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Purpose <p>This study aimed to determine <i>in vivo</i> alterations in the rat retinal distribution of a substrate for P-glycoprotein (P-gp), which restricts drug transport to the retina at the inner blood-retinal barrier (BRB), by peripheral administration of lipopolysaccharide (LPS), an inflammatory agent.</p> Methods <p>Using retinal capillaries isolated from rats 24&#xa0;h after peripheral 5&#xa0;mg/kg LPS administration, transport analyses with a fluorescent substrate of P-gp were performed. <i>In vivo</i> retinal distribution of [<sup>3</sup>H]digoxin, a P-gp substrate, in the LPS-administered rats was evaluated after intravenous or intracarotid artery injection. The mRNA and protein expression levels of P-gp in the retinal capillaries were evaluated.</p> Results <p>P-gp-mediated luminal transport of the fluorescent substrate was significantly attenuated in retinal capillaries of the LPS-administered rats. Moreover, <i>in vivo</i> retinal [<sup>3</sup>H]digoxin distribution in LPS-injected rats was significantly greater than that in saline-injected rats. Since the retinal distribution of [<sup>3</sup>H]D-mannitol, a paracellular transport marker, was not significantly altered in LPS-treated rats, it is suggested that <i>in vivo</i> elevation of retinal [<sup>3</sup>H]digoxin distribution is caused by P-gp downregulation at the inner BRB, but not a change in paracellular transport in the barrier. In retinal capillaries isolated from LPS-administered rats, expression analyses of P-gp mRNAs and protein indicated a reduction in its expression on the luminal membrane of the inner BRB.</p> Conclusion <p>Our study demonstrated that <i>in vivo</i> retinal distribution of P-gp substrates was elevated in LPS-administered rats via a decrease in the function and expression of P-gp at the inner BRB.</p>

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Decrease in In Vivo Efflux Transport via P-glycoprotein at the Rat Inner Blood-Retinal Barrier by Peripheral Administration of Lipopolysaccharide

  • 期刊论文

  • 发表日期：

    2025年6月3日

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  • Kiyotaka Daikohara,
  • Shin-ichi Akanuma,
  • Miyu Kawanishi,
  • Yuma Tega,
  • Ken-ichi Hosoya

摘要

Purpose

This study aimed to determine in vivo alterations in the rat retinal distribution of a substrate for P-glycoprotein (P-gp), which restricts drug transport to the retina at the inner blood-retinal barrier (BRB), by peripheral administration of lipopolysaccharide (LPS), an inflammatory agent.

Methods

Using retinal capillaries isolated from rats 24 h after peripheral 5 mg/kg LPS administration, transport analyses with a fluorescent substrate of P-gp were performed. In vivo retinal distribution of [3H]digoxin, a P-gp substrate, in the LPS-administered rats was evaluated after intravenous or intracarotid artery injection. The mRNA and protein expression levels of P-gp in the retinal capillaries were evaluated.

Results

P-gp-mediated luminal transport of the fluorescent substrate was significantly attenuated in retinal capillaries of the LPS-administered rats. Moreover, in vivo retinal [3H]digoxin distribution in LPS-injected rats was significantly greater than that in saline-injected rats. Since the retinal distribution of [3H]D-mannitol, a paracellular transport marker, was not significantly altered in LPS-treated rats, it is suggested that in vivo elevation of retinal [3H]digoxin distribution is caused by P-gp downregulation at the inner BRB, but not a change in paracellular transport in the barrier. In retinal capillaries isolated from LPS-administered rats, expression analyses of P-gp mRNAs and protein indicated a reduction in its expression on the luminal membrane of the inner BRB.

Conclusion

Our study demonstrated that in vivo retinal distribution of P-gp substrates was elevated in LPS-administered rats via a decrease in the function and expression of P-gp at the inner BRB.