Spinal cord injuries can cause the catastrophic loss of motor and sensory function. The neurological deficits that result are the consequence of not only the primary injury to the spinal cord, but also a complex milieu of secondary pathological processes that are now beginning to be understood. The major mechanisms that underlie this secondary pathology include vascular disruption, ischemia, oxidative stress, excitotoxicity, and inflammation. In light of this, the fact that this secondary pathology occurs after the initial impact makes it potentially amenable to therapeutic intervention. Pharmacotherapies may attenuate some of these processes and minimize secondary damage. Some of the promising treatments that are emerging for acute spinal cord injury are drugs that are already used by physicians for the treatment of unrelated diseases. These drugs, which have already been established to be safe for humans, offer the unique advantage over other novel therapeutic interventions that have yet to be tested in humans. This would save a tremendous amount of time and money needed for human safety studies, if considered as a treatment for spinal cord injury. Examples of such drugs include minocycline (an antibiotic), erythropoietin (a recombinant hormone used to treat anemia), and statins (a popular class of blood cholesterol reducers), all of which have demonstrated the ability to attenuate the various pathophysiological processes initiated after trauma to the central nervous system. In a series of studies, erythropoietin, darbepoetin, atorvastatin, simvastatin, and minocycline were all evaluated for their ability to improve neurologic recovery in a clinically relevant model of spinal cord injury. My experiments revealed that erythropoietin, darbepoetin, atorvastatin and minocycline did not significantly improve neurological recovery. These negative results were in stark contrast to the positive findings which had been published in the literature suggesting that differences in experimental models and methodology influence the neuroprotective efficacy of these drugs. Simvastatin, on the other hand, demonstrated significant improvements in locomotor and histological outcomes. Although this is indeed exciting, the results were modest at best. My results highlight the need for further preclinical work on the above treatments to refine and optimize them prior to proposing them for human testing. / Science, Faculty of / Zoology, Department of / Graduate

This study examined the acute and chronic responses of brain-derived neurotrophic factor (BDNF), cathepsin B (CatB), insulin-like growth factor-1 (IGF-1), and interleukin-6 (IL-6) and if changes in these biomarkers were correlated during resistance training. Fourteen resistance trained men performed resistance training 3 days per week for 6 weeks in two groups. The only difference between groups was the proximity to failure of each set (4-6 repetitions in reserve or 1-3 repetitions in reserve). Serum was collected immediately before and after training on day 1 of weeks 1 and 6. There were no significant group interactions for any of the biomarkers assessed, there were no main effects for time (p>0.05), and no significant correlations were observed between any of the biomarkers. However, a significant main effect for exercise for BDNF (p=0.03) and IL-6 (p=0.003) was observed. For CatB, a significant exercise × time (p=0.002) interaction was observed, indicating differences in the acute change of CatB in week 6 (+15.78%; g=0.25) vs. week 1 (-7.46%; g=0.13). In summary, these results suggest that multi-joint resistance exercise far from failure can confer a BDNF response. This investigation is the first to demonstrate the potential for acute resistance exercise to elicit a transient increase in CatB. / Includes bibliography. / Thesis (M.S.)--Florida Atlantic University, 2021. / FAU Electronic Theses and Dissertations Collection

