Possible role of cholinesterase inhibitors on memory consolidation following hypobaric hypoxia of rats.
TL;DR: The cholinesterase inhibitors could ameliorate the impairment of memory consolidation following HBH and rats which have been treated with physostigmine and galantamine showed better time spent in quaradents, rings, and counters as compared with hypoxic rats.
Abstract: High altitude (HA) generates a deleterious effect known as hypobaric hypoxia (HBH). This causes severe physiological and psychological changes such as acute mountain sickness (AMS) and cognitive functions in terms of learning and memory. The present study has evaluated the effect of cholinesterase inhibitors on memory consolidation following HBH. Adult male Sprague Dawley rats (80–90 days old) with an average body weight of 250 ± 25 g were used. Rats were assessed memory consolidation by using Morris water maze (MWM) for 8 days. After assessment of memory consolidation, rats were then exposed to HBH in stimulated chamber for 7 days at 6,100 m. After exposure to HBH, the memory consolidation of rats has been assessed in MWM. The results showed that there was memory consolidation impairment in HBH-exposed rats as compared to normoxic rats in terms of time spent in quaradents, rings, and counters. The rats which have been treated with physostigmine (PHY) and galantamine (GAL) showed better time spent...
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TL;DR: The results provide critical support for the hypothesis that cerebrovascular rarefaction is a key component of cognitive impairment post-WBRT and indicate that processes of learning and memory, once thought to be permanently impaired after WBRT, can be restored.
Abstract: Whole brain radiation therapy (WBRT) is commonly used for treatment of primary and metastatic brain tumors; however, cognitive impairment occurs in 40–50% of brain tumor survivors. The etiology of the cognitive impairment following WBRT remains elusive. We recently reported that radiation-induced cerebrovascular rarefaction within hippocampal subregions could be completely reversed by systemic hypoxia. However, the effects of this intervention on learning and memory have not been reported. In this study, we assessed the time-course for WBRT-induced impairments in contextual and spatial learning and the capacity of systemic hypoxia to reverse WBRT-induced deficits in spatial memory. A clinical fractionated series of 4.5Gy WBRT was administered to mice twice weekly for 4 weeks, and after various periods of recovery, behavioral analyses were performed. To study the effects of systemic hypoxia, mice were subjected to 11% (hypoxia) or 21% oxygen (normoxia) for 28 days, initiated 1 month after the completion of WBRT. Our results indicate that WBRT induces a transient deficit in contextual learning, disruption of working memory, and progressive impairment of spatial learning. Additionally, systemic hypoxia completely reversed WBRT-induced impairments in learning and these behavioral effects as well as increased vessel density persisted for at least 2 months following hypoxia treatment. Our results provide critical support for the hypothesis that cerebrovascular rarefaction is a key component of cognitive impairment post-WBRT and indicate that processes of learning and memory, once thought to be permanently impaired after WBRT, can be restored.
55 citations
29 Feb 2016
TL;DR: In this article, the authors provide documentation of potential long-term health effects of exposure to the agents, compounds and drugs tested by the volunteer human exposure experiments, and the purpose of these tests was to evaluate the effect of biological and chemical substances on humans in an effort to determine US vulnerability to attack.
Abstract: : Between 1954 and 1975, more than 12,000 men entering or in military service in the United States (US) served as medical research volunteers for the countrys biological and chemical warfare defense programs. With their consent, these servicemen served as human volunteers in exposure experiments to a wide variety of biological and chemical substances, medications, vaccines, or simulants. The purpose of these tests was to use volunteers to evaluate the effect of biological and chemical substances on humans in an effort to determine US vulnerability to attack. The three main programs under which this testing took place were Project White-coat, Project 112, and Project SHAD (Shipboard Hazard and Defense.) Several reviews of the health status of volunteers in these exposure experiments have been done the years following the original studies and have found no conclusive evidence that receipt of investigational agents or substances was related to adverse health outcomes. None of the follow-up studies or reviews found differences in all-cause mortality between participants and controls, and none of the studies found consistent, clinically-significant groups of symptoms in those exposed. Despite these failures to determine that the tests had a long-term negative effect on the health of the men who participated in the exposures, many test participants continue to self-report their health as consistently lower than the health of non-participant controls. The purpose of this report is to provide documentation of potential long-term health effects of exposure to the agents, compounds and drugs tested. Literature searches and analyses of scientific and medical studies published between June 30, 2006 and December 1, 2015 have been reviewed for information concerning the potential long-term health effects of the volunteer human exposures. Evidence found in the literature for potential long-term health effects or sequelae does not necessarily mean that these symptoms have occurred
26 citations
Journal Article•
TL;DR: The impact of HBH on both physiological and cognitive functions, specifically learning and memory is described and the potential therapeutic agents for the treatment ofHBH-induced cognitive impairment are discussed.
