How do cholinesterase inhibitors treat glaucoma

OHT-induced blood flow impairment is attenuated by galantamine. Both regional E and global F retinal blood flow were exceptionally improved with galantamine treatment black bars compared with PBS-treated controls hatched bars. Figure 4 OHT-induced blood flow impairment is attenuated by galantamine. Table 2. Retinal Blood Flow. Furthermore, in contrast to endothelium-intact arterioles, exposure of endothelium-denuded vessels to galantamine failed to reduce ET-1—mediated contraction Fig.

Collectively, these data demonstrated that: 1 galantamine acts directly on retinal vessels, 2 galantamine reduces ET-1—mediated vasoconstriction of retinal microvasculature in vitro, and 3 galantamine-mediated vasorelaxation requires the presence of viable endothelial cells.

Figure 5. Galantamine induces vasodilation of isolated retinal arterioles through mAChR activation. A — C Application of galantamine reduces ET-1—mediated vasoconstriction of small retinal arterioles.

The presence of endothelial cells was necessary for the vasorelaxant effect of galantamine as denudation of endothelium by CHAPS eliminated galantamine-induced relaxation of ET-1—constricted vessels C. Figure 5 Galantamine induces vasodilation of isolated retinal arterioles through mAChR activation. In contrast, application of mecamylamine MMA , a nonselective antagonist of all nAChR subtypes, did not significantly alter galantamine-induced vasodilation Fig.

These results indicate that galantamine promotes retinal microvessel relaxation through mAChR activation. To establish which mAChR subtypes were involved in this response, we used selective mAChR antagonists in combination with galantamine. In contrast, tropicamide or DX, blockers of M4 or M2 mAChR, respectively, did not have a significant effect on galantamine-induced vasodilation not shown.

These data indicate that M1 and M3 mAChRs mediate the vasodilatory effect of galantamine on isolated retinal microvasculature. To assess whether mAChR also played a role in galantamine-induced vasoprotection in vivo, we tested the effect of galantamine in combination with SCO or MMA in experimental glaucoma Fig.

A single intravitreal injection of SCO or MMA was administered at 1 week after OHT surgery, coinciding with the initiation of galantamine treatment, and analysis of microvasculature density was performed 2 weeks later. Analysis of isolectin-stained retinas demonstrated that coadministration of galantamine and SCO inhibited the vasoprotective effect of galantamine, whereas MMA had no effect Figs. Quantitative analysis of retinal microvasculature density confirmed that SCO blocked galantamine-induced vasoprotection, leading to significant loss of vessels similar to PBS-injected controls Fig.

Of interest, SCO blocks not only the vasoprotective effect of galantamine this study , but also galantamine-induced RGC neuroprotection, as previously shown. Therefore, we conclude that the vasoprotective effect of galantamine in vivo is mediated through activation of mAChR. Figure 6. Vasoprotection occurs through galantamine-mediated activation of mAChR in experimental glaucoma.

Figure 6 Vasoprotection occurs through galantamine-mediated activation of mAChR in experimental glaucoma. This study reports a number of important findings.

First, we detected substantial loss of capillaries in an OHT rat glaucoma model. Second, we found that loss of retinal microvessels occurred concomitantly with the death of RGCs following induction of high IOP.

The onset of microvasculature and RGC loss occurred early and proceeded at approximately the same rate for at least 5 weeks after the initial insult. Third, systemic administration of galantamine preserved microvasculature density and improved retinal blood flow in experimental glaucoma.

Finally, the vasoactive effects of galantamine on retinal microvessels occurred through activation of mAChR. The ONH is considered a primary site of glaucomatous injury and strong experimental evidence indicates that it is an initial point of RGC axonal damage. Importantly, many of the vascular deficits observed in the ONH in glaucoma have also been reported in the retina, 8 — 13 but the correlation between changes in the retinal microvasculature and RGC loss had not been previously studied and is, therefore, a focus of our study.

Our data demonstrate a steady and simultaneous loss of RGCs and retinal capillaries, indicating that degenerative changes in glaucoma affect both neuronal and vascular compartments.

Based on the high vulnerability of RGCs to glaucomatous damage, we predicted that RGCs would die first and, as the local need for oxygen and nutrient supply decreased, the microvasculature would undergo rapid, but slightly delayed, involution.

The surprising observation that microvessels and RGCs disappear at the same rate suggests a tighter codependence between these cellular compartments than previously expected. Furthermore, our data suggest that both RGCs and microvessels are similarly affected by IOP-induced degenerative changes; therefore the symbiotic cross-talk between these cell types is likely to be impaired in glaucoma.

Previous studies using acute retinal ischemia rat models, with or without IOP increase, demonstrated that substantial periods of ischemia are needed to induce RGC death. Nonetheless, it is important to emphasize that the bulk of the cell loss we report here occurred between 2 and 5 weeks of glaucoma induction when mean IOP values in glaucomatous eyes were 30 or 42 mm Hg, respectively, compared with 23 mm Hg in intact eyes Table 1 and RGC loss was proportional to IOP increase.

Our findings are in agreement with previous work showing that the amount of cell death depends on the magnitude of IOP elevation and the duration of the insult. We show that capillaries are dramatically affected early in the pathology, whereas small arterioles are affected only at later stages 5 weeks after glaucoma induction. Retinal and brain capillaries do not undergo classical vasoconstriction because they lack smooth muscle and their blood flow is regulated primarily by precapillary arterioles.

