Aging is characterized generally by progressive and overall physiological decline of functions and is observed in all animals. A long line of evidence has established the laboratory mouse as the ...prime model of human aging. However, relatively little is known about the detailed behavioral and functional changes that occur across their lifespan, and how this maps onto the phenotype of human aging. To better understand age-related changes across the life-span, we characterized functional aging in male C57BL/6J mice of five different ages (3, 6, 12, 18, and 22 months of age) using a multi-domain behavioral test battery. Spatial memory and physical activities, including locomotor activity, gait velocity, and grip strength progressively declined with increasing age, although at different rates; anxiety-like behaviors increased with aging. Estimated age-related patterns showed that these functional alterations across ages are non-linear, and the patterns are unique for each behavioral trait. Physical function progressively declines, starting as early as 6 months of age in mice, while cognitive function begins to decline later, with considerable impairment present at 22 months of age. Importantly, functional aging of male C57BL/6J mouse starts at younger relative ages compared to when it starts in humans. Our study suggests that human-equivalent ages of mouse might be better determined on the basis of its functional capabilities.
•Senescence-accelerated mice prone 8 (SAMP8) were subjected to the comprehensive behavioral test battery at young age.•Young SAMP8 mice failed in an object recognition task and in the probe test of ...the Morris water maze task.•Young SAMP8 exhibited enhanced anxiety-like behavior in an open field test and showed depression-like behavior in the forced-swim task.•Age-related behavioral alterations occur in SAMP8 as young as 4-month old.
Senescence-accelerated mouse (SAM) is inbred lines of mice originally developed from AKR/J mice. Among the six SAM prone (SAMP) substrains, 8- to 12-month-old SAMP8 have long been used as a model of age-related cognitive impairments. However, little is still known for younger SAMP8 mice. Here, we examined the phenotypical characteristics of 4-month-old SAMP8 using a battery of behavioral tests. Four-month-old SAMP8 mice failed to recognize spatially displaced object in an object recognition task and performed poorly in the probe test of the Morris water maze task compared to SAMR1, suggesting that SAMP8 have impaired spatial memory. In addition, young SAMP8 exhibited enhanced anxiety-like behavior in an open field test and showed depression-like behavior in the forced-swim test. Their circadian rhythm was also disrupted. These abnormal behaviors of young SAMP8 are similar to behavioral alterations also observed in aged mice. In summary, age-related behavioral alterations occur in SAMP8 as young as 4 months old.
As the population of older individuals grows worldwide, researchers have increasingly focused their attention on identifying key molecular targets of age-related cognitive impairments, with the aim ...of developing possible therapeutic interventions. Two such molecules are the intracellular cyclic nucleotides, cAMP and cGMP. These second messengers mediate fundamental aspects of brain function relevant to memory, learning, and cognitive function. Consequently, phosphodiesterases (PDEs), which hydrolyze cAMP and cGMP, are promising targets for the development of cognition-enhancing drugs. Inhibitors that target PDEs work by elevating intracellular cAMP. In this review, we provide an overview of different PDE inhibitors, and then we focus on pharmacological and physiological effects of PDE3 inhibitors in the CNS and peripheral tissues. Finally, we discuss findings from experimental and preliminary clinical studies and the potential beneficial effects of the PDE3 inhibitor cilostazol on age-related cognitive impairments. In the innovation pipeline of pharmaceutical development, the antiplatelet agent cilostazol has come into the spotlight as a novel treatment for mild cognitive impairment. Overall, the repurposing of cilostazol may represent a potentially promising way to treat mild cognitive impairment, Alzheimer’s disease, and vascular dementia. In this review, we present a brief summary of cAMP signaling and different PDE inhibitors, followed by a discussion of the pharmacological and physiological role of PDE3 inhibitors. In this context, we discuss the repurposing of a PDE3 inhibitor, cilostazol, as a potential treatment for age-related cognitive impairment based on recent research.