Abstract: High altitude (HA), defined as approximately 3000-5000 m, considerably alters physiological and psychological parameters within a few hours. Chronic HA-mediated hypoxia (5000 m) results in permanent neuronal damage to the human brain that persists for one year or longer, even after returning to sea level. At HA, there is a decrease in barometric pressure and a consequential reduction in the partial pressure of oxygen (PO2), an extreme environmental condition to which humans are occasionally exposed. This condition is referred to as hypobaric hypoxia (HBH), which represents the most unfavourable characteristics of HA. HBH causes the disruption of oxygen availability to tissue. However, no review article has explored the impact of HBH on cognitive functions or the potential therapeutic agents for HBH. Therefore, the present review aimed to describe the impact of HBH on both physiological and cognitive functions, specifically learning and memory. Finally, the potential therapeutic agents for the treatment of HBH-induced cognitive impairment are discussed.
22 citations
TL;DR: The data demonstrate that EE and once daily GAL promote cognitive recovery after TBI and the combined therapies did not negatively affect outcome and thus this therapeutic protocol may have clinical utility.
Abstract: Environmental enrichment (EE) enhances cognition after traumatic brain injury (TBI). Galantamine (GAL) is an acetylcholinesterase inhibitor that also may promote benefits. Hence, the aims of this study were to assess the efficacy of GAL alone (standard [STD] housing) and in combination with EE in adult male rats after TBI. The hypothesis was that both therapies would confer motor, cognitive, and histological benefits when provided singly, but that their combination would be more efficacious. Anesthetized rats received a controlled cortical impact or sham injury, then were randomly assigned to receive GAL (1, 2, or 3 mg/kg; intraperitoneally [i.p.]) or saline vehicle (VEH; 1 mL/kg; i.p.) beginning 24 h after surgery and once daily for 21 days (experiment 1). Motor (beam-balance/walk) and cognitive (Morris water maze [MWM]) assessments were conducted on post-operative Days 1-5 and 14-19, respectively. Cortical lesion volumes were quantified on Day 21. Sham controls were better versus all TBI groups. No differences in motor function or lesion volumes were observed among the TBI groups (p > 0.05). In contrast, GAL (2 mg/kg) enhanced MWM performance versus VEH and GAL (1 and 3 mg/kg; p < 0.05). In experiment 2, GAL (2 mg/kg) or VEH was combined with EE and the data were compared with the STD-housed groups from experiment 1. EE alone enhanced motor performance over the VEH-treated and GAL-treated (2 mg/kg) STD-housed groups (p < 0.05). Moreover, both EE groups (VEH or GAL) facilitated spatial learning and reduced lesion size versus STD + VEH controls (p < 0.05). No additional benefits were observed with the combination paradigm, which does not support the hypothesis. Overall, the data demonstrate that EE and once daily GAL (2 mg/kg) promote cognitive recovery after TBI. Importantly, the combined therapies did not negatively affect outcome and thus this therapeutic protocol may have clinical utility.
20 citations
TL;DR: Hypoxia-induced learning and memory deficit in human and rat studies is reviewed and potential mechanisms of hypobaric hypoxia–induced memory deficit are tried to elicit.
Abstract: Impairment of memory is one of the most frequently reported symptoms during sudden hypoxia exposure in human. Cortical atrophy has been linked to the impaired memory function and is suggested to occur with chronic high-altitude exposure. However, the precise molecular mechanism(s) of hypoxia-induced memory impairment remains an enigma. In this work, we review hypoxia-induced learning and memory deficit in human and rat studies. Based on data from rat studies using different protocols of continuous hypoxia, we try to elicit potential mechanisms of hypobaric hypoxia-induced memory deficit.
18 citations
Cites background from "Possible role of cholinesterase inh..."
...These AChE inhibitors improved ACh level, decreased AChE activity and increased ACh synthesis by increasing acetyltransferase activity.(95) The greatest amount of nerve growth factor (NGF) is produced in the cortex, hippocampus and pituitary gland, although significant quantities are also produced in other areas, including the basal ganglia, thalamus, spinal cord and in the retina....
