Abstract
Prion diseases still remain incurable despite multiple efforts to develop a treatment. Therefore, it is important to find strategies to at least reduce the symptoms. Lithium has been considered as a neuroprotective agent for years, and the objective of this preclinical study was to evaluate the efficacy of lithium delivered as a water-in-oil microemulsion (Aonys®). This delivery system allows using low doses of lithium and to avoid the toxicity observed in chronic treatments. C57BL/6J mice were intracranially inoculated with ME7 prion-infected brain homogenates and then were treated with lithium from day 90 post inoculation until their death. Lithium was administered at traditional doses (16 mg/kg/day) by the gavage route and at lower doses (40 or 160 µg/kg/day; Aonys®) by the rectal mucosa route. Low doses of lithium (Aonys®) improved the survival of prion-inoculated mice, and also decreased vacuolization, astrogliosis, and neuronal loss compared with controls (vehicle alone). The extent of the protective effects in mice treated with low-dose lithium was comparable or even higher than what was observed in mice that received lithium at the traditional dose. These results indicate that lithium administered using this innovative delivery system could represent a potential therapeutic approach not only for prion diseases but also for other neurodegenerative diseases.
Highlights
Prion diseases are progressive neurodegenerative disorders caused by conversion of a normal cell-surface glycoprotein (PrPC) into a conformationally altered isoform (PrPSc) that is infectious
Our results demonstrate that low doses of lithium delivered by NP03 improved the survival of prion-inoculated mice, and decreased vacuolization, astrogliosis, and neuronal loss
The incubation time, which was determined by the appearance of at least three clinical signs, was not significantly different in the four groups (Fig. 1a), it was slightly longer in the three lithium-treated groups
Summary
Prion diseases are progressive neurodegenerative disorders caused by conversion of a normal cell-surface glycoprotein (PrPC) into a conformationally altered isoform (PrPSc) that is infectious. This abnormal PrPSc is a protease-resistant isoform of the host-encoded PrPC. Conformational differences between PrPC and PrPSc are evidenced by an increase of β-sheet content as well as by the protease resistance of the PrPSc. Prion diseases are characterized by rapid neuronal cell death, vacuolization, and gliosis. Prion diseases affect humans and animals, and, today, they still remain incurable. Different therapeutic strategies have been tested in preclinical prion models with limited results; it is important to find approaches for palliating at least the disease symptoms
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