Anti-prion activity of Brilliant Blue G.
BACKGROUND
Prion diseases are fatal neurodegenerative disorders with no effective therapy currently available. Accumulating evidence has implicated over-activation of P2X7 ionotropic purinergic receptor (P2X7R) in the progression of neuronal loss in several neurodegenerative diseases. This has led to the speculation that simultaneous blockade of this receptor and prion replication can be an effective therapeutic strategy for prion diseases. We have focused on Brilliant Blue G (BBG), a well-known P2X7R antagonist, possessing a chemical structure expected to confer anti-prion activity and examined its inhibitory effect on the accumulation of pathogenic isoforms of prion protein (PrPres) in a cellular and a mouse model of prion disease in order to determine its therapeutic potential.


RESULTS
BBG prevented PrPres accumulation in infected MG20 microglial and N2a neural cells at 50% inhibitory concentrations of 14.6 and 3.2 µM, respectively. Administration of BBG in vivo also reduced PrPres accumulation in the brains of mice with prion disease. However, it did not appear to alleviate the disease progression compared to the vehicle-treated controls, implying a complex role of P2X7R on the neuronal degeneration in prion diseases.


CONCLUSIONS
These results provide novel insights into the pathophysiology of prion diseases and have important implications for the treatment.
Prion Disease Research Center, National Institute of Animal Health, Tsukuba, Ibaraki, Japan.
Yoshifumi
Y
Iwamaru
Takato
T
Takenouchi
Yuichi
Y
Murayama
Hiroyuki
H
Okada
Morikazu
M
Imamura
Yoshihisa
Y
Shimizu
Makoto
M
Hashimoto
Shirou
S
Mohri
Takashi
T
Yokoyama
Hiroshi
H
Kitani
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D015536:Down-Regulation / Q000187:drug effects; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011328:Prions / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D057165:Proteostasis Deficiencies / Q000517:prevention & control; D058920:Purinergic P2X Receptor Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D012394:Rosaniline Dyes / Q000494:pharmacology* / Q000627:therapeutic use; D012608:Scrapie / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology
D011328:Prions; D020033:Protein Isoforms; D058920:Purinergic P2X Receptor Antagonists; D012394:Rosaniline Dyes; C004692:coomassie Brilliant Blue