Long-Term Effects of Enriched Environment on Neurofunctional Outcome and CNS Lesion Volume After Traumatic Brain Injury in Rats

Maegele, Marc; Braun, Moria D.; Wafaisade, Arasch; Schäfer, Nadine; Lippert-Gruener, Marcela; Kreipke, Christian W.; Rafols, José A.; Schäfer, Ute; Dn, Angelov; Ek, Stuermer

doi:10.33549/physiolres.932664

Cited by 10 publications

(4 citation statements)

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“…The global loss of Mecp2 also leads to reductions in the numbers of microglia and perivascular meningeal macrophages [ 9 ]. While the role of microglia in mediating RTT phenotype remains elusive, it is clear that the dysregulated inflammatory and phagocytic functions in microglia could lead to changes in normal brain circuitry and function [ 64 ].…”

Section: Discussionmentioning

confidence: 99%

Dendrimer-mediated delivery of N-acetyl cysteine to microglia in a mouse model of Rett syndrome

Nance

Kambhampati

Smith

et al. 2017

J Neuroinflammation

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BackgroundRett syndrome (RTT) is a pervasive developmental disorder that is progressive and has no effective cure. Immune dysregulation, oxidative stress, and excess glutamate in the brain mediated by glial dysfunction have been implicated in the pathogenesis and worsening of symptoms of RTT. In this study, we investigated a new nanotherapeutic approach to target glia for attenuation of brain inflammation/injury both in vitro and in vivo using a Mecp2-null mouse model of Rett syndrome.MethodsTo determine whether inflammation and immune dysregulation were potential targets for dendrimer-based therapeutics in RTT, we assessed the immune response of primary glial cells from Mecp2-null and wild-type (WT) mice to LPS. Using dendrimers that intrinsically target activated microglia and astrocytes, we studied N-acetyl cysteine (NAC) and dendrimer-conjugated N-acetyl cysteine (D-NAC) effects on inflammatory cytokines by PCR and multiplex assay in WT vs Mecp2-null glia. Since the cysteine-glutamate antiporter (Xc−) is upregulated in Mecp2-null glia when compared to WT, the role of Xc− in the uptake of NAC and l-cysteine into the cell was compared to that of D-NAC using BV2 cells in vitro. We then assessed the ability of D-NAC given systemically twice weekly to Mecp2-null mice to improve behavioral phenotype and lifespan.ResultsWe demonstrated that the mixed glia derived from Mecp2-null mice have an exaggerated inflammatory and oxidative stress response to LPS stimulation when compared to WT glia. Expression of Xc− was significantly upregulated in the Mecp2-null glia when compared to WT and was further increased in the presence of LPS stimulation. Unlike NAC, D-NAC bypasses the Xc− for cell uptake, increasing intracellular GSH levels while preventing extracellular glutamate release and excitotoxicity. Systemically administered dendrimers were localized in microglia in Mecp2-null mice, but not in age-matched WT littermates. Treatment with D-NAC significantly improved behavioral outcomes in Mecp2-null mice, but not survival.ConclusionsThese results suggest that delivery of drugs using dendrimer nanodevices offers a potential strategy for targeting glia and modulating oxidative stress and immune responses in RTT.Electronic supplementary materialThe online version of this article (10.1186/s12974-017-1004-5) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Dendrimer-mediated delivery of N-acetyl cysteine to microglia in a mouse model of Rett syndrome

Nance

Kambhampati

Smith

et al. 2017

J Neuroinflammation

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“…For example, after 80 days of enriched environment exposure, differences in brain weights remained evident for only 21 days after removal of enrichment. Others have found longer lasting sensori- and neuro-motor (Maegele et al, 2015), memory (Escorihuela et al, 1995; Maegele et al, 2015), and noradrenergic functioning (Escorihuela et al, 1995) effects in rats after enriched-environment exposure.…”

