Anti-Amnesic and Neuroprotective Effects of Fluoroethylnormemantine in a Pharmacological Mouse Model of Alzheimer’s Disease

Abstract

Background Current therapies in Alzheimer's disease (AD), including Memantine, have proven to be only symptomatic but not curative nor disease-modifying. Fluoroethylnormemantine (FENM) is a structural analogue of Memantine, functionalized with a fluorine group that allowed its use as a positron emission tomography tracer. We here analyzed FENM neuroprotective potential in a pharmacological model of AD, in comparison to Memantine. Methods Swiss mice were treated intracerebroventricularly with aggregated Aβ25-35 peptide and examined after one week in a battery of memory tests (spontaneous alternation; passive avoidance; object recognition; place learning in the water-maze; topographic memory in the Hamlet). Toxicity induced in the mouse hippocampus or cortex was analyzed biochemically or morphologically. Results Both Memantine and FENM showed symptomatic anti-amnesic effects in Aβ25-35-treated mice. Interestingly, FENM was not amnesic when tested alone at 10 mg/kg, contrarily to Memantine. Drugs injected once-a-day prevented Aβ25-35-induced memory deficits, oxidative stress (lipid peroxidation, cytochrome c release), inflammation (IL-6, TNFα increases; glial fibrillary acidic protein (GFAP) and Iba1 immunoreactivity in the hippocampus and cortex), and apoptosis and cell loss (Bax/Bcl-2 ratio; cell loss in the hippocampus CA1 area). However, FENM effects were more robust than observed with Memantine, with significant attenuations vs. the Aβ25-35-treated group. Conclusions FENM therefore appeared as a potent neuroprotective drug in an AD model, with a superior efficacy as compared with Memantine, and an absence of direct amnesic effect at higher doses. These results open the possibility to use the compound at more relevant dosages than the ones actually proposed in Memantine treatment for AD.

Melatonin- and Ferulic Acid-Based HDAC6 Selective Inhibitors Exhibit Pronounced Immunomodulatory Effects In Vitro and Neuroprotective Effects in a Pharmacological Alzheimer’s Disease Mouse Model

“…Compound 10b attenuated the deficit at both 0.1 and 0.3 mg/kg, significantly at the lowest dose tested, but was not active at 1 mg/kg (Figure B). These bell-shaped dose–response effects are commonly observed in cognitive and neuroprotection responses in vivo , as shown recently with the NMDAR antagonist memantine in the same Aß 25–35 mouse model of AD . They are here observed in our study for both ACY1215 and 10b at the 1 mg/kg dose, suggesting that this biphasic effect relies on HDAC6 inhibition.…”

“…Nonspatial long-term memory was analyzed using the step-through passive avoidance response, with training on day 9 and retention on day 10. In this administration scheme, not symptomatic effects, but neuroprotectivity can be assessed in vivo . − …”

“…Protocols for the behavioral experiments were established previously. − Compound 10b and the control ACY1215 were tested for their neuroprotective properties in the in vivo pharmacological model of Alzheimer’s disease induced by intracerebroventricular (icv) injection of the oligomerized Aβ 25–35 peptide in the mouse. Compounds were injected intraperitoneally (ip) o.d.…”

Fluoroethylnormemantine, A Novel Derivative of Memantine, Facilitates Extinction Learning Without Sensorimotor Deficits

“…We speculate that FENM may alter the recall of fear memory traces, ultimately leading to a rapid and long-lasting attenuation of behavioral fear responses. Moreover, FENM was recently shown to improve spatial learning and object recognition as well as reduce spatiotemporal disorientation in a rodent model of AD, suggesting that the results we observed during cued FC were specific to fear expression ( Couly et al, 2020 ). Future studies will be necessary to test whether FENM can alter fear memory traces to attenuate learned fear.…”

“…Moreover, because both compounds bind to phencyclidine sites in the NMDAR channel pore, these data suggest that the compounds may also exert similar behavioral effects. However, while the antidepressant-like effects of FENM remain unknown, recent data indicate that FENM enhances cognitive function and exerts neuroprotective properties in a mouse model of AD ( Couly et al, 2020 ). In this study, Couly and colleagues found that FENM reversed deficits in long-term memory, navigation, and place learning, and object recognition in a pharmacological model of AD.…”