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Non-amyloidogenic effects of ?2 adrenergic agonists: implications for brimonidine-mediated neuroprotection.

ABSTRACT: The amyloid beta (A?) pathway is strongly implicated in neurodegenerative conditions such as Alzheimer's 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, 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 A?-induced neurotoxicity model (67% BMD and 88.6% Clo, both P<0.01, respectively), and in vitro, where ?2ARAs 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 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. Studies have identified the need for ?-secretase activators and sAPP?-mimetics in neurodegeneration; ?2ARAs, already clinically available, present a promising therapy, with applications not only to reducing RGC death in glaucoma but also other neurodegenerative processes involving A?.

SUBMITTER: Nizari S

PROVIDER: S-EPMC5260990 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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

Nizari Shereen S Guo Li L Davis Benjamin M BM Normando Eduardo M EM Galvao Joana J Turner Lisa A LA Bizrah Mukhtar M Dehabadi Mohammad M Tian Kailin K Cordeiro M Francesca MF

Cell death & disease 20161208 12

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 treat ...[more]

PMID: 27929541

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Project description:ImportanceAttention-deficit/hyperactivity disorder (ADHD) is diagnosed in approximately 2.4% of preschool-age children. Stimulants are recommended as first-line medication treatment. However, up to 25% of preschool-age children with ADHD are treated with α2-adrenergic agonist medications, despite minimal evidence about their efficacy or adverse effects in this age range.ObjectiveTo determine the frequency of reported improvement in ADHD symptoms and adverse effects associated with α2-adrenergic agonists and stimulant medication for initial ADHD medication treatment in preschool-age children.Design, setting, and participantsRetrospective electronic health record review. Data were obtained from health records of children seen at 7 outpatient developmental-behavioral pediatric practices in the Developmental Behavioral Pediatrics Research Network in the US. Data were abstracted for 497 consecutive children who were younger than 72 months when treatment with an α2-adrenergic agonist or stimulant medication was initiated by a developmental-behavioral pediatrician for ADHD and were treated between January 1, 2013, and July 1, 2017. Follow-up was complete on February 27, 2019.Exposuresα2-Adrenergic agonist vs stimulant medication as initial ADHD medication treatment.Main outcomes and measuresReported improvement in ADHD symptoms and adverse effects.ResultsData were abstracted from electronic health records of 497 preschool-age children with ADHD receiving α2-adrenergic agonists or stimulants. Median child age was 62 months at ADHD medication initiation, and 409 children (82%) were males. For initial ADHD medication treatment, α2-adrenergic agonists were prescribed to 175 children (35%; median length of α2-adrenergic agonist use, 136 days) and stimulants were prescribed to 322 children (65%; median length of stimulant use, 133 days). Improvement was reported in 66% (95% CI, 57.5%-73.9%) of children who initiated α2-adrenergic agonists and 78% (95% CI, 72.4%-83.4%) of children who initiated stimulants. Only daytime sleepiness was more common for those receiving α2-adrenergic agonists vs stimulants (38% vs 3%); several adverse effects were reported more commonly for those receiving stimulants vs α2-adrenergic agonists, including moodiness/irritability (50% vs 29%), appetite suppression (38% vs 7%), and difficulty sleeping (21% vs 11%).Conclusions and relevanceIn this retrospective review of health records of preschool-age children with ADHD treated in developmental-behavioral pediatric practices, improvement was noted in the majority of children who received α2-adrenergic agonists or stimulants, with differing adverse effect profiles between medication classes. Further research, including from randomized clinical trials, is needed to assess comparative effectiveness of α2-adrenergic agonists vs stimulants.

Project description:Background:Moringa peregrina (M. peregrina) is an edible, drought-resistant tree that is native to semi-arid countries. It is used as a painkiller in folk medicine. Aims:To study the antinociceptive effects of the leaf extract of M. peregrina in mice. Study Design:Animal experimentation. Methods:We employed thermal (hot plate and tail-immersion tests) and chemical (writhing and formalin tests) pain models in male BALB/c mice (eight animals per group) to investigate the mechanisms involved in the antinociceptive actions of M. peregrina. Additionally, we identified the chemical constituents present in the extract of M. peregrina by using liquid chromatography-mass spectrometry analysis, and predicted the possible active constituents that interact with the receptor based on molecular docking simulations. Results:In the writhing test, 200 mg/kg of M. peregrina extract restricted abdominal cramps by up to 55.97% (p<0.001). Further, it reduced the time of paw-licking in the early and late phases of formalin test by up to 56.8% and 65.5%, respectively, as compared to the percentage inhibitions of 50.5% and 48.4% produced by 30 mg/kg diclofenac sodium in the early and late phases, respectively (p<0.05). This effect was abrogated by yohimbine (1 mg/kg, intraperitoneally), but not by methysergide (5 mg/kg, intraperitoneally), in the late phase only, which indicates that the action of M. peregrina in formalin test is not mediated by 5-HT2 serotonin receptors, but rather via α2-adrenergic receptors. In the hot plate test, but not on tail-immersion test, the high dose (400 mg/kg) of the extract increased the latency time after 30 minutes of its administration. Yohimbine antagonized the action of M. peregrina in the hot plate test. Based on LC-MS analysis, the major constituents found in M. peregrina methanolic extract were chrysoeriol 7-O-diglucoside, lupeol acetate, quercetin, and rutin. Depending on the molecular docking results, the activity of M. peregrina extract could be due to the binding of chrysoeriol 7-O-diglucoside, quercetin, and rutin to the α2-adrenergic receptor. Conclusion:Interaction with the α2-adrenergic receptor serves as a possible mechanism of the M. peregrina analgesic effect.

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Non-amyloidogenic effects of ?2 adrenergic agonists: implications for brimonidine-mediated neuroprotection.

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

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