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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.


Effect of ARN14140 infusion for 7 days on Aβ25-35-induced toxicity.(a) Bax level in the mouse hippocampus; (b) Bax/Bcl-2 ratio in the mouse hippocampus. V, vehicle solution. N = 5–7 per group in (a,b), ANOVA: F(3,22) = 12.9, p < 0.0001 in (a), F(3,22) = 9.13, p < 0.0001 in (b), ***p < 0.001 vs. Sc.Aβ/V, #p < 0.05, ##p < 0.01, ###p < 0.001 vs. Aβ25–35/V; Dunnett’s test. Note that Bcl-2 levels did not differ among groups (F(3,22) = 0.04, p > 0.05).
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f4: Effect of ARN14140 infusion for 7 days on Aβ25-35-induced toxicity.(a) Bax level in the mouse hippocampus; (b) Bax/Bcl-2 ratio in the mouse hippocampus. V, vehicle solution. N = 5–7 per group in (a,b), ANOVA: F(3,22) = 12.9, p < 0.0001 in (a), F(3,22) = 9.13, p < 0.0001 in (b), ***p < 0.001 vs. Sc.Aβ/V, #p < 0.05, ##p < 0.01, ###p < 0.001 vs. Aβ25–35/V; Dunnett’s test. Note that Bcl-2 levels did not differ among groups (F(3,22) = 0.04, p > 0.05).

Mentions: As reported in Fig. 4a, Aβ25-35 administration induced a highly significant increase (+90%) in hippocampal Bax content compared to Sc.Aβ-injected mice. This translates into a highly significant increase (+85%) of Bax/Bcl-2 ratio relative to Sc.Aβ-injected mice (Fig. 4b).


In Vivo Characterization of ARN14140, a Memantine/Galantamine-Based Multi-Target Compound for Alzheimer ’ s Disease
Effect of ARN14140 infusion for 7 days on Aβ25-35-induced toxicity.(a) Bax level in the mouse hippocampus; (b) Bax/Bcl-2 ratio in the mouse hippocampus. V, vehicle solution. N = 5–7 per group in (a,b), ANOVA: F(3,22) = 12.9, p < 0.0001 in (a), F(3,22) = 9.13, p < 0.0001 in (b), ***p < 0.001 vs. Sc.Aβ/V, #p < 0.05, ##p < 0.01, ###p < 0.001 vs. Aβ25–35/V; Dunnett’s test. Note that Bcl-2 levels did not differ among groups (F(3,22) = 0.04, p > 0.05).
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC5016838&req=5

f4: Effect of ARN14140 infusion for 7 days on Aβ25-35-induced toxicity.(a) Bax level in the mouse hippocampus; (b) Bax/Bcl-2 ratio in the mouse hippocampus. V, vehicle solution. N = 5–7 per group in (a,b), ANOVA: F(3,22) = 12.9, p < 0.0001 in (a), F(3,22) = 9.13, p < 0.0001 in (b), ***p < 0.001 vs. Sc.Aβ/V, #p < 0.05, ##p < 0.01, ###p < 0.001 vs. Aβ25–35/V; Dunnett’s test. Note that Bcl-2 levels did not differ among groups (F(3,22) = 0.04, p > 0.05).
Mentions: As reported in Fig. 4a, Aβ25-35 administration induced a highly significant increase (+90%) in hippocampal Bax content compared to Sc.Aβ-injected mice. This translates into a highly significant increase (+85%) of Bax/Bcl-2 ratio relative to Sc.Aβ-injected mice (Fig. 4b).

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.