The aggregation of misfolded proteins in the endoplasmic reticulum (ER) is a pathological trait shared by many neurodegenerative disorders. This aggregation leads to the persistent activation of the unfolded protein response (UPR) and ultimately apoptosis due to ER stress. Cannabinoids, such as tetrahydrocannabinol (THC) and cannabidiol (CBD), have been reported to be neuroprotective in in vitro and in vivo models of neurodegeneration through their antioxidant and anti-inflammatory properties. However, little is known about the role of these cannabinoids in the context of ER stress. STHdhQ7/Q7 cells were treated with the ER stress inducer thapsigargin (TG) and cannabinoids in three different experimental paradigms to investigate the effect of 2.5 µM THC and 1 µM CBD monotreatment and cotreatment on ER stress-induced cell death. The mouse striatal neurons survived significantly more when THC or CBD was given before TG exposure. To further investigate this experimental paradigm, the gene and protein expression of UPR proteins was measured to determine the effect of cannabinoid pre-treatment on cell survival through ER stress modulation. A significant increase in the gene expression of the ER chaperone GRP78 and the ER-resident neurotrophic factor MANF in pre-treated samples suggest that with THC or CBD pre-treatment, the protein folding capacity of the cell is improved. Additionally, a decrease in the ER-mediated apoptotic markers such as BIM and caspase 12 with THC or CBD pre-treatment provides further evidence that cannabinoid pre-treatments are neuroprotective through ER stress modulation. These data suggest that prior cannabinoid monotherapy prepares the cell for future insults to the ER. Understanding the role of ER stress in the neuroprotective properties of THC and CBD provides insight into the therapeutic potential of cannabinoids and the role of ER dysfunction in various neurodegenerative disorders. / Thesis / Master of Health Sciences (MSc) / With the worldwide ageing population increasing, finding new treatments for illnesses that affect the elderly is crucial. Disorders such as Parkinson’s and Alzheimer’s disease mainly affect older individuals and are caused when brain cells stop working or when brain cells die. These disorders share some common causes. One is the inability to fold proteins properly. The cellular process that is responsible for protein folding and the changes that occur within that process are studied in this project. Also, the impact of the cannabinoids THC and CBD, a major component of cannabis, on the protein folding process is studied. This project found that using cannabinoids before the protein folding system is disrupted helps brain cells survive. This study is a step in understanding how THC and CBD are helpful in brain cell survival in patients suffering from diseases that damage brain cells.

Les homéoprotéines sont des facteurs de transcription morphogénétiques qui ont des fonctions cellulaire et non cellulaire-autonomes. Par exemple, En1 et En2 (Engrailed/En) sont importants pour le développement des neurones dopaminergiques du mésencéphale (mDA) et cruciaux pour leur maintien chez l'adulte. Les souris En1+/- présentent une dégénération progressive et spécifique des neurones mDA de la Substantia Nigra pars compacta (SNpc), rappelant la maladie de Parkinson. De plus, l'infusion d'En dans plusieurs modèles de la maladie sauve ces neurones. Dans le modèle MPTP, cela passe par l'augmentation de la traduction d'une sous-unité du complexe 1 de la mitochondrie, Ndufs1. Le but de ma thèse était de trouver d'autres mécanismes neuro-protecteurs d'En. En étudiant les souris En1+/-, nous avons montré que la neurodégénérescence est accompagnée de cassures d'ADN et d'une relaxation de la chromatine. Dans un modèle de fort stress oxydatif, on trouve un phénotype similaire mais accéléré, qui est guéri par En. L'amélioration de ces marqueurs majeurs du vieillissement après l'injection d'En renforce l'idée qu'il est un facteur anti-âge prometteur dans le traitement de la maladie de Parkinson. Les LINEs sont des rétrotransposons qui ont la capacité de se propager dans le génome, via un mécanisme de copier/coller. Bien que longtemps considérés comme silencieux, nous avons montré qu'ils sont exprimés dans la SNpc et suractivés par un fort stress oxydatif, entrainant cassures d'ADN et neurodégénération. Leur répression transcriptionnelle ou épigénétique par En pourrait expliquer l'activité protectrice de cette protéine dans des modèles de stress oxydatif progressifs ou forts. / Homeoproteins are morphogenetic transcription factors, which have cell and non-cell autonomous functions. For example, En1 and En2, collectively Engrailed (En), are important for midbrain dopaminergic (mDA) neuron development and crucial for their adult maintenance. En1+/- mice display a selective and progressive degeneration of the mDA neurons of the Substantia Nigra pars compacta (SNpc), reminiscent of Parkinson disease (PD). Furthermore, En infusion in the SNpc saves neurons in several models of the disease. In the case of MPTP, En-mediated neuroprotection partially necessitates its ability to upregulate the translation of Ndufs1, a subunit of the mitochondrial Complex I. The main aim of my thesis was to study additional neuroprotective pathways mediated by En. We first studied En1+/- mice and showed that neurodegeneration was accompanied by increased DNA damage and chromatin relaxation. In an acute oxidative stress model, similar but accelerated phenotypes were seen, which were antagonized by En injection. The En-mediated positive impact on these key hallmarks of ageing lends weight to the idea that En is a promising anti-ageing factor, possibly useful in the treatment of PD. Long interspersed nuclear elements (LINE-1) are a class of retrotransposons with the ability to multiply in the genome. Although considered silent, they are expressed in mouse mDA neurons and their expression is increased by an acute oxidative stress, leading to DNA damage and degeneration. Their direct repression by En allows us to propose that their transcriptional and/or epigenetic silencing explains part of En protective activity in mouse models of acute and progressive oxidative stress.

