Non-amyloidogenic effects of α2 adrenergic agonists: implications for brimonidine-mediated neuroprotection

Abstract

The amyloid beta (Aβ) pathway is strongly implicated in neurodegenerative conditions such as Alzheimer's disease and more recently, glaucoma. Here, we identify the α2 adrenergic receptor agonists (α2ARA) used to lower intraocular pressure can prevent retinal ganglion cell (RGC) death via the non-amyloidogenic Aβ-pathway. Neuroprotective effects were confirmed in vivo and in vitro in different glaucoma-related models using α2ARAs brimonidine (BMD), clonidine (Clo) and dexmedetomidine. α2ARA treatment significantly reduced RGC apoptosis in experimental-glaucoma models by 97.7% and 92.8% (BMD, P<0.01) and 98% and 92.3% (Clo, P<0.01)) at 3 and 8 weeks, respectively. A reduction was seen in an experimental Aβ-induced neurotoxicity model (67% BMD and 88.6% Clo, both P<0.01, respectively), and in vitro, where α2ARAs significantly (P<0.05) 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 Aβ 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 α2ARAs. BMD significantly increased soluble APPα (sAPPα) 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 sAPPα antibody significantly reduced cell viability compared with BMD-treated control (52%), co-treatment (33%) and untreated control (27%). Finally, we show that α2ARAs modulate levels of laminin and MMP-9 in RGCs, potentially linked to changes in Aβ through APP processing. Together, these results provide new evidence that α2ARAs are neuroprotective through their effects on the Aβ pathway and sAPPα, which to our knowledge, is the first description. Studies have identified the need for α-secretase activators and sAPPα-mimetics in neurodegeneration; α2ARAs, already clinically available, present a promising therapy, with applications not only to reducing RGC death in glaucoma but also other neurodegenerative processes involving Aβ.

Memantine‐Loaded PEGylated Biodegradable Nanoparticles for the Treatment of Glaucoma

“…Here, reduction of APP endocytosis results in the accumulation of a greater proportion of cellular APP at the plasma membrane where it is predominantly processed via the nonamyloidogenic pathway so reducing amyloid β production . This is significant as there is growing evidence for the involvement of amyloid β accumulation in glaucoma pathology and increasing recognition of mechanistic similarities between these neurodegenerative disorders . In further support of this hypothesis, we recently demonstrated brimonidine‐mediated RGC neuroprotection (an α2‐adrenergic receptor agonist) in the OHT model were mediated in part by a reduction in amyloid β production and promotion of the nonamyloidogenic pathway .…”

“…This is significant as there is growing evidence for the involvement of amyloid β accumulation in glaucoma pathology and increasing recognition of mechanistic similarities between these neurodegenerative disorders . In further support of this hypothesis, we recently demonstrated brimonidine‐mediated RGC neuroprotection (an α2‐adrenergic receptor agonist) in the OHT model were mediated in part by a reduction in amyloid β production and promotion of the nonamyloidogenic pathway . Finally, as multiple studies now also link the progression of age‐related macular degeneration (AMD) with amyloid β accumulation, nonamyloidogenic promoting therapies such as, brimonidine and memantine may also provide useful therapies for the treatment of AMD.…”

“…To date, the majority of the preclinical studies examining memantine for the treatment of glaucoma, intraperitoneal, subcutaneous, or oral administration routes were investigated. For studies involving oral administration in monkeys, doses of between 2 and 8 mg kg −1 day are reported, while Alzheimer's disease patients are currently prescribed between 10 and 20 mg d −1 .…”

Therapeutic Approaches with Intravitreal Injections in Geographic Atrophy Secondary to Age-Related Macular Degeneration: Current Drugs and Potential Molecules

“…Brimonidine is an α2 adrenergic (α2A) receptor agonist that has been used for its pressure lowering effects in the treatment of glaucoma for several years. Its mechanism in lowering the intraocular pressure involves both the decrease of aqueous humor production and increased uveoscleral outflow [13]. In short, brimonidine has been demonstrated to be neuroprotective via the modulation of Aβ toxicity.…”

“…Furthermore, α2A receptor agonists can also increase levels of phosphorylated arabinoseinducible BAD promoter (P-Bad), and therefore promote cell survival and neuroprotection [13,14]. The initial results of a study (Clinical trials.gov: NCT00658619) involving 119 [14].…”