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References
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TL;DR: Developments of an open-field water-maze procedure in which rats learn to escape from opaque water onto a hidden platform are described, suggesting that they may lend themselves to a variety of behavioural investigations, including pharmacological work and studies of cerebral function.
6,609 citations
"Possible role of cholinesterase inh..." refers background or methods in this paper
...(1993) and Morris (1984), in terms of the time spent in different quadrants, rings, and counters. In case of the time spent in different quadrants, it was observed that the hypoxic rats showed unequal preference to quadrants as compared with equal preference before exposure to HBH. It was also seen that the normoxic rats spent more time in Ring B and showed the preference to Ring B than the hypoxic rats. The preference for Ring B and less time spent in Ring B by hypoxic rats may be due to impairment in memory consolidation by hypoxic exposure. Further, as the time spent by the hypoxic rats in counters (C1, C2, C3, and C4) was significantly less due to impairment in memory consolidation. Similar findings have been reported where HBH and similar stressors have been implicated in loss of memory consolidation. Gozal, Daniel, and Dohanich (2001) have reported that HA induces sleep disturbances leading to impairment of memory consolidation....
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...If the rat failed to locate the platform within 60 s, it was guided by hand to the platform (Morris, 1984; Netto et al., 1993)....
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...This also enabled to measure the time spent in quadrants, rings, and counters, as described by Morris, 1984....
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...(1993) and Morris (1984), in terms of the time spent in different quadrants, rings, and counters....
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...The consolidation of memory was assessed using three different parameters as described by Netto et al. (1993) and Morris (1984), in terms of the time spent in different quadrants, rings, and counters....
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3,312 citations
TL;DR: The nucleus basalis of Meynert provides diffuse cholinergic input to the neocortex and loss of this neuronal population may represent an anatomical correlate of the well‐documented cholinerential derangement in Alzheimer disease.
Abstract: The nucleus basalis of Meynert provides diffuse cholinergic input to the neocortex. When compared with an age- and sex-matched control, the nucleus basalis from a patient with Alzheimer disease demonstrated substantial reduction of neurons. Loss of this neuronal population may represent an anatomical correlate of the well-documented cholinergic derangement in Alzheimer disease.
1,704 citations
TL;DR: It is concluded that EHYP is associated with marked cellular changes over time within neural regions associated with cognitive functions and may underlie components of the learning and memory impairments found in OSA.
Abstract: The role played by chronic episodic hypoxia (EHYP) in the neurocognitive morbidity of obstructive sleep apnea (OSA) is unknown. Sleep recordings, Morris water maze experiments, and immunohistochemistry for NMDA NR1 glutamate receptor, c-fos protein, and apoptosis [nuclear immunoreactivity for single-stranded DNA and terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling assay] were conducted in EHYP-exposed Sprague Dawley male rats. Exposures consisted of up to14 d in an environmental chamber in which O(2) concentrations were cycled between 10 and 21% every 90 sec or 30 min during 12 hr of daylight. For the remaining 12 hr, EHYP rats breathed room air, while controls spent 14 d in room air. Although EHYP induced significant disruption of sleep architecture during the initial day of exposure, sleep patterns normalized thereafter. Marked increases in apoptosis occurred in the CA1 hippocampal region (sevenfold) and cortex (Cx; eightfold) after 1-2 d of EHYP but not in CA3 and were followed by decreases toward normoxic levels by 14 d. Double labeling for NMDA NR1 and c-fos revealed marked architectural disorganization in CA1 and Cx with increases in c-fos over time. Rats exposed to EHYP displayed significantly longer escape latencies and swim path lengths to escape a hidden platform during 12 training trials given over 2 d. Differences in the performances of EHYP and control rats, although reduced, persisted after 14 d of recovery. We conclude that EHYP is associated with marked cellular changes over time within neural regions associated with cognitive functions. Furthermore, EHYP impaired performance during acquisition of a cognitive spatial task without affecting sensorimotor function. Such changes may underlie components of the learning and memory impairments found in OSA.
508 citations
"Possible role of cholinesterase inh..." refers background in this paper
...Gozal, Daniel, and Dohanich (2001) have reported that HA induces sleep disturbances leading to impairment of memory consolidation....
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