L’amyotrophie spinale infantile (SMA) est une maladie neurodégénérative rare, caractérisée par une perte progressive des motoneurones de la moelle épinière, et pour laquelle aucun traitement curatif n’est disponible. Cette maladie est causée par la mutation du gène SMN1 qui induit une diminution de l’expression de la protéine SMN. Depuis plusieurs des années, notre l’équipe examine les effets de l’exercice sur le développement ou le maintien de l’unité motrice dans des maladies neurodégénératives affectant spécifiquement le motoneurone. Ces études ont notamment permis de mettre en évidence que l’exercice physique pourrait avoir des effets bénéfiques pour l’amyotrophie spinale, dans un modèle de souris SMA de type 2 soumis à un exercice de course sur roue pendant 5 jours (Grondard et al., 2005). Dans notre étude, nous avons comparé les effets de deux programmes d’entraînement différents, d’une durée de 10 mois, basés sur un exercice de course ou sur un exercice de nage, sur des populations de souris SMA de type 3, la forme la moins sévère de la maladie. Dans nos conditions, la course est un exercice de faible intensité et de faible amplitude, mais qui induit plus de lésions musculaires, au contraire de la nage, comme le confirme les mesures de lactate et de créatine kinase circulants. Ces deux paramètres ont des valeurs anormalement hautes chez les souris SMA, suggérant des anomalies métaboliques et de fragilité musculaire, qui sont limitées par les deux programmes d’entraînement. Les analyses du comportement moteur indiquent également que les 10 mois d’entraînement améliorent significativement les capacités motrices des souris SMA, et notamment la résistance à la fatigue avec la nage. Comme attendu, la perte de 46% des motoneurones spinaux enregistrée à 12 mois chez les souris SMA sédentaires est significativement limitée par les deux types d’entrainement, mais avec des efficacités différentes sur les différentes sous‐populations de motoneurones spinaux. En effet, la course protège préférentiellement les motoneurones de faible surface et exprimant ERR‐β, assimilés à des motoneurones lents, et la nage les motoneurones de large surface et exprimant Chodl, assimilés à des motoneurones rapides. De manière surprenante, la neuroprotection induite par l’exercice est indépendante de l’expression de SMN dans la moelle épinière des souris SMA. Une étude de la forme et de la surface des jonctions neuromusculaires dans trois muscles du mollet, le soleus, le plantaris et le tibialis, et une étude du phénotype musculaire de ces mêmes trois muscles confirment le rôle bénéfique de l’entrainement mais aussi les effets différentiels des deux programmes, avec un effet plus important pour la nage. Les améliorations de l’unité motrice, induites par l’exercice, permettent un meilleur fonctionnement neuromusculaire, comme le suggère les mesures électrophysiologiques du muscle plantaire. Pris tous ensemble, ces résultats suggèrent qu’un exercice de nage, à haute intensité, dans des conditions anaérobies, et axé sur le recrutement des muscles extenseurs pourrait être bénéfique pour les patients SMA, notamment pour améliorer les capacités motrices et donc la qualité de vie des patients. / Objective: Spinal Muscular Atrophy (SMA) is a group of autosomal recessive neurodegenerative diseases differing in their clinical outcome, characterized by the specific loss of spinal motor‐neurons, caused by insufficient levels of SMN protein expression. No cure is presently available for SMA. While physical exercise might represent a promising approach for alleviating SMA symptoms, the lack of data dealing with the effects of different exercise types on diseased motor‐units still precludes the use of exercise in SMA patients. Methods: We have evaluated the efficiency of two long‐term physical exercise paradigms, either based on high intensity swimming or on low intensity running, in alleviating SMA symptoms in a mild type 3 SMA‐like mouse model. Results: We found that a 10‐month physical training induced significant benefits in terms of resistance to muscle damages, energetic metabolism, muscle fatigue and motor behavior. Both exercise types significantly enhanced motor‐neuron survival, independently of SMN expression, leading to the maintenance of neuromuscular junctions and skeletal muscle phenotypes, particularly in the soleus, plantaris and tibialis of trained mice. Most importantly, both exercises significantly improved neuromuscular excitability properties. Besides, all these training‐induced benefits are quantitatively and qualitatively related to the specific characteristics of each exercise, suggesting that the related neuroprotection is strongly dependent on the specific activation of some motor‐neuron subpopulations. Interpretation: Taken together, the present data show significant long‐term exercise benefits in a mild type 3 SMA context and provide important clues for designing rehabilitation programs in patients.

