AVCRI104P3, a novel multitarget compound with cognition-enhancing and anxiolytic activities: Studies in cognitively poor middle-aged mice

Ratia, Miriam; Pérez, Belén; Camps, P.; Muñoz‐Torrero, Diego; Badı́a, Albert; Clos, M. Victòria

doi:10.1016/j.bbr.2015.02.042

Cited by 9 publications

(5 citation statements)

References 28 publications

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“…In summary, in the present study we have demonstrated that AVCRI104P3 activates the expression of several proteins involved in the anti-apoptotic process such as Akt, Bcl2 and pGSK3β and furthermore, it shows an important anti-inflammatory effect through inhibition of microglia. Overall, these results suggest that the positive behavioral effects previously reported after AVCRI104P3 treatment [ 21 ] could be partly related to the neuroprotective mechanisms unveiled in this study, which further support the potential of this compound for the treatment of brain dysfunction associated with aging and/or dementia.…”

Section: Discussionsupporting

confidence: 84%

“…Previous in vitro studies supported the idea that the multitarget hybrid compound AVCRI104P3 could behave as a disease-modifying agent, as it concurrently modulates different proteins involved in neurodegenerative processes [ 19 ]. More recently we have demonstrated that AVCRI104P3 induced cognitive improvement as well as anxiolytic effects [ 21 ]. It is known that aged brain is more prone to events associated with neuroinflammation, apoptosis and other damage processes [ 27 ], which mostly affect areas such as hippocampus and cortex [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

“…It shows a potent in vitro inhibitory activity against human AChE (IC 50 = 5.4 nM) and human BChE (IC 50 = 88 nM) and a moderately potent inhibitory activity of BACE-1 (29% inhibition at 5 µM), and Aβ aggregation (28% inhibition at 10 µM) [ 19 ]. In an in vivo study, we recently found that AVCRI104P3 exerted pro-cognitive effects in middle-aged mice, improving both short- and long-term processes and leading to a fast and efficient acquisition of the place task in the Morris water maze [ 21 ]. In addition to the cognitive enhancement, AVCRI104P3 exerted anxiolytic-like effects with a lack of adverse effects.…”

Section: Introductionmentioning

confidence: 99%

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Neuroprotective Effects of the Multitarget Agent AVCRI104P3 in Brain of Middle-Aged Mice

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Come

Pérez

et al. 2018

IJMS

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Molecular factors involved in neuroprotection are key in the design of novel multitarget drugs in aging and neurodegeneration. AVCRI104P3 is a huprine derivative that exhibits potent inhibitory effects on human AChE, BuChE, and BACE-1 activities, as well as on AChE-induced and self-induced Aβ aggregation. More recently, cognitive protection and anxiolytic-like effects have also been reported in mice treated with this compound. Now, we have assessed the ability of AVCRI104P3 (0.43 mg/kg, 21 days) to modulate the levels of some proteins involved in the anti-apoptotic/apoptotic processes (pAkt1, Bcl2, pGSK3β, p25/p35), inflammation (GFAP and Iba1) and neurogenesis in C57BL/6 mice. The effects of AVCRI104P3 on AChE-R/AChE-S isoforms have been also determined. We have observed that chronic treatment of C57BL/6 male mice with AVCRI104P3 results in neuroprotective effects, increasing significantly the levels of pAkt1 and pGSK3β in the hippocampus and Bcl2 in both hippocampus and cortex, but slightly decreasing synaptophysin levels. Astrogliosis and neurogenic markers GFAP and DCX remained unchanged after AVCRI104P3 treatment, whereas microgliosis was found to be significantly decreased pointing out the involvement of this compound in inflammatory processes. These results suggest that the neuroprotective mechanisms that are behind the cognitive and anxiolytic effects of AVCRI104P3 could be partly related to the potentiation of some anti-apoptotic and anti-inflammatory proteins and support the potential of AVCRI104P3 for the treatment of brain dysfunction associated with aging and/or dementia.

