The tyrosine kinase inhibitor imatinib mesylate delays prion neuroinvasion by inhibiting prion propagation in the periphery

Abstract

Prion diseases are fatal neurodegenerative disorders with no effective therapy. A hallmark of prion disease is the conversion of the normal cellular form of prion protein PrP(C) into a disease-associated isoform PrP(Sc). The authors recently have shown that a tyrosine kinase inhibitor, imatinib mesylate, induces clearance of PrP(Sc) via specific inhibition of c-Abl in prion-infected cell culture models. In this study, the authors assessed the in vivo effects of imatinib mesylate on prion disease using a scrapie-infected mouse model and further investigated prion infectivity of the drug-treated scrapie-infected neuroblastoma (ScN2a) cells. The authors found that imatinib mesylate abolished prion infectivity to almost undetectable level in ScN2a cells and the level of PrP(Sc) was significantly decreased by the drug in scrapie-infected mouse spleens as well as in ScN2a cells. Moreover, the drug treatment at an early phase of peripheral scrapie infection delayed the appearance of PrP(Sc) in the central nervous system (CNS) and onset of clinical disease in mice. However, neither intraperitoneal nor intracerebroventricular delivery of the drug exerted any PrP(Sc) clearance effect in the CNS.

Autophagy induction by trehalose counter-acts cellular prion-infection

“…Previously, similar results were obtained in mice treated with imatinib. 46 Imatinib treatment at an early phase of peripheral prion infection delayed both appearance of PrP Sc in the CNS and onset of clinical disease in mice, but neither intraperitoneal nor intracerebroventricular delivery of the drug exerted significant PrP Sc clearance effects in the brain. In terms of trehalose this finding was not unexpected as the anti-prion effect in cultured cells was highly dose-dependent and the effective anti-prion concentration of 100 mM is probably not achievable in tissues.…”

Rapamycin Delays Disease Onset and Prevents PrP Plaque Deposition in a Mouse Model of Gerstmann–Sträussler–Scheinker Disease

“…Induction of autophagy in experimental models of prion disease has also been attempted, although the results have been mixed. Imatinib, a cancer drug that activates autophagy, enhanced the lysosomal degradation of PrP Sc , the proteinase K (PK)-resistant pathogenic isoform of PrP, in vitro Heiseke et al, 2009b) and it delayed the onset of symptoms and appearance of PrP Sc in the CNS of mice peripherally inoculated with scrapie (Yun et al, 2007), while rapamycin modestly extended survival in scrapieinfected mice (Heiseke et al, 2009a). Trehalose, a novel autophagy inducer, also reduced the load of PK-resistant PrP Sc in cells chronically infected with scrapie prions; however, it did not affect the course of disease in scrapie-infected mice (Aguib et al, 2009).…”

Prion Disease Therapy: Trials and Tribulations

“…The inhibitor STI571, also known as imatinib mesylate, targets tyrosine kinase c-Abl and is thought to exert its anti-prion effect through lysosomal degradation pathways. It enhanced the clearance of PrP res in cell culture, with complete cure after 10 days of treatment [204,205]. In vivo it decreased spleen PrP res and delayed neuroinvasion if administered early and after intraperitoneal inoculation, but even intracerebral administration of the drug could not clear PrP res from the brain [205].…”