Influx Transport of Cationic Drug at the Blood–Retinal Barrier: Impact on the Retinal Delivery of Neuroprotectants

Abstract

The retina is a tissue essential for vision, and the blood-retina barrier (BRB) helps to maintain an optimal microenvironment for the neural system in the retina. Recent findings concerning the BRB showed the involvement of transporters at the inner and outer BRB in drug and nutrient transport, suggesting their utility in the development of novel drug delivery systems to the retina. An in vitro-in vivo relationship study of permeability suggested the influx transport of verapamil, a cationic drug, across the BRB, and further in vivo and in vitro studies of cationic drugs, such as verapamil, propranolol and clonidine, revealed the involvement of carrier-mediated process in their influx transport at the BRB. Studies on substrate specificity in TR-iBRB2 cells, an in vitro model cell line of the inner BRB, suggests the involvement of novel organic cation transporter in the influx transport of cationic drugs at the inner BRB. Considering the neuroprotective effect previously reported for several cationic drugs, such as propranolol and clonidine, the study of cation transport at the BRB is widely expected to improve the treatment of retinal diseases, such as diabetic retinopathy and age-related macular degeneration.

Uptake Study in Lysosome-Enriched Fraction: Critical Involvement of Lysosomal Trapping in Quinacrine Uptake but Not Fluorescence-Labeled Verapamil Transport at Blood-Retinal Barrier

“…However, the study of relationship between the BRB permeability and the lipophilicity of compounds showed a greater in vivo retinal uptake of verapamil, a substrate of P-glycoprotein [ 42 ], revealing the influx transport of verapamil at the BRB and the different barrier function between the BRB and the blood-brain barrier (BBB). Furthermore, the carrier-mediated blood-to-retina transport of cationic drugs at the BRB has been reported [ 13 , 14 , 15 , 16 , 17 ], and is suggested to be promising for the establishment of the safe and efficient delivery of cationic drugs to the retina where neurological dysfunctions are caused by severe retinal diseases such as macular degeneration and diabetic retinopathy [ 3 , 12 ]. In addition, lysosomal trapping has been implied to exert the undesirable influence on the blood-to-retina transport of cationic neuroprotectants across the BRB since its unignorable influence had been suggested in the accumulating reports [ 28 , 29 , 30 ].…”

“…In addition, recent advances in the study of the BRB have revealed the involvement of novel transport systems in the blood-to-retina transport of cationic drugs, such as pyrilamine, nicotine, propranolol, clonidine and verapamil at the inner and outer BRB [ 12 , 13 , 14 , 15 , 16 , 17 ]. These transport systems are considered to be promising in the efficient and safe delivery of drugs to the retina, because they recognize cationic drugs, such as desipramine, imipramine, memantine, and clonidine, whose neuroprotective effects on cerebral ischemia and optic nerve injury have been reported [ 18 , 19 , 20 ].…”

“…These transport systems are considered to be promising in the efficient and safe delivery of drugs to the retina, because they recognize cationic drugs, such as desipramine, imipramine, memantine, and clonidine, whose neuroprotective effects on cerebral ischemia and optic nerve injury have been reported [ 18 , 19 , 20 ]. Therefore, the combination of neuroprotective cations and transport systems at the BRB is expected to be beneficial in the effective therapy of neurological dysfunction of the retina, such as macular degeneration and diabetic retinopathy with severe symptoms, including blindness [ 3 , 12 ].…”

“…Furthermore, functional studies have revealed the temperature-dependent and saturable characteristics of the carrier-mediated cationic drug transport systems at the inner BRB, suggesting that they involve unknown membrane transporters expressed at the BRB [ 12 , 13 , 14 , 15 , 16 , 17 ]. In addition, cumulative evidence demonstrates that the substrate candidates of the systems include several cationic amphiphilic drugs that possibly undergo lysosomal trapping and are sequestrated in lysosomes, which are acidic organelles [ 21 , 22 , 23 ].…”

The anti-inflammatory nanocrystals development of phthalimide associated with budesonide hybrid compound for ophthalmic application

“…Among the receptors of influx, there is the novel organic cation transporter (NOCT), which is responsible for the internalization of cationic drugs used in the treatment for diseases in the retina, such as propranolol, clonidine and verapamil hydrochloride (Kubo et al, 2017). On the other hand, the efflux transporters represent the main barrier for drugs administered systemically, especially for ABC-family transporters.…”