Effetti di un trattamento cronico con fluoxetina nel recupero della memoria spaziale e della plasticita' sinaptica ippocampale in un modello murino della sindrome Down

La presente Tesi di Laurea intende investigare gli effetti di un trattamento cronico con fluoxetina nel recupero delle disfunzioni mnemoniche e di plasticità sinaptica ippocampale nel topo Ts65Dn. La fluoxetina è un inibitore selettivo del reuptake della serotonina attualmente utilizzato come trattamento farmacologico standard per numerose patologie psichiatriche. Nella prima parte della Tesi ho eseguito uno studio volto a stabilire un dosaggio appropriato per minimizzare il rischio di effetti collaterali. Precedenti studi hanno dimostrato come la fluoxetina abbia un'azione pro-convulsivante in modelli animali; inoltre, un dosaggio elevato di tale farmaco può essere responsabile di crisi di tipo epilettico anche nell'uomo. Tramite un’indagine dose-effetto ho potuto stabilire che il dosaggio di 10 mg/Kg/die si dimostra sicuro nei topi Ts65Dn, non lasciando registrare nessun caso di attacchi convulsivi o morti improvvise. Nella seconda parte della Tesi, ho quindi potuto valutare gli effetti di un trattamento cronico con fluoxetina al dosaggio precedentemente stabilito; la fluoxetina è stata somministrata nell’acqua da bere per 8 settimane. I risultati hanno mostrato che tale trattamento consente un recupero delle abilità di memoria spaziale e della plasticità sinaptica ippocampale nei topi Ts65Dn adulti. Complessivamente, i risultati riportati nella presente Tesi di Laurea suggeriscono una possibile applicazione clinica della fluoxetina nel trattamento delle disfunzioni fenotipiche associate alla sindrome di Down

Pterostilbene Improves Cognitive Performance in Aged Rats: An in Vivo Study

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Intranasal delivery of BDNF rescues memory deficits in AD11 mice and reduces brain microgliosis

A decrease in brain-derived neurotrophic factor (BDNF), a neurotrophin essential for synaptic function, plasticity and neuronal survival, is evident early in the progression of Alzheimer's disease (AD), being apparent in subjects with mild cognitive impairment or mild AD, and both proBDNF and mature BDNF levels are positively correlated with cognitive measures. BDNF delivery is, therefore, considered of great interest as a potentially useful therapeutic strategy to contrast AD. Invasive BDNF administration has indeed been recently used in animal models of AD with promising results in rescuing memory deficits, synaptic density and cell loss. Here, we tested whether non-invasive intranasal administration of different BDNF concentrations after the onset of cognitive and anatomical deficits (6 months of age) could rescue neuropathological and memory deficits in AD11 mice, a model of NGF deprivation-induced neurodegeneration. In addition to AD hallmarks, we investigated BDNF effects on microglia presence in the brain of AD11 mice, since alterations in microglia activation have been associated with ageing-related cognitive decline and with the progression of neurodegenerative diseases, including AD. We found that intranasal delivery of 42 pmol BDNF (1 mu M), but not PBS, was sufficient to completely rescue performance of AD11 mice both in the object recognition test and in the object context test. No further improvement was obtained with 420 pmol (10 mu M) BDNF dose. The strong improvement in memory performance in BDNF-treated mice was not accompanied by an amelioration of AD-like pathology, A beta burden, tau hyperphosphorylation and cholinergic deficit, but there was a dramatic decrease of CD11b immunoreactive brain microglia. These results reinforce the potential therapeutic uses of BDNF in AD and the non-invasive intranasal route as an effective delivery strategy of BDNF to the brain. They also strengthen the connection between neuroinflammation and neurodegenerative dementia and suggest microglia as a possible mediator of BDNF therapeutic actions in the brain

From Basic Visual Science to Neurodevelopmental Disorders: The Voyage of Environmental Enrichment-Like Stimulation

Genes and environmental stimuli cooperate in the regulation of brain development and formation of the adult neuronal architecture. Genetic alterations or exposure to perturbing environmental conditions, therefore, can lead to altered neural processes associated with neurodevelopmental disorders and brain disabilities. In this context, environmental enrichment emerged as a promising and noninvasive experimental treatment for favoring recovery of cognitive and sensory functions in different neurodevelopmental disorders. The aim of this review is to depict, mainly through the much explicative examples of amblyopia, Down syndrome, and Rett syndrome, the increasing interest in the potentialities and applications of enriched environment-like protocols in the field of neurodevelopmental disorders and the understanding of the molecular mechanisms underlying the beneficial effects of these protocols, which might lead to development of pharmacological interventions

Early environmental therapy rescues brain development in a mouse model of Down syndrome

Early environmental therapy rescues brain development in a mouse model of Down syndrom

Experience-dependent reduction of soluble \u3b2-amyloid oligomers and rescue of cognitive abilities in middle-age Ts65Dn mice, a model of Down syndrome

Down syndrome (DS) is the most diffused genetic cause of intellectual disability and, after the age of forty, is invariantly associated with Alzheimer's disease (AD). In the last years, the prolongation of life expectancy in people with DS renders the need for intervention paradigms aimed at improving mental disability and counteracting AD pathology particularly urgent. At present, however, there are no effective therapeutic strategies for DS and concomitant AD in mid-life people. The most intensively studied mouse model of DS is the Ts65Dn line, which summarizes the main hallmarks of the DS phenotype, included severe learning and memory deficits and age-dependent AD-like pathology. Here we report for the first time that middle-age Ts65Dn mice display a marked increase in soluble A\u3b2 oligomer levels in their hippocampus. Moreover, we found that long-term exposure to environmental enrichment (EE), a widely used paradigm that increases sensory-motor stimulation, reduces A\u3b2 oligomers and rescues spatial memory abilities in trisomic mice. Our findings underscore the potential of EE procedures as a non-invasive paradigm for counteracting brain aging processes in DS subjects