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Section: Discussionsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Neuroprotective Effects of the Multitarget Agent AVCRI104P3 in Brain of Middle-Aged Mice

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Pérez

et al. 2018

IJMS

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“…Heterogeneity is found in the aging process, and prognostic tools to identify end-of-life dementia stages are difficult [7]. In NTg and 3xTg-AD mice, we described heterogeneity as part of the complexity of age-related scenarios [8,40,41]. The frailty index, a common tool to measure health status that seems to be sensitive to predict mortality [5], is a valuable tool in longevity and aging studies in mice [31].…”

Section: Sex-and Genotype-dependent Mortality/morbidity Paradoxmentioning

confidence: 99%

Sex-Dependent End-of-Life Mental and Vascular Scenarios for Compensatory Mechanisms in Mice with Normal and AD-Neurodegenerative Aging

et al. 2021

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Life expectancy decreases with aging, with cardiovascular, mental health, and neurodegenerative disorders strongly contributing to the total disability-adjusted life years. Interestingly, the morbidity/mortality paradox points to females having a worse healthy life expectancy. Since bidirectional interactions between cardiovascular and Alzheimer’s diseases (AD) have been reported, the study of this emerging field is promising. In the present work, we further explored the cardiovascular–brain interactions in mice survivors of two cohorts of non-transgenic and 3xTg-AD mice, including both sexes, to investigate the frailty/survival through their life span. Survival, monitored from birth, showed exceptionally worse mortality rates in females than males, independently of the genotype. This mortality selection provided a “survivors” cohort that could unveil brain–cardiovascular interaction mechanisms relevant for normal and neurodegenerative aging processes restricted to long-lived animals. The results show sex-dependent distinct physical (worse in 3xTg-AD males), neuropsychiatric-like and cognitive phenotypes (worse in 3xTg-AD females), and hypothalamic–pituitary–adrenal (HPA) axis activation (higher in females), with higher cerebral blood flow and improved cardiovascular phenotype in 3xTg-AD female mice survivors. The present study provides an experimental scenario to study the suggested potential compensatory hemodynamic mechanisms in end-of-life dementia, which is sex-dependent and can be a target for pharmacological and non-pharmacological interventions.

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“…Thus, AVCRI104P4 (10 to 40 mg/kg/day, 3 months, oral administration) improved short-term memory in APP SL mice [34], whereas chronic treatment of middle-aged (12-month-old) male 129/Sv x C57BL/6 mice with a low dose of AVCRI104P3 (0.43 mg/kg/day, 21 days, i.p.) ameliorated short-and long-term learning and memory and exerted anxiolytic actions [37,38], and elicited neuroprotective effects by increasing cortical and/or hippocampal levels of the anti-apoptotic proteins pAKt1, pGSK3β, and Bcl2, and by reducing microgliosis [39]. The effect of AVCRI104P4 on Aβ aggregation has been studied in vitro and in vivo.…”

Section: Introductionmentioning

confidence: 99%

Protective Role of a Donepezil-Huprine Hybrid against the β-Amyloid (1-42) Effect on Human Erythrocytes

Zambrano

Suwalsky

Jemioła-Rzemińska

et al. 2021

IJMS

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Aβ(1-42) peptide is a neurotoxic agent strongly associated with the etiology of Alzheimer’s disease (AD). Current treatments are still of very low effectiveness, and deaths from AD are increasing worldwide. Huprine-derived molecules have a high affinity towards the enzyme acetylcholinesterase (AChE), act as potent Aβ(1-42) peptide aggregation inhibitors, and improve the behavior of experimental animals. AVCRI104P4 is a multitarget donepezil-huprine hybrid that improves short-term memory in a mouse model of AD and exerts protective effects in transgenic Caenorhabditis elegans that express Aβ(1-42) peptide. At present, there is no information about the effects of this compound on human erythrocytes. Thus, we considered it important to study its effects on the cell membrane and erythrocyte models, and to examine its protective effect against the toxic insult induced by Aβ(1-42) peptide in this cell and models. This research was developed using X-ray diffraction and differential scanning calorimetry (DSC) on molecular models of the human erythrocyte membrane constituted by lipid bilayers built of dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylethanolamine (DMPE). They correspond to phospholipids representative of those present in the external and internal monolayers, respectively, of most plasma and neuronal membranes. The effect of AVCRI104P4 on human erythrocyte morphology was studied by scanning electron microscopy (SEM). The experimental results showed a protective effect of AVCRI104P4 against the toxicity induced by Aβ(1-42) peptide in human erythrocytes and molecular models.

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AVCRI104P3, a novel multitarget compound with cognition-enhancing and anxiolytic activities: Studies in cognitively poor middle-aged mice

Cited by 9 publications

References 28 publications

Neuroprotective Effects of the Multitarget Agent AVCRI104P3 in Brain of Middle-Aged Mice

Neuroprotective Effects of the Multitarget Agent AVCRI104P3 in Brain of Middle-Aged Mice

Sex-Dependent End-of-Life Mental and Vascular Scenarios for Compensatory Mechanisms in Mice with Normal and AD-Neurodegenerative Aging

Protective Role of a Donepezil-Huprine Hybrid against the β-Amyloid (1-42) Effect on Human Erythrocytes

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