Progress in the basic and clinical research on the Schlemm’s canal

Therapeutic Drugs and Devices for Tackling Ocular Hypertension and Glaucoma, and Need for Neuroprotection and Cytoprotective Therapies

“…Additionally, damaged or dying TM cells release numerous deleterious compounds (e.g., nestin, A-kinase anchor protein, actinrelated protein 2/3 complex, numerous miRNAs that negatively impact the ANC) which increase cell aging, TM cell apoptosis and ECM deposition (Izzotti et al, 2011) thus exacerbating the issues in the ANC. Additionally, as mentioned earlier, increased resistance at the SC (Stamer et al, 2015;Wang et al, 2020) and distal veinous drainage plexi resulting from upregulation of the angiopoietin/Tie-2 pathway (Thomson et al, 2014;Thomson et al, 2019;Bernier-Latmani and Petrova, 2017) also contributes to the overall OHT and eventual RGC death (Figure 6).…”

“…Since the ANC is avascular, the AQH flowing through the ANC has very important functions that provide a nurturing (provision of O 2 , glucose and growth factors) and a stable environment (achieved by balancing nutrient provision and removal of waste products) for the cells/ tissue lining the ANC (Kaufman, 2020). As shown in Figure 1B, POAG begins most frequently with an imbalance of AQH production by the CE and its drainage from the ANC of the eye via the conventional (TM/SC) and unconventional (uveoscleral, UVS) outflow pathways (Acott et al, 2020;Wang et al, 2020). TM outflow of AQH accounts for 70-90% and UVS outflow for 10-30% of total AQH drainage from the ANC.…”

“…Research has shown that TM/SC-mediated AQH efflux is pressure-dependent, and that IOP is mainly due to the backpressure generated due to blockage of this system (Acott et al, 2020;Wang et al, 2020). Since AQH ultimately exits the eye via collector channels of the TM/SC system and empties into the intrascleral venous plexus, deep-scleral plexus, and into episcleral vessels and thus the veinous circulation, the total resistance within this collective group of channels/plexi/blood vessels causes the elevation of IOP (Thomson et al, 2014;Kaufman, 2020).…”

“…Under normal circumstances, especially in young eyes, the TM cells are abundant and actively phagocytose cellular debris and other accumulating substances such as collagen and fibronectin within the extracellular matrix (ECM;De Groef et al, 2016) to keep the AQH flow constant as the TM filters the AQH in a relatively passive manner. The SC endothelial cells appear to actively transport AQH by generating pores across their surfaces, and perhaps via aquaporins, thereby helping AQH exit the ANC (Acott et al, 2020;Wang et al, 2020). During aging and due to other local deleterious events and processes and ECM accumulation, the number of TM cells decreases as does their remaining phagocytic/autophagic activity (Alvarado et al, 1981;Alvarado et al, 1984;Grierson and Howes, 1987;Matsumoto and Johnson, 1997;Sherwood and Richardson, 1988).…”

“…Normal average IOP is 15 mmHg and >90% of human subject have IOPs between 10 and 21 mmHg. However, in POAG, it is the AQH outflow pathway that is compromised (due to ECM/cellular debris accumulation due to increased transforming growth factor-β (TGF-β) (Tripathi et al, 1994;Hasenbach et al, 2016;Rao and Stubbs, 2021), aberrant cross-linking of ECM which stiffens the TM cells (Yemanyi et al, 2020), possible defects in the SC pore/aquaporin system (Wang et al, 2020), increased resistance at the SC due to angiopoietin/Tie-2 pathway defects (Thomson et al, 2014;Thomson et al, 2019;Bernier-Latmani and Petrova, 2017) and the IOP continues to rise due to the constant addition of AQH to the ANC from the CB. It is estimated that the veinous blood vessel component of the AQH drainage system accounts for <25-50% of total outflow resistance whereas the juxtacanalicular region of the TM/SC area is the major contributor providing >50-75% of total outflow resistance in POAG.…”