No description available.

The goal of this study was to investigate the therapeutic potential of memantine on functional recovery following a cortical contusion impact (CCI) traumatic brain injury (TBI) in a rodent model. A unilateral parietal injury was induced and compared to open sham surgeries under controlled experimental conditions. Animals were randomly assigned to a sham group, vehicle-treated injured group, or memantine-treated injured group. Dosage regimens were designed to provide serum concentrations in the range obtained with clinically approved doses, using both a low (5 mg/kg) and high (20 mg/kg) dose for 48 h. Functional recovery was assessed using five behavioral assessments, as well as neuropathological measurements. Motor function was observed using the locomotor placing task, the rotor-rod procedure, and a photobeam activity monitoring system. Cognitive function as learning ability was assessed through the Morris Water Maze and a passive avoidance assessment. Memantine did not improve motor or cognitive function in any of the behavioral assessments. These results indicate that while memantine may provide benefits at a neurobiological level, its therapeutic potential on the recovery of behavioral function following TBI is severely limited.

Yes / Provides a timely overview of critical advances in molecular and cellular neurobiology, covers key methodologies driving progress, and highlights key future directions for research on neuronal injury and neurodegeneration relevant to neuronal brain pathologies. The editors bring together contributions from internationally recognized workers in the field to provide an up to date account of how and why molecular and cellular neurobiology is such an important area for clinical neuroscience. Understanding the molecular aspects of a number of neurodegenerative conditions such as Parkinson's or Alzheimer's disease for the purpose of improving patient management remains a major challenge of neurobiology be it from the basic or clinical perspective. A strategic evaluation of research contributions and the power of modern methods will help advance knowledge over the next years.

Patterns of physiological electrical activity in the central nervous system (CNS) cause longlasting changes in gene expression that promote neuronal survival. These changes can be mediated by signalling pathways activated by Ca2+ influx through synaptic N-methyl DAspartate receptors (NMDARs). Identification and study of these, and other neuroprotective signalling pathways of the CNS, is invaluable; as this may one day lead to therapeutic strategies against the deleterious effects of CNS injury or degeneration. The data presented in this thesis focuses on activity-dependent neuroprotection and how it interacts with other signalling pathways to protect against apoptotic and oxidative insults. A previously unobserved role of activity-dependent neuroprotection in mediating the effects of the neuropeptide PACAP is demonstrated. By promoting cAMP/PKA signalling PACAP triggers neuronal firing activity, which is essential for the neuroprotective effects mediated by PACAP. This firing activity cooperates with direct signalling by PKA in promoting longlasting CREB-mediated gene expression. The molecular events associated with PACAP mediated stimulation of CRE-dependent gene expression are presented. Investigation of the control of neuronal antioxidant defences by neuronal activity, both on its own and in cooperation with astrocyte-derived support, was also investigated. Neuronal activity is demonstrated to strongly increase the capacity of the antioxidant glutathione (GSH) system, through a program of coordinated transcriptional events. The utilisation, biosynthesis and recycling of GSH is enhanced in neurons, leading to increased resistance against oxidative insults. Since several GSH pathway enzyme genes are regulated by the transcription factor Nrf2, the ability of CDDO-F3, a small molecule activator of Nrf2, to mimic the effect of firing activity on neuronal GSH levels was examined. CDDO-F3 sustains neuronal GSH levels and confers neuroprotection against oxidative insult. These actions are dependent on the presence of astrocytes; whereas Nrf2 mediated regulation of GSH pathway genes is essentially inactive in neurons. Neuronal activity and activation of the astrocytic Nrf2 pathway can cooperate, maintaining neuronal GSH levels and protecting neurons against strong oxidative insults. Collectively this work expands our knowledge as to the molecular mechanisms of activity-dependent neuroprotection, and how such signals may synergise with other protective pathways to promote neuronal health.

