Gallic acid attenuates blood-spinal cord barrier disruption by inhibiting Jmjd3 expression and activation after spinal cord injury.

After spinal cord injury (SCI), blood-spinal cord barrier (BSCB) disruption results in secondary injury including apoptotic cell death of neurons and oligodendrocytes, thereby leads to permanent neurological deficits. Recently, we reported that the histone H3K27me3 demethylase Jmjd3 plays a role in regulating BSCB integrity after SCI. Here, we investigated whether gallic acid (GA), a natural phenolic compound that is known to be anti-inflammatory, regulates Jmjd3 expression and activation, thereby attenuates BSCB disruption following the inflammatory response and improves functional recovery after SCI. Rats were contused at T9 and treated with GA (50 mg/kg) via intraperitoneal injection immediately, 6 h and 12 h after SCI, and further treated for 7 d with the same dose once a day. To elucidate the underlying mechanism, we evaluated Jmjd3 activity and expression, and assessed BSCB permeability by Evans blue assay after SCI. GA significantly inhibited Jmjd3 expression and activation after injury both in vitro and in vivo. GA also attenuated the expression and activation of matrix metalloprotease-9, which is well known to disrupt the BSCB after SCI. Consistent with these findings, GA attenuated BSCB disruption and reduced the infiltration of neutrophils and macrophages compared with the vehicle control. Finally, GA significantly alleviated apoptotic cell death of neurons and oligodendrocytes and improved behavior functions. Based on these data, we propose that GA can exert a neuroprotective effect by inhibiting Jmjd3 activity and expression followed the downregulation of matrix metalloprotease-9, eventually attenuating BSCB disruption after SCI.

Prediction of the permeability of drugs through study on quantitative structure-permeability relationship.

This study is to research the quantitative structure-permeability relationship of 20 drugs having similar structure. Permeability was determined by using the Caco-2 cell in vitro model. The apparent permeability coefficient (Papp) of each drug both of apical to basolateral side and basolateral to apical side was measured at the concentration corresponding to 0.1 times the highest dose strength of 250 mL dissolved buffer. In order to test the permeability system suitability, we measured the Papp of 19 model drugs out of 20 which presented in 'Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms based on the Biopharmaceutics Classification System' of FDA guidance. Also, we demonstrated the functional expression of efflux systems (e.g., p-gp) by bi-directional transport studies with rhodamine 123. Also, as a result of the study on quantitative structure-permeability relationship by using the partial least square method, it was possible to predict the permeability of drugs from their 3D structure. The quantitative structure-permeability relationship provided a cross-validated q2=0.789, a normal r2=0.998. Considering all of above results, analysis on this quantitative structure-permeability relationship appears to be a very useful tool to predict the permeability.