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, 8 (1), 163

Lithium as a Disease-Modifying Agent for Prion Diseases

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Lithium as a Disease-Modifying Agent for Prion Diseases

A Relaño-Ginés et al. Transl Psychiatry.

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.

Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1. Incubation and survival time of control mice (vehicle; n = 10), mice treated with NP03-40 (n = 14), NP03-160 (n = 14), and lithium by gavage (n = 14) from day 90 after intracranial inoculation of ME7 prion-infected brain homogenates.
a Incubation time (mean ± SEM). No significant difference was found with the Mann–Whitney test. b Kaplan–Meier curves showing the percentage of incubation time per mouse for each group. c Survival time (mean ± SEM); the unpaired Mann–Whitney test was used for statistical analysis. d Kaplan–Meier survival curve showing the percent of survival for each mouse per group
Fig. 2
Fig. 2. Postmortem analysis of PrPSc accumulation in control mice (vehicle; n = 10), and mice treated with NP03-40 (n = 14), NP03-160 (n = 14), and lithium by gavage (n = 14).
a Quantification (mean ± SEM) of the PrP signal after immunoblotting of brain protein extracts with the SAFmix of anti-PrP antibodies; data were normalized to the reference signal of a ME7 brain homogenate pool. b Individual PrPSc levels for each mouse as a function of its survival time
Fig. 3
Fig. 3
a Representative images of the postmortem immunohistological analysis of hippocampus tissue sections to evaluate a PrPSc accumulation using the SAF84 antibody, b the presence of vacuoles (arrows) after hematoxylin–eosin staining, c GFAP-positive astrocytes, and d NeuN (neuronal marker)-positive cells. Scale bar 400 µm
Fig. 4
Fig. 4. Quantification (mean ± SEM) of the number of vacuoles/mm2 in hippocampus sections after hematoxylin–eosin staining (n = 11 control; n = 11 NP03-40; n = 10 NP03-160; n = 10 lithium-gavage).
a Quantification of the surface of GFAP-positive astrocytes (n = 10 control; n = 10 NP03-40; n = 8 NP03-160; n = 9 lithium-gavage) and b of the surface occupied by NeuN-positive neurons (n = 5 control; n = 6 NP03-40; n = 7 NP03-160; n = 6 lithium-gavage). c The unpaired Mann–Whitney test was used for statistical analysis in all cases. df Individual vacuole number and GFAP-positive and NeuN-positive cell surface as a function of the individual survival time
Fig. 5
Fig. 5
a Immunohistological analysis of LC3 expression (representative images). b, c Quantification of LC3-positive cells (mean ± SEM) in the striatum and cortex, respectively (n = 2 control; n = 5 NP03-40; n = 6 NP03-160; n = 7 lithium-gavage, for striatum; and n = 2 control; n = 5 NP03-40; n = 5 NP03-160; n = 5 lithium-gavage, for cortex). The unpaired Mann–Whitney test was used for statistical analysis in all cases. d, e Individual LC3 levels as a function of the survival time. Scale bar 400 µm
Fig. 6
Fig. 6. Schematic representation of the signaling pathways implicated in the improvement of the neuropathology following treatment with NP03-lithium in C57BL/6J mice inoculated with ME7 prion-infected brain homogenates.
Lithium (Li) inhibits the activation of the transcription factor STAT3, a regulator of GFAP transcription and astrogliogenesis. This pathway explains the decrease of astrogliosis in mice following treatment with lithium. Lithium also restores Wnt/β-catenin signaling that is impaired in prion diseases (PrPSc) through inactivation of GSK3β. This leads to transcription activation of Wnt target genes, and consequently to the limitation of neuronal loss. Lithium also increases autophagy by activation of mTOR via inactivation of GSK3β. Autophagy regulation is also affected by STAT3 activation that disrupts the interaction with PKR kinase, resulting in eIF2A activation and subsequently induction of autophagy

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