We propose two plausible scenarios to explain our findings. First, since RGCs also disappear early on, it is possible that the levels of RGC-derived factor s essential for capillary maintenance decrease, thus leading to capillary loss. Indeed, RGCs produce vascular endothelial growth factor and angiopoietins 1 and 2, which are required for capillary stability, growth, and survival. Candidates that might potentially contribute to this response include nitric oxide NO , ET-1, reactive oxygen species, tumor necrosis factor alpha, and glutamate, some of which have the potential to trigger both RGC and endothelial cell dysfunction or apoptosis.

The branches of retinal arteries expand to form deeper capillary networks, which are most prominent between the inner nuclear and outer plexiform layers. Interestingly, chronic OHT has been shown to induce cone photoreceptor death 55 that correlated with important deficits in the electroretinogram response, including a reduction in the amplitude of a- and b-waves. However, with the exception of one study reporting a decrease in cholinergic and GABAergic amacrine cells, 57 most groups have failed to detect a significant loss of these neurons in experimental glaucoma.

Consistent with this, a decrease in the amplitude of oscillatory potentials, presumed to be generated by amacrine cells, has been reported in human glaucomatous eyes. Given the tight functional relationship between RGCs and the retinal microvasculature during experimental glaucoma onset and progression, we asked whether strategies that promote RGC neuroprotection can also maintain the integrity of the capillary network and enhance blood flow.

We previously demonstrated that galantamine promotes structural and functional RGC protection in experimental rat glaucoma. RGCs stimulate vessel growth and endothelial cell survival 26 ; therefore, our findings raise the question: is galantamine-induced vasoprotection a consequence of increased RGC survival? Our experiments using isolated retinal arterioles indicate that galantamine can act directly on the vasculature to inhibit vasoconstriction in the absence of RGCs, and that this response depends on the presence of viable endothelial cells.

Although these studies do not establish a role for vasoconstriction per se, they identify a direct effect of galantamine on isolated retinal arterioles, suggesting a possible mechanism of action that involves arteriole vasodilation and enhanced blood flow to the glaucomatous retina. Therefore, it is likely that galantamine can boost endothelial cell survival and blood flow independently of its neuroprotective effect on RGCs. This is consistent with a previous study showing that galantamine can enhance the survival of isolated brain endothelial cells in culture.

Therefore, we cannot rule out that the prosurvival effect of galantamine on RGCs, previously reported, 30 is partly due to enhanced endothelial cell survival leading to improved capillary density and blood flow. To elucidate whether the mechanisms by which galantamine-induced vasoprotection were different from those leading to RGC survival, we investigated the role of ACh receptors in this response.

Retinal and brain endothelial cells abundantly express M1 and M3 mAChR subtypes, 66 , 67 which have been implicated in cholinergic-mediated vasomodulation in the brain, 68 and ACh-dependent vascular relaxation is lost in M3 mAchR knockout mice. Furthermore, activation of retinal M1 and M3 mAChR subtypes stimulates neuronal NO synthase activity leading to vasodilation 72 ; thus, activation of mAChR in cells other than endothelial cells might contribute to vasoprotection and blood flow restoration in glaucoma.

In summary, this study demonstrates early and progressive loss of the retinal microvasculature intimately associated with RGC death in experimental glaucoma. As new imaging tools become available, it might be relevant to closely monitor microvasculature changes in patients with high risk to develop glaucoma as well as during disease progression. We show that a clinically approved drug, galantamine, promotes effective vasoprotection and restores retinal blood flow in an OHT rat model.

These findings are particularly important for the treatment of glaucomatous neuropathies because, although RGC death is irreversible, the retinal microvasculature maintains the capacity to regenerate.

Given the dual role of galantamine in neuronal and vascular protection, this drug is a promising therapeutic candidate for glaucoma and other neurodegenerative diseases involving ischemia.

A better understating of early microvascular changes in glaucomatous neuropathies as well as the molecular pathways involved in endothelial cell death might reveal new therapeutic targets for the treatment of this disease. Disclosure: M. Almasieh , None; J. MacIntyre , None; M. Pouliot , None; C. Casanova , None; E. Vaucher , None; M. Kelly , None; A. Di Polo , None. Quigley HA. Number of people with glaucoma worldwide.

Br J Ophthalmol. Predictors of long-term progression in the early manifest glaucoma trial. Ocular perfusion pressure and ocular blood flow in glaucoma.

Curr Opin Pharmacol. Drance S. Disc hemorrhages in the glaucomas. Surv Ophthalmol. What is the link between vascular dysregulation and glaucoma? Selective atrophy of the radial peripapillary capillaries in chronic glaucoma. Arch Ophthalmol. A hypothesis to explain ganglion cell death caused by vascular insults at the optic nerve head: possible implication for the treatment of glaucoma. Perfusion of the juxtapapillary retina and the neuroretinal rim area in primary open angle glaucoma.

J Glaucoma. Yamazaki Y Drance S. The relationship between progression of visual field defects and retrobulbar circulation in patients with glaucoma. Am J Ophthalmol. The cholinergic agents have the advantages of systemic safety, fewer undesirable local side effects, and usefulness in angle-closure and narrow-angle glaucoma. The powerful cholinesterase inhibitors, on the other hand, produce better diurnal reduction of intraocular pressure, require less frequent administration, and can control many cases whose pressures cannot be otherwise brought to heal.

Neither group constitutes the ideal agent, and the search for this must therefore continue. It must always be kept in mind that the agents used are powerful toxic drugs and for some people may be incapacitating. One must not be afraid to use them when indicated, but they should not be used indiscriminately.

Purchase this article with an account. Author Affiliations. Access through your institution. Add or change institution. Save Preferences. Privacy Policy Terms of Use. Access your subscriptions.

Free access to newly published articles. Purchase access. Rent article Rent this article from DeepDyve. Access to free article PDF downloads.