The modulation of protein kinase A and heat shock protein 70 is involved in the reversible increase of blood-brain tumor barrier permeability induced by papaverine.
Intra-arterial administration of papaverine has been revealed to cause an increase in the blood-brain tumor barrier (BTB) permeability. The exact mechanism of papaverine opening the BTB in chemotherapy of malignant cerebral tumors, however, has not been well described. We used a rat brain glioma (C6) model for studying how papaverine modulates the permeability of BTB by monitoring the activities of the tight junction (TJ)-associated protein occludin, claudin-5 and cytoskeletal protein filamentous actin (F-actin) and whether protein kinase A (PKA) and heat shock protein 70 (HSP70) were involved in the regulation of this biological process. The levels of occludin, claudin-5 and F-actin protein in the tumor tissues were down-regulated by papaverine via immunohistochemistry, immunofluorescence assays and Western blot, corresponding to the time-dependent change of the BTB permeability. The most obvious attenuation of occludin, claudin-5 and F-actin protein was observed at 1h after papaverine perfusion, companied by a significant decrease in expression levels of PKA protein. The expression level of HSP70 in the tumor tissues was also progressively increased after papaverine perfusion and reached the maximum at 3h. The results demonstrate that the reversible openning of BTB mediated by papaverine may be associated with the functional combination between PKA and HSP70. That is, BTB opening may be attributable to the down-regulation of occludin, claudin-5 and F-actin, and cAMP/PKA signaling pathway might be involved in this process. HSP70 is likely responsible for the BTB closing, which helping the repairment of injured TJ protein and the rebuilding of the BTB.
Wang
Zhen-Hua
ZH
Department of Physiology, College of Basic Medicine, China Medical University, Shenyang, People's Republic of China.
Xue
Yi-Xue
YX
Liu
Yun-Hui
YH
D000199:Actins / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000503:physiopathology*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000473:pathology*; D062507:Claudin-5; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005070:Evans Blue; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology*; D005910:Glioma / Q000188:drug therapy / Q000473:pathology*; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D062793:Occludin; D010208:Papaverine / Q000494:pharmacology / Q000627:therapeutic use; D010539:Permeability / Q000187:drug effects; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
D000199:Actins; D062507:Claudin-5; C491510:Cldn5 protein, rat; D018840:HSP70 Heat-Shock Proteins; D008565:Membrane Proteins; D062793:Occludin; C568987:Ocln protein, rat; D010726:Phosphodiesterase Inhibitors; D005070:Evans Blue; D010208:Papaverine; D017868:Cyclic AMP-Dependent Protein Kinases