Huperzine A lowers intraocular pressure via the M3 mAChR and provides retinal neuroprotection via the M1 mAChR: a promising agent for the treatment of glaucoma
العنوان: | Huperzine A lowers intraocular pressure via the M3 mAChR and provides retinal neuroprotection via the M1 mAChR: a promising agent for the treatment of glaucoma |
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المؤلفون: | Ya-Bin Tang, Yong-Yao Cui, Hong-Zhuan Chen, Ping Yu, Wen-Pei Dong, Xiao-Lan Bian |
المصدر: | Ann Transl Med |
بيانات النشر: | AME Publishing Company, 2021. |
سنة النشر: | 2021 |
مصطلحات موضوعية: | MAPK/ERK pathway, genetic structures, medicine.drug_class, Antagonist, Retinal, General Medicine, Pharmacology, Pirenzepine, Neuroprotection, 03 medical and health sciences, chemistry.chemical_compound, Atropine, 0302 clinical medicine, chemistry, Acetylcholinesterase inhibitor, Muscarinic acetylcholine receptor, 030221 ophthalmology & optometry, medicine, Original Article, 030217 neurology & neurosurgery, medicine.drug |
الوصف: | Background Glaucoma is a neurodegenerative disease that shares similar pathological mechanisms with Alzheimer's disease (AD). Drug treatments for glaucoma increasingly rely upon both lowering of intraocular pressure (IOP) and optic nerve protection, as lowering of IOP alone has been unsatisfactory. Huperzine A (HupA) is an acetylcholinesterase inhibitor (AChEI) used for AD. This study investigated the potential of HupA as a treatment for glaucoma. Methods The ability of HupA to lower IOP via causing pupil constriction was assessed using New Zealand rabbits. The retinal neuroprotective effects of HupA were assessed in vivo using rat retinas subjected to ischemia-reperfusion (I/R) and in vitro using primary retinal neurons (PRNs) suffering from oxygen-glucose deprivation (OGD). Results HupA caused pupil constriction in a dose-time dependent manner which was reversed by the nonselective muscarinic acetylcholine receptor (mAChR) antagonist atropine and the selective M3 mAChR antagonist 4-DAMP. However, HupA had no effect on isolated iris muscle tension and calcium flow indicating an indirect M3 mAChR mediated effect. HupA exerted a neuroprotective effect against I/R and OGD to attenuate the retinal pathological lesion, improve retinal neuronal cell viability, reverse oxidative stress injury by increasing GSH levels and SOD activity, and decreasing MDA content and reduce the retinal neuronal apoptosis by decreasing Bax/Bcl-2 ratio and caspase-3 expression with no effect on the calcium flow tests. The effects were abolished by atropine and the selective M1 mAChR antagonist pirenzepine in OGD-induced PRNs suggesting an indirect M1 mAChR-mediated effect via inhibiting AChE activity to increase endogenous ACh level. Furthermore, HupA increased phosphorylated AKT level and decreased the levels of phosphorylated JNK, P38 MAPK and ERK via M1 mAChR antagonists indicating an involvement of activating the M1 mAChR and the downstream AKT/MAPK signaling pathway in the protective effects of HupA. Conclusions HupA could significantly decrease IOP via activating M3 mAChR indirectly and produce retinal neuroprotective effect through M1 mAChR/AKT/MAPK by increasing endogenous ACh level. These investigations demonstrated that HupA was an effective drug in glaucoma treatment and the clinical application of HupA and other AChEIs for glaucoma patients should be further investigated. |
تدمد: | 2305-5847 2305-5839 |
URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::aba8cd5eb0d32fc2f9c0ab73d25fc18b https://doi.org/10.21037/atm-20-8093 |
حقوق: | OPEN |
رقم الأكسشن: | edsair.doi.dedup.....aba8cd5eb0d32fc2f9c0ab73d25fc18b |
قاعدة البيانات: | OpenAIRE |
تدمد: | 23055847 23055839 |
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