Phosphodiesterases (PDEs) are enzymes that hydrolyze and inactivate 3′, 5′-cyclic adenosine monophosphate (cAMP) and/or 3′, 5′-cyclic guanosine monophosphate (cGMP). The regulation of intracellular ...signaling pathways mediated by cyclic nucleotides is imperative to synaptic plasticity and memory in animals. Because PDEs play an important role in this regulation, PDE inhibitors are considered as candidate compounds for treating cognitive and memory disorders. In the present study, we tested whether cilostazol, a selective PDE3 inhibitor, prevents the cognitive deterioration that occurs during the course of normal aging in mice. Ten months of cilostazol administration (1.5%) in 13-month-old mice improved spatial memory when tested at 23 months of age. First, it prevented the decline in the ability of these aged mice to recognize a change in an object's location in the object recognition task. Second, spatial memory of these cilostazol-treated aged mice in the Morris water maze was comparable to that of untreated middle-aged mice (13 months old). Cilostazol administration had no effect on the emotional states and physical ability of aged mice. Thus, long-term cilostazol administration prevented hippocampus-dependent memory decline in aged mice, allowing them to achieve a level of cognitive performance similar to middle-aged mice and without negative behavioral side effects. Considering its well-established safety in other medical contexts, cilostazol may be a potential therapeutic candidate drug for staving off cognitive decline in the aging human population.
•Serum cilostazol concentration in mice was at the clinically effective level in humans.•Cilostazol improved spatial memory in mice when tested at 23-months of age.•Memory of cilostazol-treated aged mice was similar to middle-aged untreated mice.•Cilostazol had no effect on emotional state or physical ability of aged mice.•Long-term cilostazol administration may prevent cognitive decline in aging humans.
Phosphodiesterases (PDEs), which hydrolyze and inactivate 3′, 5′-cyclic adenosine monophosphate (cAMP) and 3′, 5′-cyclic guanosine monophosphate (cGMP), play an important role in synaptic plasticity ...that underlies memory. Recently, several PDE inhibitors were assessed for their possible therapeutic efficacy in treating cognitive disorders. Here, we examined how cilostazol, a selective PDE3 inhibitor, affects brain functions in senescence-accelerated mouse prone 8 (SAMP8), an animal model of age-related cognitive impairment. Long-term administration of cilostazol restored the impaired context-dependent conditioned fear memory of SAMP8 to match that in normal aging control substrain SAMR1. Cilostazol also increased the number of cells containing phosphorylated cAMP-responsive element binding protein (CREB), a downstream component of the cAMP pathway. Finally, cilostazol improves blood-brain barrier (BBB) integrity, demonstrated by reduced extravasation of 2-deoxy-2-18F-fluoro-d-glucose and Evans Blue dye in the brains of SAMP8. This improvement in BBB integrity was associated with an increased amount of zona occludens protein 1 (ZO-1) and occludin proteins, components of tight junctions integral to the BBB. The results suggest that long-term administration of cilostazol exerts its beneficial effects on age-related cognitive impairment through a dual mechanism: by enhancing the cAMP system in the brain and by maintaining or improving BBB integrity.
•Senescence-accelerated mouse prone 8 (SAMP8) was used as an animal model of aging.•Long-term administration of cilostazol restored the impaired fear memory of SAMP8.•Cilostazol administration increased phosphorylation of CREB in hippocampal dentate gyrus.•Cilostazol administration reduced extravasation of 2-deoxy-2-18F-fluoro-d-glucose and Evans Blue dye from SAMP8 brain.•Cilostazol increased the amount of tight junction proteins.
The nucleotide second messenger 3', 5'-cyclic adenosine monophosphate (cAMP) and 3', 5'-cyclic guanosine monophosphate (cGMP) mediate fundamental functions of the brain, including learning and ...memory. Phosphodiesterase 3 (PDE3) can hydrolyze both cAMP and cGMP and appears to be involved in the regulation of their contents in cells. We previously demonstrated that long-term administration of cilostazol, a PDE3 inhibitor, maintained good memory performance in aging mice. Here, we report on studies aimed at determining whether cilostazol also reverses already-impaired memory in aged male mice. One month of oral 1.5% cilostazol administration in 22-month-old mice reversed age-related declines in hippocampus-dependent memory tasks, including the object recognition and the Morris water maze. Furthermore, cilostazol reduced neuroinflammation, as evidenced by immunohistochemical staining, and increased glucose uptake in the brain, as evidence by positron emission tomography (PET) with 2-deoxy-2-
Ffluoro-d-glucose (
FFDG). These results suggest that already-expressed memory impairment in aged male mice that depend on cyclic nucleotide signaling can be reversed by inhibition of PDE3. The reversal of age-related memory impairments may occur in the central nervous system, either through cilostazol-enhanced recall or strengthening of weak memories that otherwise may be resistant to recall.
