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Molecular Mechanisms of Brain Remodeling in Response to Aging and Injuries

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 October 2017) | Viewed by 39273

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Special Issue Editor

Prof. Dr. Aurel Popa-Wagner

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Guest Editor

1. Chair of Vascular Neurology and Dementia, Essen University Medical School, Essen, Germany
2. Experimental Research Center for Normal and Pathological Aging Director, University of Medicine and Pharmacy of Craiova, Craiova, Romania
Interests: ageing; cerebrovascular diseases; rehabilitation; cell therapies; genomics; proteomics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Brain plasticity allows continuous remodeling of brain structure and function during aging and disease. People who incur a brain injury are prone to the development of neurodegenerative and neuroendocrine disorders. Thus, traumatic brain injury (TBI) can trigger pathological changes within brain circuits and might lead long-term cognitive and neuropsychological impairments. However, our understanding of secondary injury mechanisms is limited. Astrocytes play an important role in brain repair after brain injury and astrocyte-mediated mechanisms are likely important in injury-induced synapse remodeling.

Likewise, brain circuits can undergo continual remodeling in response to temporal-lobe epilepsy. The alterations induced by seizures include neuronal death and birth, axonal and dendritic sprouting, gliosis, molecular reorganization of membrane and extracellular-matrix proteins.

Old age is associated with an enhanced susceptibility to stroke and aged animals, recover poorly from brain injuries as compared to young rodents. Despite the initial hope that cell-based therapies may stimulate restorative processes in the ischemic brain, it is now recognized that aging processes may promote an unfavorable environment for such treatments. It is also well established that overt brain lesions like stroke, initiate vigorous neurogenesis in the subventricular zone of adult and even aged animals. However, it seems that most of the newly generated neurons in the subventricular zone either will die or never reach the infarcted area. It could be shown that the aged rat brain is not refractory to cell-based therapy as previously thought, and that it also supports plasticity and remodeling. Similarly, contrary to prevailing dogma, astrocytic scar formation is not a principal cause for the failure of injured mature CNS axons to regrow across severe CNS lesions and that scar-forming astrocytes permit and support robust amounts of appropriately stimulated CNS axon regeneration.

This Special Issue of IJMS, will provide an up-to-date information on molecular, cellular and behavioral events associated with brain remodeling in response to aging and disease and open new avenues for treatment options.

Prof. Dr. Aurel Popa-Wagner
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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Keywords

aging
stroke
traumatic brain injury
epilepsy
Alzheimer’s disease
schizophrenia
depression

Published Papers (6 papers)

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Research

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15 pages, 2696 KiB

Open AccessArticle

Synergistic Association of Valproate and Resveratrol Reduces Brain Injury in Ischemic Stroke

by Lara Faggi, Giuseppe Pignataro, Edoardo Parrella, Vanessa Porrini, Antonio Vinciguerra, Pasquale Cepparulo, Ornella Cuomo, Annamaria Lanzillotta, Mariana Mota, Marina Benarese, Paolo Tonin, Lucio Annunziato, PierFranco Spano and Marina Pizzi

Int. J. Mol. Sci. 2018, 19(1), 172; https://doi.org/10.3390/ijms19010172 - 06 Jan 2018

Cited by 27 | Viewed by 4897

Abstract

Histone deacetylation, together with altered acetylation of NF-κB/RelA, encompassing the K310 residue acetylation, occur during brain ischemia. By restoring the normal acetylation condition, we previously reported that sub-threshold doses of resveratrol and entinostat (MS-275), respectively, an activator of the AMP-activated kinase (AMPK)-sirtuin 1 pathway and an inhibitor of class I histone deacetylases (HDACs), synergistically elicited neuroprotection in a mouse model of ischemic stroke. To improve the translational power of this approach, we investigated the efficacy of MS-275 replacement with valproate, the antiepileptic drug also reported to be a class I HDAC blocker. In cortical neurons previously exposed to oxygen glucose deprivation (OGD), valproate elicited neuroprotection at 100 nmol/mL concentration when used alone and at 1 nmol/mL concentration when associated with resveratrol (3 nmol/mL). Resveratrol and valproate restored the acetylation of histone H3 (K9/18), and they reduced the RelA(K310) acetylation and the Bim level in neurons exposed to OGD. Chromatin immunoprecipitation analysis showed that the synergistic drug association impaired the RelA binding to the Bim promoter, as well as the promoter-specific H3 (K9/18) acetylation. In mice subjected to 60 min of middle cerebral artery occlusion (MCAO), the association of resveratrol 680 µg/kg and valproate 200 µg/kg significantly reduced the infarct volume as well as the neurological deficits. The present study suggests that valproate and resveratrol may represent a promising ready-to-use strategy to treat post-ischemic brain damage. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Brain Remodeling in Response to Aging and Injuries)

