Evaluation of Anti-Prion Activity of Congo Red and its Derivatives in Experimentally Infected Hamsters

Abstract

Among transmissible spongiform encephalopathies (TSE), particularly dreadful are the bovine spongiform encephalopathy (BSE), because of its epidemic character, and the new variant of Creutzfeldt-lakob disease (vCJD) in man, possibly related to BSE prion, through the intake of infected food. To treat TSE, many potentially therapeutic agents have been tested: some of them, among which is Congo Red (CAS 573-58-0, CR), delayed the onset of symptoms in scrapie-infected rodents, and some CR derivatives proved to be effective in vitro. The capacity of a synthesized CR derivative (CR-A) and of the aromatic central benzidine rings of CR (CR-B) to abrogate scrapie-induced disease in experimentally infected hamsters was assayed. CR, used as reference substance, administered i.c. after pre-incubation with the scrapie inoculum, was strongly effective in slowing the progression of the infection, while both CR-A and CR-B, administered alone or together, were not effective. Both CR-A and CR, when administered by subcutaneous route in i.c. scrapie-infected animals. prolonged the survival time in comparison to controls; CR-B was not effective. Moreover, both CR and CR-A were very effective in prolonging the survival time of i.p. scrapie-infected hamsters. The hypothesis of possible different mechanisms of interaction between CR or CR-A and the scrapie agent related to the chemical structures of the molecules is discussed.

Styryl-Based and Tricyclic Compounds as Potential Anti-Prion Agents

“…However, due to its benzidine structure, Congo red is carcinogenic and toxic, making it unsuitable for animal or human use. We and another group have developed Congo red analogs that have effectiveness in tissue culture, but in vivo effectiveness was much more limited [13], [15]. The Doh-ura group have tested a number of PrP amyloid imaging ligands for anti-prion clearance in cell culture and shown some effectiveness in vivo using Tg20 PrP over-expressing transgenic mice [14], [16].…”

“…Very few of these have been shown to be effective in vivo using animal models of prion scrapie infection and none have been shown to have a clinical effect in humans [6], [8]. A number of compounds which are amyloidophilic, such as Congo red derivates, have been shown to have some anti-prion effectiveness [13]–[16]. In addition compounds with a similar scaffold structure to quinacrine and chlorpromazine have been shown to have effectiveness in prion tissue culture [17], [18].…”

Prion Disease Therapy: Trials and Tribulations

“…It decreases PrP res in cells [103,121,122,[124][125][126][127][128] and in cell-free conversions [126,127,129,130] and decreases surface PrP c in normal cells [21]. It has also been shown to prolong incubation times in hamsters after intraperitoneal or intracerebral inoculation [131,132]. Its clinical use is limited by its toxicity and its poor penetration of the blood-brain barrier.…”

Recent Advances in Prion Chemotherapeutics

“…In vitro , Congo red and analogues thereof decrease PrP res and scrapie infectivity in cells [30,47,51,52,53,54,55,56], block cell-free conversion reactions [53,54,57,58], and decrease surface PrP c in normal cells [19]. In vivo , Congo red prolongs incubation times in hamsters [59,60], but its clinical use is limited by the potential teratogenic and/or carcinogenic activity of the benzidine moiety, and by its poor blood brain barrier permeability.…”