Wheel slip prediction on rough terrain is crucial for secure, long-term operations of planetary exploration rovers. Although rough, unstructured terrain hampers mobility, prediction by modeling ...wheel–terrain interactions remains difficult owing to unclear terrain conditions and complexities of terramechanics models. This study proposes a vision-based approach with machine learning for predicting wheel slip risk by estimating the slope from 3D information and classifying terrain types from image information. It considers the slope estimation accuracy for risk prediction under sharp increases in wheel slip due to inclined ground. Experimental results obtained with a rover testbed on several terrain types validate this method.
Alzheimer's disease (AD) is characterized by the deposition of amyloid‐β peptide (Aβ) and the formation of neurofibrillary tangles. Transplantation of bone marrow‐derived mesenchymal stem cells ...(BM‐MSCs) has been suggested as a potential therapeutic approach to prevent various neurodegenerative disorders, including AD. However, the actual therapeutic impact of BM‐MSCs and their mechanism of action in AD have not yet been ascertained. The aim of this study was therefore to evaluate the therapeutic effect of BM‐MSC transplantation on the neuropathology and memory deficits in amyloid precursor protein (APP) and presenilin one (PS1) double‐transgenic mice. Here we show that intracerebral transplantation of BM‐MSCs into APP/PS1 mice significantly reduced amyloid β‐peptide (Aβ) deposition. Interestingly, these effects were associated with restoration of defective microglial function, as evidenced by increased Aβ‐degrading factors, decreased inflammatory responses, and elevation of alternatively activated microglial markers. Furthermore, APP/PS1 mice treated with BM‐MSCs had decreased tau hyperphosphorylation and improved cognitive function. In conclusion, BM‐MSCs can modulate immune/inflammatory responses in AD mice, ameliorate their pathophysiology, and improve the cognitive decline associated with Aβ deposits. These results demonstrate that BM‐MSCs are a potential new therapeutic agent for AD. STEM CELLS 2010;28:329–343
Signaling through extracellular signal-regulated kinase (ERK) is important in multiple signal transduction networks in the CNS. However, the specific role of ERK2 in in vivo brain functions is not ...fully understood. Here we show that ERK2 play a critical role in regulating social behaviors as well as cognitive and emotional behaviors in mice. To study the brain function of ERK2, we used a conditional, region-specific, genetic approach to target Erk2 using the Cre/loxP strategy with a nestin promoter-driven cre transgenic mouse line to induce recombination in the CNS. The resulting Erk2 conditional knock-out (CKO) mice, in which Erk2 was abrogated specifically in the CNS, were viable and fertile with a normal appearance. These mice, however, exhibited marked anomalies in multiple aspects of social behaviors related to facets of autism-spectrum disorders: elevated aggressive behaviors, deficits in maternal nurturing, poor nest-building, and lower levels of social familiarity and social interaction. Erk2 CKO mice also exhibited decreased anxiety-related behaviors and impaired long-term memory. Pharmacological inhibition of ERK1 phosphorylation in Erk2 CKO mice did not affect the impairments in social behaviors and learning disabilities, indicating that ERK2, but not ERK1 plays a critical role in these behaviors. Our findings suggest that ERK2 has complex and multiple roles in the CNS, with important implications for human psychiatric disorders characterized by deficits in social behaviors.
The critical period is a distinct time-window during the neonatal stage when animals display elevated sensitivity to certain environmental stimuli, and particular experiences can have profound and ...long-lasting effects on behaviors. Increasing evidence suggests that disruption of neuronal activity during the critical period contributes to autistic phenotype, although the pathogenic mechanism is largely unknown. Herein we show that extracellular signal-regulated protein kinases (ERKs) play important roles in proper formation of neural circuits during the critical period. Transient blockade of ERKs phosphorylation at postnatal day 6 (P6) by intraperitoneal injection of blood-brain barrier-penetrating MEK inhibitor, α-amino(4-aminophenyl)thiomethylene-2-(trifluoromethyl)benzeneacetonitrile (SL327) caused significant increase of apoptosis in the forebrain. Furthermore, this induced long-term deleterious effects on brain functioning later in adulthood, resulting in social deficits, impaired memory and reduced long-term potentiation (LTP). Conversely, blockade of ERK phosphorylation at P14 no longer induced apoptosis, nor behavioral deficits, nor the reduced LTP. Thus, surprisingly, these effects of ERKs are strongly age-dependent, indicating that phosphorylation of ERKs during the critical period is absolutely required for proper development of brain functioning. This study provides novel insight into the mechanistic basis for neurodevelopment disorders: various neurodevelopment disorders might be generally linked to defects in ERKs signaling during the critical period.
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