L’encéphalopathie néonatale (EN) affecte plus de 0.8% des nouveau-nés à terme et est la deuxième cause d’handicap neurologique durant l’enfance. Le traitement des enfants atteints d’EN consiste en une prise en charge symptomatique et en l’hypothermie (HT). Néanmoins, plus de 50% des patients traités par HT gardent des séquelles neurologiques majeures. Les données provenant du Canadian Cerebral Palsy Registry montrent que l’HT prévient seulement 4% des cas de paralysie cérébrale (PC). Le fait que l’HT ait des effets neuroprotecteurs chez certains nouveau-nés, mais pas chez tous les nouveau-nés atteints d’EN n’est pas encore totalement élucidé. Il a été rapporté que les nouveau-nés exposés à l’inflammation (sepsis néonatal, infections placentaires) et à l’hypoxie-ischémie (HI) semblent avoir moins d’effets bénéfiques de l’HT que ceux qui ont été seulement exposés à l’HI. Des études précliniques ont établi que l’HT avait des effets neuroprotecteurs dans les cas d’encéphalopathies hypoxique-ischémiques chez les nouveau-nés à terme ou peu prématurés (plus de 35 semaines d’âge gestationnel). Cependant, peu d’études ont investigué les effets de l’HT lorsque l’EN résulte de la combinaison d’HI et d’infection/inflammation, alors qu’il s’agit du scénario pathophysiologique le plus fréquemment rencontré chez les nouveau-nés humains atteints d’EN. Ceci nous a amené à tester les effets neuroprotecteurs de l’HT dans un modèle animal (rat) d’EN induite par l’inflammation et l’HI. Des ratons Lewis au jour postnatal 12 sont injectés avec du lipopolysaccharide (LPS) d’E.coli afin de recréer l’inflammation, puis sont soumis à l’ischémie (ligature de la carotide commune droite) et à l’hypoxie (8% O[indice inférieur 2], 1h30). Les ratons sont ensuite traités ou non par l’HT (32 ± 0.5°C, 4 h). L‘étendue des lésions cérébrales ainsi que les cascades inflammatoires et oxydatives ont été étudiées. Nos résultats montrent que l’HT prévient l’étendue des lésions dans la composante de pénombre ischémique (néocortex et hippocampe). Cet effet neuroprotecteur est indépendant d’un effet anti-inflammatoire cérébral de l’HT portant sur le système de l’interleukine-1. Nos données indiquent que l’HT module l’expression des enzymes responsables de l’élimination des réactifs de l’oxygène (ROS). En conclusion, nos résultats montrent que l'HT a des effets neuroprotecteurs dans un modèle d’EN induite par l’exposition combinée au LPS et à l’HI. Ce projet devrait ouvrir des perspectives translationnelles pour prévenir la PC au-delà de l'hypothermie seule, comme par exemple celle visant à tester le bénéfice de la combinaison thérapeutique d’HT jointe au blocage de cytokines pro-inflammatoires.