Fullerene C₆₀ Derivatives Attenuated Microglia-Mediated Prion Peptide Neurotoxicity

Prion disorders are progressive neurodegenerative diseases characterized by extensive neuronal loss, which is linked to the extracellular accumulation of the scrapie isoform (PrP^SC) of the normal cellular prion protein (PrP^C). As microglial activation is a central event in pathogenesis of prion disease, the strategies that reduce microglial activation may have therapeutic benefits. In this study, the neuroprotective effects of hydroxylated C₆₀(C₆₀-OH) and amino modified-C₆₀(C₆₀-NH₂) were evaluated by using PrP(106-126)-stimulated BV-2 cells as a model of activated microglia. Herein, we showed that microglial activation in response to PrP(106-126) was effectively attenuated by pretreatment with C₆₀-OH as compared with C₆₀-NH₂. C₆₀-OH significantly inhibited the excessive production of inflammatory mediators, such as prostaglandin E2 (PGE₂), nitric oxide (NO), tumor necrosis factors (TNF)-α, interleukin (IL)-1β, and IL-6, and blocked the expression of cyclooxygenase-2 (COX-2) and inducible nitric-oxide synthase (iNOS) in PrP(106-126)-stimulated BV-2 cells. C₆₀-OH exerted anti-inflammatory potential by up-regulating the expression of antioxidant enzymes via activation of nuclear factor erythroid 2-related factor 2 (Nrf2). The inhibitory effect of C₆₀-OH against PrP(106-126)-induced inflammatory response was abolished by siRNA of Nrf2. In addition, conditioned culture media taken from PrP(106-126)-stimulated microglia cause apoptotic neuronal cell death, which was suppressed by pretreatment with C₆₀-OH. Take together, these results suggest that C₆₀-OH protects neuronal cells against PrP(106-126)-mediated neurotoxicity through activation of Nrf2 pathway, and provides evidence that fullerene derivatives may have therapeutic potential in prion diseases.