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18122 KiB

Open AccessArticle

Inhibition of Aquaporin-4 Improves the Outcome of Ischaemic Stroke and Modulates Brain Paravascular Drainage Pathways

by Ionica Pirici, Tudor Adrian Balsanu, Catalin Bogdan, Claudiu Margaritescu, Tamir Divan, Vacaras Vitalie, Laurentiu Mogoanta, Daniel Pirici, Roxana Octavia Carare and Dafin Fior Muresanu

Int. J. Mol. Sci. 2018, 19(1), 46; https://doi.org/10.3390/ijms19010046 - 23 Dec 2017

Cited by 65 | Viewed by 7878

Abstract

Aquaporin-4 (AQP4) is the most abundant water channel in the brain, and its inhibition before inducing focal ischemia, using the AQP4 inhibitor TGN-020, has been showed to reduce oedema in imaging studies. Here, we aimed to evaluate, for the first time, the histopathological effects of a single dose of TGN-020 administered after the occlusion of the medial cerebral artery (MCAO). On a rat model of non-reperfusion ischemia, we have assessed vascular densities, albumin extravasation, gliosis, and apoptosis at 3 and 7 days after MCAO. TGN-020 significantly reduced oedema, glial scar, albumin effusion, and apoptosis, at both 3 and 7 days after MCAO. The area of GFAP-positive gliotic rim decreased, and 3D fractal analysis of astrocytic processes revealed a less complex architecture, possibly indicating water accumulating in the cytoplasm. Evaluation of the blood vessels revealed thicker basement membranes colocalizing with exudated albumin in the treated animals, suggesting that inhibition of AQP4 blocks fluid flow towards the parenchyma in the paravascular drainage pathways of the interstitial fluid. These findings suggest that a single dose of an AQP4 inhibitor can reduce brain oedema, even if administered after the onset of ischemia, and AQP4 agonists/antagonists might be effective modulators of the paravascular drainage flow. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Brain Remodeling in Response to Aging and Injuries)

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Review

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14 pages, 622 KiB

Open AccessReview

Present Status and Future Challenges of New Therapeutic Targets in Preclinical Models of Stroke in Aged Animals with/without Comorbidities

by Aurel Popa-Wagner, Daniela-Gabriela Glavan, Andrei Olaru, Denissa-Greta Olaru, Otilia Margaritescu, Oana Tica, Roxana Surugiu and Raluca Elena Sandu

Int. J. Mol. Sci. 2018, 19(2), 356; https://doi.org/10.3390/ijms19020356 - 25 Jan 2018

Cited by 18 | Viewed by 4155

Abstract

The aging process, comorbidities, and age-associated diseases are closely dependent on each other. Cerebral ischemia impacts a wide range of systems in an age-dependent manner. However, the aging process has many facets which are influenced by the genetic background and epigenetic or environmental factors, which can explain why some people age differently than others. Therefore, there is an urgent need to identify age-related changes in body functions or structures that increase the risk for stroke and which are associated with a poor outcome. Multimodal imaging, electrophysiology, cell biology, proteomics, and transcriptomics, offer a useful approach to link structural and functional changes in the aging brain, with or without comorbidities, to post-stroke rehabilitation. This can help us to improve our knowledge about senescence firstly, and in this context, aids in elucidating the pathophysiology of age-related diseases that allows us to develop therapeutic strategies or prevent diseases. These processes, including potential therapeutical interventions, need to be studied first in relevant preclinical models using aged animals, with and without comorbidities. Therefore, preclinical research on ischemic stroke should consider age as the most important risk factor for cerebral ischemia. Furthermore, the identification of effective therapeutic strategies, corroborated with successful translational studies, will have a dramatic impact on the lives of millions of people with cerebrovascular diseases. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Brain Remodeling in Response to Aging and Injuries)

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1501 KiB

Open AccessReview

Cellular and Molecular Mechanisms Underlying Non-Pharmaceutical Ischemic Stroke Therapy in Aged Subjects

by Raluca Elena Sandu, Danut Dumbrava, Roxana Surugiu, Daniela-Gabriela Glavan, Andrei Gresita and Eugen Bogdan Petcu

Int. J. Mol. Sci. 2018, 19(1), 99; https://doi.org/10.3390/ijms19010099 - 29 Dec 2017

