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

Abstract

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 OGDinduced 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

Gastrodin protects retinal ganglion cells from ischemic injury by activating phosphatidylinositol 3-kinase/protein kinase B/nuclear factor erythroid 2-related factor 2 (PI3K/AKT/Nrf2) signaling pathway

“…Retinal I/R injury is a pathophysiological process of glaucoma [ 5 ]. If an effective treatment is not provided, it may cause the loss of retinal function and eventually lead to blindness [ 29 , 30 ].…”

“…It is well known that retinal blood supply disorder, reperfusion injury, and nutritional deficiency caused by elevated IOP are considered to be the most important risk factors for the occurrence and development of glaucoma [ 4 ]. However, progressive optic nerve injury still occurs in some patients after drug intervention, laser therapy, or surgical treatment, which are only aimed to reduce IOP [ 5 ]. Therefore, in this case, it is urgent to find effective drugs that protect vision by preventing the death of retinal ganglion cells.…”

Nanocarriers for the Delivery of Neuroprotective Agents in the Treatment of Ocular Neurodegenerative Diseases

“…Latanoprost-prostaglandin analogues have demonstrated neuroprotective effects on glutamate-induced RGC death and axotomy-induced ocular neuropathy in animal models, in addition to significantly lowering IOP [ 98 ]. Latanoprost is a glutamate inhibitor and it also inhibits hypoxia-induced apoptosis and functions through cyclooxygenase-2 pathway in order to achieve its neuroprotective benefits [ 99 ].…”

Muscarinic Acetylcholine Receptors in the Retina—Therapeutic Implications

“…Additionally, activation of PKC delta was suggested to regulate neurotrophin levels by M 1 muscarinic receptor activation ultimately leading to an increase in RGCs’ survival in vitro in the retina [ 89 , 90 ]. In 2021, an in vivo study in rats showed that huperzine A lowers intraocular pressure via the M 3 receptor and exerts neuroprotective effects in the retina by increasing endogenous ACh levels and activating M 1 receptors and their downstream AKT/MAPK signaling pathways [ 31 ].…”

“…However, M 2 and M 4 receptors have been shown to preferentially couple to G proteins of the Gi and Go family [ 3 , 29 ]. Some studies reported that mAChR agonists reduce IOP and exert neuroprotective effects in glaucoma [ 30 , 31 , 32 ]. The non-subtype-selective mAChR antagonist, atropine, has been shown to inhibit scleral proliferation and matrix synthesis, and to prevent axial elongation of the eyeball providing a novel therapeutic approach for myopia control [ 14 , 33 ].…”