Protection of retinal cells from ischemia by a novel gap junction inhibitor.
Retinal cells which become ischemic will pass apoptotic signal to adjacent cells, resulting in the spread of damage. This occurs through open gap junctions. A class of novel drugs, based on primaquine (PQ), was tested for binding to connexin 43 using simulated docking studies. A novel drug has been synthesized and tested for inhibition of gap junction activity using R28 neuro-retinal cells in culture. Four drugs were initially compared to mefloquine, a known gap junction inhibitor. The drug with optimal inhibitory activity, PQ1, was tested for inhibition and was found to inhibit dye transfer by 70% at 10 microM. Retinal ischemia was produced in R28 cells using cobalt chloride as a chemical agent. This resulted in activation of caspase-3 which was prevented by PQ1, the gap junction inhibitor. Results demonstrate that novel gap junction inhibitors may provide a means to prevent retinal damage during ischemia.
Das
Satyabrata
S
Department of Biochemistry, Kansas State University, 141 Chalmers Hall, Manhattan, KS 66506, USA.
Lin
Dingbo
D
Jena
Snehalata
S
Shi
Aibin
A
Battina
Srinivas
S
Hua
Duy H
DH
Allbaugh
Rachel
R
Takemoto
Dolores J
DJ
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D003035:Cobalt / Q000037:antagonists & inhibitors / Q000633:toxicity; D017629:Gap Junctions / Q000187:drug effects*; D007511:Ischemia / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D015767:Mefloquine / Q000737:chemistry / Q000494:pharmacology; D011319:Primaquine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D012160:Retina / Q000187:drug effects* / Q000473:pathology; D012171:Retinal Vessels / Q000187:drug effects*
D003035:Cobalt; C018021:cobaltous chloride; D011319:Primaquine; D015767:Mefloquine