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. 2019 Dec 2;9(1):18045.
doi: 10.1038/s41598-019-54557-5.

The Selective GSK3 Inhibitor, SAR502250, Displays Neuroprotective Activity and Attenuates Behavioral Impairments in Models of Neuropsychiatric Symptoms of Alzheimer's Disease in Rodents

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The Selective GSK3 Inhibitor, SAR502250, Displays Neuroprotective Activity and Attenuates Behavioral Impairments in Models of Neuropsychiatric Symptoms of Alzheimer's Disease in Rodents

Guy Griebel et al. Sci Rep. .
Free PMC article

Abstract

Glycogen synthase kinase 3 (GSK3) has been identified as a promising target for the treatment of Alzheimer's disease (AD), where abnormal activation of this enzyme has been associated with hyperphosphorylation of tau proteins. This study describes the effects of the selective GSK3 inhibitor, SAR502250, in models of neuroprotection and neuropsychiatric symptoms (NPS) associated with AD. In P301L human tau transgenic mice, SAR502250 attenuated tau hyperphosphorylation in the cortex and spinal cord. SAR502250 prevented the increase in neuronal cell death in rat embryonic hippocampal neurons following application of the neurotoxic peptide, Aβ25-35. In behavioral studies, SAR502250 improved the cognitive deficit in aged transgenic APP(SW)/Tau(VLW) mice or in adult mice after infusion of Aβ25-35. It attenuated aggression in the mouse defense test battery and improved depressive-like state of mice in the chronic mild stress procedure after 4 weeks of treatment. Moreover, SAR502250 decreased hyperactivity produced by psychostimulants. In contrast, the drug failed to modify anxiety-related behaviors or sensorimotor gating deficit. This profile confirms the neuroprotective effects of GSK3 inhibitors and suggests an additional potential in the treatment of some NPS associated with AD.

Conflict of interest statement

Organizations from whom the authors have received compensation for professional services: Guy Griebel, employee of Sanofi; Jeanne Stemmelin, employee of Sanofi; Mati Lopez-Grancha, employee of Sanofi; Denis Boulay, employee of Sanofi; Gérald Boquet, employee of Sanofi; Franck Slowinski, employee of Sanofi; Philippe Pichat, employee of Sanofi; Sandra Beeské, employee of Sanofi; Shinji Tanaka, employee of Mitsubishi Tanabe Pharma Corporation; Akiko Mori, employee of Mitsubishi Tanabe Pharma Corporation; Masatake Fujimura, employee of Mitsubishi Tanabe Pharma Corporation; Junichi Eguchi, employee of Mitsubishi Tanabe Pharma Corporation.

Figures

Figure 1
Figure 1
Chemical structure of SAR502250.
Figure 2
Figure 2
Effects of increasing concentrations of SAR502250 and lithium on Aβ25–35-induced cell death in rat embryonic hippocampal neurons. Cells were treated with the experimental drugs and Aβ25–35 for 36 hours. Data represent mean ± SEM. ##P < 0.01 (vs Basal, t-test); *P < 0.05, **P < 0.01 (vs Control, Dunnett). N = 6.
Figure 3
Figure 3
Effect of increasing doses of SAR502250 on tau hyperphosphorylation (S396) in the cortex (A) and spinal cord (B) of P301L human tau transgenic mice. Time of administration was 60 minutes. Data represent mean + SEM. *P < 0.05, **P < 0.01 and ***P < 0.01 (vs Ctrl, Kruskal-Wallis). Blots cropped from different parts of the same gel are shown. Full-length blots are shown in Fig. S1. N = 6.
Figure 4
Figure 4
Effects of SAR502250 on short-term visual episodic memory deficit following the central infusion of Aβ25–35 peptide in Swiss mice. The vehicle or the drug was given 60 min before the acquisition session (A) or in APP (SW)/Tau (VLW) mice (B) using the novel object recognition test. The vehicle or the drug was administered once-a-day for 7 weeks. The last administration was given 30 minutes prior to the second session. Data are expressed as recognition index + SEM. *P < 0.05 and ***P < 0.001 (vs. chance level); #P < 0.05 (vs. Scrambled or WT); +P < 0.05 (vs. Ctrl APP-Tau) (Kruskal-Wallis or Dunnett). N = 7–11.
Figure 5
Figure 5
Effect of SAR502250, fluoxetine and lithium in the chronic mild stress procedure in mice. The vehicle or the drugs were given once-a-day 15 days after the beginning of the stress exposure and lasted until the CMS was completed. Data are expressed as mean physical state score + SEM. #P < 0.01 (Wilcoxon test versus non-stressed control group), *P < 0.05, **P < 0.001 (Kruskal-Wallis one sided upper multiple comparison tests with Bonferroni-Holm correction versus stressed control group). N = 20 mice per group.
Figure 6
Figure 6
Effects of SAR502250 and diazepam in the mouse defense test battery on (A), locomotor activity prior to the exposure to the threat; (B), flight response in response to the approaching rat; (C), risk assessment when the rat was chasing the mouse, and (D), defensive attack reactions upon forced contact with the rat. The vehicle or the drugs were administered 60 minutes prior to testing. Data represent mean + SEM, *P < 0.05 and ***P < 0.001. N = 8–11 mice per group.
Figure 7
Figure 7
Effects of SAR502250 on motor hyperactivity induced by amphetamine in mice. Animals were pretreated with SAR502250 or vehicle, followed 30 min later by a challenge administration of vehicle or amphetamine. Immediately thereafter, they were placed in the activity cages devices. Data represent mean + SEM, *P < 0.05, **P < 0.01 and ***P < 0.001 (vs vehicle control); ###P < 0.001 (vs amphetamine, Newman-Keuls). N = 10–11 mice per group.
Figure 8
Figure 8
Antagonism by SAR502250 of the hypersensitivity to an acute challenge with PCP in rats sensitized to PCP. Data represent mean + SEM number of infrared beam interruptions recorded for 90 min, immediately after an injection of PCP (1.5 mg/kg i.p.) or vehicle, which was preceded 30 min earlier by an p.o. injection of SAR502250 or vehicle. **P < 0.01, PCP-sensitized rats compared to vehicle-treated rat. #P < 0.05 compared to acute PCP/PCP-sensitized rats. N = 9–10 rats per group.
Figure 9
Figure 9
Reversion by SAR502250 and clozapine of a spontaneous deficit of prepulse inhibition of the startle reflex in Wistar rats. Prepulse inhibition expressed as a function of prepulse (PP) intensity (in dB). The vehicle or the drugs were administered 60 minutes prior to testing. Each bar represents the mean + SEM. *P < 0.05, **P < 0.01 vs vehicle (Kruskal-Wallis or Wilcoxon test at the corresponding prepulse intensity. N = 16–19 rats per group.

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