Limits...
In Vivo Characterization of ARN14140, a Memantine/Galantamine-Based Multi-Target Compound for Alzheimer ’ s Disease

View Article: PubMed Central - PubMed

ABSTRACT

Alzheimer’s disease (AD) is a chronic pathological condition that leads to neurodegeneration, loss of intellectual abilities, including cognition and memory, and ultimately to death. It is widely recognized that AD is a multifactorial disease, where different pathological cascades (mainly amyloid and tau) contribute to neural death and to the clinical outcome related to the disease. The currently available drugs for AD were developed according to the one-target, one-drug paradigm. In recent times, multi-target strategies have begun to play an increasingly central role in the discovery of more efficacious candidates for complex neurological conditions, including AD. In this study, we report on the in vivo pharmacological characterization of ARN14140, a new chemical entity, which was obtained through a multi-target structure-activity relationship campaign, and which showed a balanced inhibiting profile against the acetylcholinesterase enzyme and the NMDA receptor. Based on the initial promising biochemical data, ARN14140 is here studied in mice treated with the amyloidogenic fragment 25–35 of the amyloid-β peptide, a consolidated non-transgenic AD model. Sub-chronically treating animals with ARN14140 leads to a prevention of the cognitive impairment and of biomarker levels connected to neurodegeneration, demonstrating its neuroprotective potential as new AD agent.

No MeSH data available.


Effects of ARN14140 infusion for 7 days on Aβ25-35-induced decrease in viable pyramidal cells in the CA1 layer of the mouse hippocampus.(a) Typical CA1 field in zone c; (b) typical CA1 field in zone b; (c) quantification including zones a–c. V, vehicle solution. N = 10–11 animals per group, with 3 areas counted per animal. ANOVA: F(3,40) = 3.01, p < 0.05, *p < 0.05 vs. Sc.Aβ/V, #p < 0.05 vs. Aβ25-35/V; Dunnett’s test. Scale bar = 50 μm in (a,b).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC5016838&req=5

f5: Effects of ARN14140 infusion for 7 days on Aβ25-35-induced decrease in viable pyramidal cells in the CA1 layer of the mouse hippocampus.(a) Typical CA1 field in zone c; (b) typical CA1 field in zone b; (c) quantification including zones a–c. V, vehicle solution. N = 10–11 animals per group, with 3 areas counted per animal. ANOVA: F(3,40) = 3.01, p < 0.05, *p < 0.05 vs. Sc.Aβ/V, #p < 0.05 vs. Aβ25-35/V; Dunnett’s test. Scale bar = 50 μm in (a,b).

Mentions: We studied the neuroprotective potential of ARN14140 at a cellular level by evaluating its effect on Aβ25-35 induced CA1 mouse hippocampus cell loss. Cresyl violet was used as a vital stain and a significant decrease in cell count was observed in Aβ25-35 treated mice 9 days after i.c.v. injection of the peptides (Fig. 5a,b). The continuous infusion of ARN14140 treatment dose-dependently prevented the effect in viable cells, with a significant difference when compared to the Aβ25-35/V-treated group at a dose of 7.5 μg/day (Fig. 5c).


In Vivo Characterization of ARN14140, a Memantine/Galantamine-Based Multi-Target Compound for Alzheimer ’ s Disease
Effects of ARN14140 infusion for 7 days on Aβ25-35-induced decrease in viable pyramidal cells in the CA1 layer of the mouse hippocampus.(a) Typical CA1 field in zone c; (b) typical CA1 field in zone b; (c) quantification including zones a–c. V, vehicle solution. N = 10–11 animals per group, with 3 areas counted per animal. ANOVA: F(3,40) = 3.01, p < 0.05, *p < 0.05 vs. Sc.Aβ/V, #p < 0.05 vs. Aβ25-35/V; Dunnett’s test. Scale bar = 50 μm in (a,b).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5016838&req=5

f5: Effects of ARN14140 infusion for 7 days on Aβ25-35-induced decrease in viable pyramidal cells in the CA1 layer of the mouse hippocampus.(a) Typical CA1 field in zone c; (b) typical CA1 field in zone b; (c) quantification including zones a–c. V, vehicle solution. N = 10–11 animals per group, with 3 areas counted per animal. ANOVA: F(3,40) = 3.01, p < 0.05, *p < 0.05 vs. Sc.Aβ/V, #p < 0.05 vs. Aβ25-35/V; Dunnett’s test. Scale bar = 50 μm in (a,b).
Mentions: We studied the neuroprotective potential of ARN14140 at a cellular level by evaluating its effect on Aβ25-35 induced CA1 mouse hippocampus cell loss. Cresyl violet was used as a vital stain and a significant decrease in cell count was observed in Aβ25-35 treated mice 9 days after i.c.v. injection of the peptides (Fig. 5a,b). The continuous infusion of ARN14140 treatment dose-dependently prevented the effect in viable cells, with a significant difference when compared to the Aβ25-35/V-treated group at a dose of 7.5 μg/day (Fig. 5c).

View Article: PubMed Central - PubMed

ABSTRACT

Alzheimer&rsquo;s disease (AD) is a chronic pathological condition that leads to neurodegeneration, loss of intellectual abilities, including cognition and memory, and ultimately to death. It is widely recognized that AD is a multifactorial disease, where different pathological cascades (mainly amyloid and tau) contribute to neural death and to the clinical outcome related to the disease. The currently available drugs for AD were developed according to the one-target, one-drug paradigm. In recent times, multi-target strategies have begun to play an increasingly central role in the discovery of more efficacious candidates for complex neurological conditions, including AD. In this study, we report on the in vivo pharmacological characterization of ARN14140, a new chemical entity, which was obtained through a multi-target structure-activity relationship campaign, and which showed a balanced inhibiting profile against the acetylcholinesterase enzyme and the NMDA receptor. Based on the initial promising biochemical data, ARN14140 is here studied in mice treated with the amyloidogenic fragment 25&ndash;35 of the amyloid-&beta; peptide, a consolidated non-transgenic AD model. Sub-chronically treating animals with ARN14140 leads to a prevention of the cognitive impairment and of biomarker levels connected to neurodegeneration, demonstrating its neuroprotective potential as new AD agent.

No MeSH data available.