There is increasing evidence that inflammatory processes play a pivotal role in the pathophysiology of ischaemic brain injury. Cerebrovascular endothelial cells that form the blood-brain barrier are critical for maintaining brain homeostasis, however, during cerebral ischaemia they contribute to the post-ischaemic inflammatory responses. It is not yet fully understood how different cerebral cells interact during this inflammatory response. This study aimed to test the hypothesis that oxygen-glucose deprivation (OGD) induces the inflammatory activation of the cerebrovascular endothelium and glial cells in vitro and that intercommunication between these cells regulate their responses to OGD. Primary murine brain endothelial cells (MBECs) monocultures, murine mixed-glial monocultures and MBEC-glial co-cultures were exposed to OGD for up to 24 hours (h), then reperfused cultures were returned to normoxia for a further 24 hours. MBECs and glia remained viable over a 24 h OGD exposure and during reperfusion. OGD induced a time-dependent increase in MBEC glucose transporter 1 (GLUT-1) expression but a time-dependent decline in expression and secretion of monocyte chemoattractant protein-1 (MCP-1). A significant increase in keratinocyte-derived chemokine (KC) secretion by MBEC monocultures was observed during reperfusion after prolonged exposure (18-24 h) to OGD whereas, KC secretion by co-cultured MBECs was increased during reperfusion after short exposure (4 h) to OGD. Co-cultured MBECs displayed a significant increase in intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) expression in response to a short or prolonged exposure to OGD with 24 h of reperfusion. Neither OGD nor reperfusion had any effect on permeability of the MBEC monolayer. OGD induced a time-dependent increase in nuclear stabilisation of hypoxia inducible factor-1 alpha (HIF-1α) in glial cells which correlated to vascular endothelial growth factor (VEGF) secretion during OGD and subsequent reperfusion. Nuclear stabilisation of the nuclear factor kappa B (NFκB)p65 subunit by glial cells was dependent upon the duration of OGD. Reperfusion induced a significant increase in KC secretion by co-cultured glial cells after short exposure to OGD. Inflammatory activation of co-cultured MBECs and glia after 4 or 24 h OGD caused a significant increase in neutrophil transendothelial migration which correlated with MBEC expression of ICAM-1 and VCAM-1. A combination of these cell adhesion molecules with neutrophil integrins and soluble glial-derived mediators contributed to neutrophil transendothelial migration. These studies provide evidence that combined hypoxia and glucose withdrawal induces the activation of MBECs and glial cells in vitro. Cross-talk between these two cell types may further regulate their activation. As a result of this inflammatory activation, soluble MBEC and glial-derived mediators may contribute to neutrophil transendothelial migration through the regulation of MBEC cell adhesion molecule expression.

Lacunar strokes account for approximately a quarter of all ischaemic strokes and traditionally are thought to result from occlusion of a small deep perforating arteriole in the brain. Lacunar infarcts can be up to 2cm in diameter and are found in deep brain structures such as the thalamus and internal capsule. Despite their prevalence and specific accompanying clinical syndromes, the cause of lacunar stroke and its associated vascular pathology remain unclear. Many hypotheses as to the cause exist, which fall broadly into two categories; firstly, a direct occlusion via emboli or thrombus usually from a cardiac or large artery source, microatheroma (intrinsic lenticulostriate occlusion) or macroatheroma (parent artery occlusion) all operating primarily via ischaemia. Secondly, there could be an indirect occlusion resulting from vasospasm, endothelial dysfunction or other forms of endovascular damage (e.g. inflammation). Therefore the question of whether the resulting lesions are truly “ischaemic” or actually arise secondary to an alternative process is still under debate. To clarify the chain of pathological events ultimately resulting in lacunar stroke, in this thesis I firstly undertook a systematic assessment of human lacunar stroke pathology literature to determine the information currently available and the quality of these studies (including terminology). The majority of these studies were performed in patients who had died long after their stroke making it difficult to determine the early changes, and there were few patients with a clinically verified