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

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.

Download Full-text

Neuroprotective Effects of Kinin B2 Receptor in Organotypic Hippocampal Cultures of Middle-Aged Mice

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2019.00168 ◽

2019 ◽

Vol 11 ◽

Cited By ~ 2

Author(s):

Mariana Toricelli ◽

Sebastiana Ribeiro Evangelista ◽

Larissa Rolim Oliveira ◽

Tania Araujo Viel ◽

Hudson Sousa Buck

Keyword(s):

Middle Aged ◽

Neuroprotective Effects ◽

Aged Mice ◽

Hippocampal Cultures

Download Full-text

Progesterone exerts neuroprotective effects and improves long-term neurologic outcome after intracerebral hemorrhage in middle-aged mice

Neurobiology of Aging ◽

10.1016/j.neurobiolaging.2016.02.029 ◽

2016 ◽

Vol 42 ◽

pp. 13-24 ◽

Cited By ~ 31

Author(s):

Chao Jiang ◽

Fangfang Zuo ◽

Yuejuan Wang ◽

Jieru Wan ◽

Zengjin Yang ◽

...

Keyword(s):

Intracerebral Hemorrhage ◽

Neurologic Outcome ◽

Middle Aged ◽

Neuroprotective Effects ◽

Aged Mice

Download Full-text

Abstract TMP36: Exogenous Oxytocin Confers Significant Neuroprotective Effects and Improves Recovery in Young and Aged Animals After Stroke

Stroke ◽

10.1161/str.51.suppl_1.tmp36 ◽

2020 ◽

Vol 51 (Suppl_1) ◽

Author(s):

Juneyoung Lee ◽

Yan Xu ◽

Diego Morales Scheihing ◽

Louise McCullough ◽

Venugopal Reddy Venna

Keyword(s):

Neuroprotective Effect ◽

Control Group ◽

Male Mice ◽

Behavioral Recovery ◽

Neuroprotective Effects ◽

Delayed Treatment ◽

Aged Mice ◽

Beneficial Effects ◽

Human Use ◽

To Receive

Introduction: Oxytocin (OXT) is a highly evolutionary conserved neuropeptide and an important modulator of inflammation in response to stressors such as ischemia. Recent studies have implicated OXT signaling in neuroprotection in young mice after ischemic injury, but it is not known if OXT is efficacious in aged animals. In our ongoing studies, we found that OXT levels decline after stroke and with age. Therefore, we tested if exogenous OXT administration could provide beneficial effects and improve recovery in aged animals. Methods: Aged (18-20m) C57BL/6 male mice were purchased from Jax Labs and aged in house. Stroke was induced by a right MCAO-60min. Mice were randomly assigned to receive OXT or Atosiban, an OXT antagonist (OXTA) (0.5mg/kg) or vehicle. In the first set of experiments, aged mice were pre-treated with OXT, vehicle, or OXTA for 10 days before stroke. Infarcts were quantified 7-days after stroke (n=6-9/grp). In a second set, we tested the efficacy of delayed treatment, at 3hrs after stroke, and OXT was administered intranasally or i.p.. Functional and behavioral recovery and brain infarct size was assessed 7-day post-stroke. OXT levels 24hrs after stroke in human plasma were measured. Results: OXT treatment (0.5mg/kg/i.p. QD) prior to stroke led to significant neuroprotection in aged male mice, whereas OXTA treatment significantly increased infarct (p<0.05, n=6-9/grp) compared to control group (total: 39.4±2.9% control; 20.8±3.1% OXT; 51.3±2.8% OXTA). Importantly, no differences in cerebral blood flow or temperature were seen between groups. Interestingly, the neuroprotective effect of OXT treatment was observed even when treatment was initiated 3hrs (administered either i.p. or nasally) after stroke onset. Also, we observed a significant decrease in circulating OXT levels at 24hrs in stroke patients (n=26) compared to healthy controls, highlighting the translational relevance of this pathway. Conclusions: We found that OXT treatment either before or after stroke is neuroprotective in aged mice and both i.p. and nasal OXT administration improves recovery in parallel to reductions in brain injury. Given that intranasal formulations of OXT are approved for human use, our proposed strategy of supplementing OXT is highly translatable.

Download Full-text

Corrigendum to “Progesterone exerts neuroprotective effects and improves long-term neurologic outcome after intracerebral hemorrhage in middle-aged mice” [Neurobiol. Aging 42 (2016) 13–24]

Neurobiology of Aging ◽

10.1016/j.neurobiolaging.2021.09.005 ◽

2021 ◽

Author(s):

Chao Jiang ◽

Fangfang Zuo ◽

Yuejuan Wang ◽

Jieru Wan ◽

Zengjin Yang ◽

...

