3 and 8 weeks (2.1 and 1.6-fold) in vivo and in vitro with the CoCl2 and UV-light insults. Furthermore, treatment of UV-insulted cells with an sAPP antibody significantly reduced cell viability compared with BMD-treated control (52%), co-treatment (33%) and untreated control (27%). Finally, we show that 2ARAs modulate levels of laminin and MMP-9 in RGCs, potentially linked to changes in A through APP processing. Together, these results provide new evidence that 2ARAs are neuroprotective through their effects on the A pathway and sAPP, which to our knowledge, is the first description.