lacunar syndrome. Therefore I adopted alternative approaches. In this thesis, I systematically looked for all potential experimental models of lacunar stroke and identified what appears at present to be the most pertinent - the spontaneous pathology of the stroke-prone spontaneously hypertensive rat (SHRSP). However, the cerebral pathology described in this model to date is biased towards end stage pathology, with little information concerning the microvasculature (as opposed to the brain parenchyma) and confounding by use of salt to exacerbate pathology. Therefore, the aim of the experimental work in this thesis was to assess pathological changes within the cerebral vasculature and brain parenchyma of the SHRSP across a variety of ages (particularly young pre-hypertensive animals) and to look at the effects of salt loading on both the SHRSP and its parent strain (the Wistar Kyoto rat - WKY). Three related studies (qualitative and quantitative histology, immunohistochemistry and a microarray study of gene expression confirmed by quantitative PCR), revealed that the presence of inflammation (via significant changes in gene expression in the acute phase response pathway and increased immunostaining of activated microglia and astrocytes) plus alterations in vascular tone regulation, (via genetic alteration of the nitric oxide signaling pathway probably secondary to abnormal oxidative state), impaired structural integrity of the blood brain barrier (histological evidence of endothelial dysfunction and significantly decreased Claudin-5 staining) and reduced plasma oncotic potential (reduced albumin gene expression) are all present in the native SHRSP at 5 weeks of age, i.e. well before the onset of hypertension and without exposure to high levels of salt. We also confirmed previous findings of vessel remodelling at older ages likely as a secondary response to hypertension (thickened arteriolar smooth muscle, increased smooth muscle actin immunostaining). Furthermore, we found not only that salt exacerbated the changes see in the SHRSP at 21 weeks, but also that the control animals (WKY) exposed to a high salt intake developed features of cerebral microvascular pathology independently of hypertension (e.g. white matter vacuolation and significant changes in myelin basic protein expression). In conclusion, via the assessment of the most pertinent experimental model of lacunar stroke currently available, this thesis has provided two very important pieces of evidence: firstly that cerebral small vessel disease is primarily caused by a non-ischaemic mechanism and that any thrombotic vessel lesions occur as secondary end stage pathology; secondly that these features are not simply the consequence of exposure to raised blood pressure but occur secondary to abnormal endothelial integrity, inflammation, abnormal oxidative pathways influencing regulation of vascular tone and low plasma oncotic pressure. Patients with an innate susceptibility to increased blood brain barrier permeability and/or chronic inflammation could therefore have a higher risk of developing small vessel disease pathology and ultimately lacunar stroke and other features of small vessel disease. Research, addressing whether lacunar stroke patients should be treated differently to those with atherothromboembolic stroke is urgently needed.

Introduction. The glial cell water channel aquaporin-4 (AQP4) plays an important ro le in brain oedema, astrocyte migration and neuronal excitability. Current theories of AQP4 function are based largely on experiments using AQP4 -1- mice. These mice have only been partially characterized. I therefore undertook a detailed investigation of baseline brain properties in AQP4 -1- mice. In the second part of my experiments I investigated the role of AQP4 in brain oedema in a mouse model of subarachnoid haemorrhage. Method. Gross anatomical measurements included estimates of brain and ventricle size. Neurons, astrocytes and oligodendrocytes were assessed using the neuronal nuclear marker NeuN, the astrocyte marker GFAP, and the myelin stain Luxol Fast Blue. The blood brain barrier was studied by electron microscopy and the horseradish peroxidase extravasation technique. A mouse model in which 30~1 of autologous blood was injected into the basal cisterns was used to reproduce subarachnoid haemorrhage. Brain water content, intracranial pressure and neurological score were compared in wildtype and AQP4 -/- mice. I also measured blood brain barrier permeability and the osmotic permeability of the glia lim itans, one of the routes of oedema elimination.