Keyword(s):

Intracerebral Hemorrhage ◽

Neurologic Outcome ◽

Middle Aged ◽

Neuroprotective Effects ◽

Aged Mice ◽

Neurobiol Aging

Download Full-text

Chronic Treatment With the ACE Inhibitor Enalapril Attenuates the Development of Frailty and Differentially Modifies Pro- and Anti-inflammatory Cytokines in Aging Male and Female C57BL/6 Mice

The Journals of Gerontology Series A ◽

10.1093/gerona/gly219 ◽

2018 ◽

Vol 74 (8) ◽

pp. 1149-1157 ◽

Cited By ~ 18

Author(s):

Kaitlyn Keller ◽

Alice Kane ◽

Stefan Heinze-Milne ◽

Scott A Grandy ◽

Susan E Howlett

Keyword(s):

Chronic Treatment ◽

Ace Inhibitor ◽

Frailty Index ◽

Protective Effects ◽

Aging Male ◽

Male Mice ◽

Middle Aged ◽

Male And Female ◽

Female Mice ◽

Anti Inflammatory

Abstract Studies on interventions that can delay or treat frailty in humans are limited. There is evidence of beneficial effects of angiotensin converting enzyme (ACE) inhibitors on aspects related to frailty, such as physical function, even in those without cardiovascular disease. This study aimed to longitudinally investigate the effect of an ACE inhibitor on frailty in aging male and female mice. Frailty was assessed with a clinical frailty index (FI) which quantifies health-related deficits in middle-aged (9–13 months) and older (16–25 months) mice. Chronic treatment with enalapril (30 mg/kg/day in feed) attenuated frailty in middle-aged and older female mice, and older male mice, without a long-term effect on blood pressure. Enalapril treatment resulted in a reduction in the proinflammatory cytokines interleukin (IL)-1α, monocyte chemoattractant protein-1 and macrophage inflammatory protein-1a in older female mice, and an increase in the anti-inflammatory cytokine IL-10 in older male mice compared with control animals. These sex-specific effects on inflammation may contribute to the protective effects of enalapril against frailty. This is the first study to examine the longitudinal effect of an intervention on the FI in mice, and provides preclinical evidence that enalapril may delay the onset of frailty, even when started later in life.

Download Full-text

Chronic treatment with ginsenoside Rg1 promotes memory and hippocampal long-term potentiation in middle-aged mice

Neuroscience ◽

10.1016/j.neuroscience.2015.02.031 ◽

2015 ◽

Vol 292 ◽

pp. 81-89 ◽

Cited By ~ 44

Author(s):

G. Zhu ◽

Y. Wang ◽

J. Li ◽

J. Wang

Keyword(s):

Chronic Treatment ◽

Long Term Potentiation ◽

Ginsenoside Rg1 ◽

Middle Aged ◽

Aged Mice ◽

Term Potentiation

Download Full-text

A 1-Month Ketogenic Diet Increased Mitochondrial Mass in Red Gastrocnemius Muscle, but not in the Brain or Liver of Middle-Aged Mice

Nutrients ◽

10.3390/nu13082533 ◽

2021 ◽

Vol 13 (8) ◽

pp. 2533

Author(s):

Zeyu Zhou ◽

Jocelyn Vidales ◽

José A González-Reyes ◽

Bradley Shibata ◽

Keith Baar ◽

...

Keyword(s):

Prefrontal Cortex ◽

Gastrocnemius Muscle ◽

Left Lobe ◽

Middle Aged ◽

Mitochondrial Content ◽

Mitochondrial Mass ◽

Aged Mice ◽

Fractional Area ◽

Ketogenic Diets ◽

The Impact

Alterations in markers of mitochondrial content with ketogenic diets (KD) have been reported in tissues of rodents, but morphological quantification of mitochondrial mass using transmission electron microscopy (TEM), the gold standard for mitochondrial quantification, is needed to further validate these findings and look at specific regions of interest within a tissue. In this study, red gastrocnemius muscle, the prefrontal cortex, the hippocampus, and the liver left lobe were used to investigate the impact of a 1-month KD on mitochondrial content in healthy middle-aged mice. The results showed that in red gastrocnemius muscle, the fractional area of both subsarcolemmal (SSM) and intermyofibrillar (IMM) mitochondria was increased, and this was driven by an increase in the number of mitochondria. Mitochondrial fractional area or number was not altered in the liver, prefrontal cortex, or hippocampus following 1 month of a KD. These results demonstrate tissue-specific changes in mitochondrial mass with a short-term KD and highlight the need to study different muscle groups or tissue regions with TEM to thoroughly determine the effects of a KD on mitochondrial mass.

Download Full-text