Section: Origins Of Interest In Enriched Environmentsmentioning

confidence: 99%

Enriched Environments as a Potential Treatment for Developmental Disorders: A Critical Assessment

2019

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The beneficial effects of enriched environments have been established through a long history of research. Enrichment of the living conditions of captive animals in the form of larger cages, sensory stimulating objects, and opportunities for social interaction and physical exercise, has been shown to reduce emotional reactivity, ameliorate abnormal behaviors, and enhance cognitive functioning. Recently, environmental enrichment research has been extended to humans, in part due to growing interest in its potential therapeutic benefits for children with neurodevelopmental disorders (NDDs). This paper reviews the history of enriched environment research and the use of enriched environments as a developmental intervention in studies of both NDD animal models and children. We argue that while environmental enrichment may sometimes benefit children with NDDs, several methodological factors need to be more closely considered before the efficacy of this approach can be adequately evaluated, including: (i) operationally defining and standardizing enriched environment treatments across studies; (ii) use of control groups and better control over potentially confounding variables; and (iii) a comprehensive theoretical framework capable of predicting when and how environmental enrichment will alter the trajectory of NDDs.

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“…EE exposure also stimulates neurogenesis (Hu et al, 2010) and reduces cognitive deficits (Ambree et al, 2006;Lazarov et al, 2005), the latter correlating with reductions in brain Aβ load (Berardi et al, 2007;Costa et al, 2007;Cracchiolo et al, 2007;Hu et al, 2010;Lazarov et al, 2005;Maesako et al, 2012;Mainardi et al, 2014;Verret et al, 2013). Exposure of rats to 90 days of EE resulted in marked reductions in brain atrophy and improvement on the Barnes maze test of spatial memory following FPI in adult rat (Maegele et al, 2015) indicating that prolonged exposure to EE is a promising therapeutic strategy. As a non-invasive therapy approach, EE could be combined with pharmacotherapy for improved long-term recovery after TBI, as has been explored in several recent studies (Bondi et al, 2014), which would avoid potential drug interaction complications.…”

Section: Environmental Enrichmentmentioning

confidence: 97%

Novel therapies for combating chronic neuropathological sequelae of TBI

et al. 2019

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Traumatic brain injury (TBI) is a risk factor for development of chronic neurodegenerative disorders later in life. This review summarizes the current knowledge and concepts regarding the connection between long-term consequences of TBI and aging-associated neurodegenerative disorders including Alzheimer's disease (AD), chronic traumatic encephalopathy (CTE), and Parkinsonism, with implications for novel therapy targets. Several aggregation-prone proteins such as the amyloid-beta (Aβ) peptides, tau proteins, and α-synuclein protein are involved in secondary pathogenic cascades initiated by a TBI and are also major building blocks of the hallmark pathological lesions in chronic human neurodegenerative diseases with dementia. Impaired metabolism and degradation pathways of aggregation-prone proteins are discussed as potentially critical links between the long-term aftermath of TBI and chronic neurodegeneration. Utility and limitations of previous and current preclinical TBI models designed to study the link between TBI and chronic neurodegeneration, and promising intervention pharmacotherapies and non-pharmacologic strategies to break this link, are also summarized. Complexity of long-term neuropathological consequences of TBI is discussed, with a goal of guiding future preclinical studies and accelerating implementation of promising therapeutics into clinical trials.

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Long-Term Effects of Enriched Environment on Neurofunctional Outcome and CNS Lesion Volume After Traumatic Brain Injury in Rats

Cited by 10 publications

References 142 publications

Dendrimer-mediated delivery of N-acetyl cysteine to microglia in a mouse model of Rett syndrome

Dendrimer-mediated delivery of N-acetyl cysteine to microglia in a mouse model of Rett syndrome

Enriched Environments as a Potential Treatment for Developmental Disorders: A Critical Assessment

Novel therapies for combating chronic neuropathological sequelae of TBI

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