Galantamine improves olfactory learning in the Ts65Dn mouse model of Down syndrome

Souza, Fábio M. Simões de; Busquet, Nicolas; Blatner, Megan J.; Maclean, Kenneth N.; Restrepo, Diego

doi:10.1038/srep00137

Cited by 26 publications

(13 citation statements)

References 64 publications

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“…Studies in the SVZ, the RMS and the olfactory bulb have revealed a reduction in cell proliferation in the Ts65Dn mice model (Chakrabarti et al, 2011 ; Bianchi et al, 2014 ). Moreover olfactory learning is impaired in Ts65Dn mice (de Souza et al, 2011 ), similarly to the observed impairment in olfactory performance in adult with DS (Nijjar and Murphy, 2002 ). Activation of the olfactory system by odor exposition doesn't affect the number of proliferating cells; however the number of survival cells in the olfactory bulb is increased (Rochefort et al, 2002 ).…”

Section: Introductionmentioning

confidence: 54%

Hypocellularity in the Murine Model for Down Syndrome Ts65Dn Is Not Affected by Adult Neurogenesis

et al. 2016

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Down syndrome (DS) is caused by the presence of an extra copy of the chromosome 21 and it is the most common aneuploidy producing intellectual disability. Neural mechanisms underlying this alteration may include defects in the formation of neuronal networks, information processing and brain plasticity. The murine model for DS, Ts65Dn, presents reduced adult neurogenesis. This reduction has been suggested to underlie the hypocellularity of the hippocampus as well as the deficit in olfactory learning in the Ts65Dn mice. Similar alterations have also been observed in individuals with DS. To determine whether the impairment in adult neurogenesis is, in fact, responsible for the hypocellularity in the hippocampus and physiology of the olfactory bulb, we have analyzed cell proliferation and neuronal maturation in the two major adult neurogenic niches in the Ts656Dn mice: the subgranular zone (SGZ) of the hippocampus and the subventricular zone (SVZ). Additionally, we carried out a study to determine the survival rate and phenotypic fate of newly generated cells in both regions, injecting 5′BrdU and sacrificing the mice 21 days later, and analyzing the number and phenotype of the remaining 5′BrdU-positive cells. We observed a reduction in the number of proliferating (Ki67 positive) cells and immature (doublecortin positive) neurons in the subgranular and SVZ of Ts65Dn mice, but we did not observe changes in the number of surviving cells or in their phenotype. These data correlated with a lower number of apoptotic cells (cleaved caspase 3 positive) in Ts65Dn. We conclude that although adult Ts65Dn mice have a lower number of proliferating cells, it is compensated by a lower level of cell death. This higher survival rate in Ts65Dn produces a final number of mature cells similar to controls. Therefore, the reduction of adult neurogenesis cannot be held responsible for the neuronal hypocellularity in the hippocampus or for the olfactory learning deficit of Ts65Dn mice.

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Section: Introductionmentioning

confidence: 54%

Hypocellularity in the Murine Model for Down Syndrome Ts65Dn Is Not Affected by Adult Neurogenesis

et al. 2016

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“… 110 Based on the hypothesis that donepezil might prevent the loss of ChAT seen in the BFCN of Ts65Dn mice after ~6 months of age, and therefore it would prevent or rescue some cognitive impairment, 4-month-old male Ts65Dn mice were treated for 7 weeks with donepezil; no improvement was seen in acquisition in the MWM. 31 This contrasts with the positive effects of the other anticholinesterases, physostigmine and galantamine, 60 , 61 discussed earlier, that rescued learning deficits in Ts65Dn of similar age (in the case of physostigmine with a single injection 60 ). However, the structure of donepezil is not related to those of other acetylcholinesterases and, in addition, the effects of donepezil in other mouse models have been sensitive to dose and have not been completely consistent.…”

Section: Ts65dn and Preclinical Evaluation Of Drug Efficacymentioning

confidence: 68%

“…In a second study, galantamine was used with an olfactory test of L/M. 61 This test was also chosen because it is nonaversive, and because it exploits a normal sensory drive that is particularly strong in rodents. Furthermore, there are data showing that people with DS have impaired olfaction, even at young ages, 62 and that the impairment increases with age.…”

Section: Ts65dn and Preclinical Evaluation Of Drug Efficacymentioning

confidence: 99%

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Pharmacological approaches to improving cognitive function in Down syndrome: current status and considerations

Gardiner¹

2014

DDDT

105

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Down syndrome (DS), also known as trisomy 21, is the most common genetic cause of intellectual disability (ID). Although ID can be mild, the average intelligence quotient is in the range of 40–50. All individuals with DS will also develop the neuropathology of Alzheimer’s disease (AD) by the age of 30–40 years, and approximately half will display an AD-like dementia by the age of 60 years. DS is caused by an extra copy of the long arm of human chromosome 21 (Hsa21) and the consequent elevated levels of expression, due to dosage, of trisomic genes. Despite a worldwide incidence of one in 700–1,000 live births, there are currently no pharmacological treatments available for ID or AD in DS. However, over the last several years, very promising results have been obtained with a mouse model of DS, the Ts65Dn. A diverse array of drugs has been shown to rescue, or partially rescue, DS-relevant deficits in learning and memory and abnormalities in cellular and electrophysiological features seen in the Ts65Dn. These results suggest that some level of amelioration or prevention of cognitive deficits in people with DS may be possible. Here, we review information from the preclinical evaluations in the Ts65Dn, how drugs were selected, how efficacy was judged, and how outcomes differ, or not, among studies. We also summarize the current state of human clinical trials for ID and AD in DS. Lastly, we describe the genetic limitations of the Ts65Dn as a model of DS, and in the preclinical testing of pharmacotherapeutics, and suggest additional targets to be considered for potential pharmacotherapies.

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“…Galantamine [19,[53][54][55] A competitive, rapidly reversible potent AChE inhibitor, galantamine was approved in AD therapy in 2001. It is well absorbed with an 85% to 100% bioavailability in oral delivery.…”

Section: Traditional Cheismentioning

confidence: 99%

Alzheimer’s Disease Pharmacotherapy in Relation to Cholinergic System Involvement

et al. 2019

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Alzheimer’s disease, a major and increasing global health challenge, is an irreversible, progressive form of dementia, associated with an ongoing decline of brain functioning. The etiology of this disease is not completely understood, and no safe and effective anti-Alzheimer’s disease drug to prevent, stop, or reverse its evolution is currently available. Current pharmacotherapy concentrated on drugs that aimed to improve the cerebral acetylcholine levels by facilitating cholinergic neurotransmission through inhibiting cholinesterase. These compounds, recognized as cholinesterase inhibitors, offer a viable target across key sign domains of Alzheimer’s disease, but have a modest influence on improving the progression of this condition. In this paper, we sought to highlight the current understanding of the cholinergic system involvement in Alzheimer’s disease progression in relation to the recent status of the available cholinesterase inhibitors as effective therapeutics.

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Galantamine improves olfactory learning in the Ts65Dn mouse model of Down syndrome

Cited by 26 publications

References 64 publications

Hypocellularity in the Murine Model for Down Syndrome Ts65Dn Is Not Affected by Adult Neurogenesis

Hypocellularity in the Murine Model for Down Syndrome Ts65Dn Is Not Affected by Adult Neurogenesis

Pharmacological approaches to improving cognitive function in Down syndrome: current status and considerations

Alzheimer’s Disease Pharmacotherapy in Relation to Cholinergic System Involvement

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