Cited by 17 | Viewed by 3887

Abstract

The incidence of ischemic stroke in humans increases exponentially above 70 years both in men and women. Comorbidities like diabetes, arterial hypertension or co-morbidity factors such as hypercholesterolemia, obesity and body fat distribution as well as fat-rich diet and physical inactivity are common in elderly persons and are associated with higher risk of stroke, increased mortality and disability. Obesity could represent a state of chronic inflammation that can be prevented to some extent by non-pharmaceutical interventions such as calorie restriction and hypothermia. Indeed, recent results suggest that H₂S-induced hypothermia in aged, overweight rats could have a higher probability of success in treating stroke as compared to other monotherapies, by reducing post-stroke brain inflammation. Likewise, it was recently reported that weight reduction prior to stroke, in aged, overweight rats induced by caloric restriction, led to an early re-gain of weight and a significant improvement in recovery of complex sensorimotor skills, cutaneous sensitivity, or spatial memory. Conclusion: animal models of stroke done in young animals ignore age-associated comorbidities and may explain, at least in part, the unsuccessful bench-to-bedside translation of neuroprotective strategies for ischemic stroke in aged subjects. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Brain Remodeling in Response to Aging and Injuries)

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1356 KiB

Open AccessReview

The Glutamatergic System in Primary Somatosensory Neurons and Its Involvement in Sensory Input-Dependent Plasticity

by Julia Fernández-Montoya, Carlos Avendaño and Pilar Negredo

Int. J. Mol. Sci. 2018, 19(1), 69; https://doi.org/10.3390/ijms19010069 - 27 Dec 2017

Cited by 37 | Viewed by 9298

Abstract

Glutamate is the most common neurotransmitter in both the central and the peripheral nervous system. Glutamate is present in all types of neurons in sensory ganglia, and is released not only from their peripheral and central axon terminals but also from their cell bodies. Consistently, these neurons express ionotropic and metabotropic receptors, as well as other molecules involved in the synthesis, transport and release of the neurotransmitter. Primary sensory neurons are the first neurons in the sensory channels, which receive information from the periphery, and are thus key players in the sensory transduction and in the transmission of this information to higher centers in the pathway. These neurons are tightly enclosed by satellite glial cells, which also express several ionotropic and metabotropic glutamate receptors, and display increases in intracellular calcium accompanying the release of glutamate. One of the main interests in our group has been the study of the implication of the peripheral nervous system in sensory-dependent plasticity. Recently, we have provided novel evidence in favor of morphological changes in first- and second-order neurons of the trigeminal system after sustained alterations of the sensory input. Moreover, these anatomical changes are paralleled by several molecular changes, among which those related to glutamatergic neurotransmission are particularly relevant. In this review, we will describe the state of the art of the glutamatergic system in sensory ganglia and its involvement in input-dependent plasticity, a fundamental ground for advancing our knowledge of the neural mechanisms of learning and adaptation, reaction to injury, and chronic pain. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Brain Remodeling in Response to Aging and Injuries)

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2032 KiB

Open AccessReview

Neuro-Coagulopathy: Blood Coagulation Factors in Central Nervous System Diseases

by Ciro De Luca, Assunta Virtuoso, Nicola Maggio and Michele Papa

Int. J. Mol. Sci. 2017, 18(10), 2128; https://doi.org/10.3390/ijms18102128 - 12 Oct 2017

Cited by 64 | Viewed by 8551

Abstract

Blood coagulation factors and other proteins, with modulatory effects or modulated by the coagulation cascade have been reported to affect the pathophysiology of the central nervous system (CNS). The protease-activated receptors (PARs) pathway can be considered the central hub of this regulatory network, mainly through thrombin or activated protein C (aPC). These proteins, in fact, showed peculiar properties, being able to interfere with synaptic homeostasis other than coagulation itself. These specific functions modulate neuronal networks, acting both on resident (neurons, astrocytes, and microglia) as well as circulating immune system cells and the extracellular matrix. The pleiotropy of these effects is produced through different receptors, expressed in various cell types, in a dose- and time-dependent pattern. We reviewed how these pathways may be involved in neurodegenerative diseases (amyotrophic lateral sclerosis, Alzheimer’s and Parkinson’s diseases), multiple sclerosis, ischemic stroke and post-ischemic epilepsy, CNS cancer, addiction, and mental health. These data open up a new path for the potential therapeutic use of the agonist/antagonist of these proteins in the management of several central nervous system diseases. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Brain Remodeling in Response to Aging and Injuries)

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