L'aspirine est l'anti-plaquettaire le plus largement prescrit à la phase aiguë de l'accident vasculaire cérébral (AVC) ischémique. Cependant, la survenue de récidives, malgré cette prescription, est fréquente. La description de l'effet de l'aspirine sur l'activité plaquettaire durant cette phase n'a jamais été réalisée. Elle pourrait mettre en évidence une moindre réponse plaquettaire et aider à établir de nouvelles stratégies thérapeutiques. Cinquante patients, ont reçu par voie orale 300 mg d'aspirine, suite à un AVC ischémique. Ensuite, des prélèvements sanguins ont été réalisés : entre 2 et 3 heures (T1), entre 23 et 24 heures (T2) après la prise d'aspirine et, pour des patients déjà traités quotidiennement par une dose inférieure, avant la prise d'aspirine (T0). Les concentrations sériques de thromboxane (TX) B2 ont été mesurées, ainsi que les agrégations induites par l'acide arachidonique, par le collagène à la concentration de 2µg/L (Col2) et 20 µg/L (Col20). Afin de diminuer l'effet des variations de condition d'expérience, les résultats pour Col2 ont été rapportés à ceux pour Col20 (Col2/20). Tous les patients ont présenté une réponse à l?aspirine visible à T1 avec de plus, des concentrations de TXB2 abaissées en comparaison à T0. Il existe une récupération de l'activité plaquettaire à T2 comparée à T1, montrée par les concentrations de TXB2 et le rapport Col2/20. La dose orale de 300 mg d'aspirine, donnée à la phase aiguë de l'AVC, entraîne une inhibition plaquettaire, mais avec une récupération visible sur 24 heures. Pour les patients déjà traités quotidiennement par une dose inférieure, elle permet de compléter l'inhibition de la voie TXA2 dépendante / Aspirin is the most commonly used antiplatelet treatment during the acute phase of cerebral ischemic events. But, despite this protection, early ischemic recurrences are frequent, and considered as clinical failures of this therapy. We studied laboratory parameters of the first 300 mg oral dose of aspirin given, within 48 hours, after ischemic cerebral event. Fifty patients were included. For all patients, two blood sampling were performed, the first, during the third hour after aspirin intake (T1) and the second during the twenty-fourth hour (T2). For patients already treated with a daily dose of aspirin, a supplementary withdrawn was done before aspirin intake (T0). Platelet reactivity was studied on the basis of serum thromboxane (TX) B2 levels and light transmission aggregometry after stimulation of platelet-rich plasma by acid arachidonic and collagen 2µg/mL reported to results with collagen 20 µg/mL (ratio Col2/20). Inhibition of platelet activity was observed, at T1, for all patients. There is a significant increase of TXB2 values, and of relative values of the ratio Col2/20, at T2 as compared to T1. For already aspirin treated patients, there is a significant decrease of TXB2 levels at T1 as compared to T0. There is a platelet reactivity recovery within 24 hours, following the first 300 mg oral dose of aspirin, during the acute phase of a cerebral ischemic event, and demonstrated by TXB2 levels and ratio Col2/20. This fact would favour early ischemic recurrences. However, this dose is able to complete the inhibition of the TXA2 pathway for already aspirin treated patients

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La prise en charge de l’aphasie en phase aiguë de l’accident vasculaire cérébral a été au centre de mon activité d’orthophoniste à l’assistance publique pendant 20 ans. Au cours de ces années, j’ai pu développer une activité de recherche en parallèle de mon activité clinique. En particulier, je me suis intéressée à l’évaluation et à la prise en charge très précoce de l’aphasie dans le contexte d’AVC en phase très aiguë. Un outil d’évaluation de l’aphasie a pu être élaboré dans le service, et a ensuite été le centre de plusieurs travaux : son adaptation dans d’autres langues, la comparaison de l’aphasie et le l’hémiplégie, la détermination de profils aphasiologiques types… Le champ de l’aphasiologie est très vaste et il reste de nombreux axes de recherche à approfondir. Notre outil d’évaluation de phase aiguë pourrait participer à apporter la preuve du bénéfice d’une prise en charge précoce de l’aphasie, et pourrait également permettre de proposer une nouvelle classification des aphasies. / The management of aphasia in the acute phase of stroke has been the focus of my speech therapist activity in a public hospital for 20 years. During these years I have been able to develop a research activity in parallel with my clinical activity. In particular, I was interested in the assessment and the treatment of aphasia in the context of the very acute phase of stroke. An assessment tool for aphasia has been developed in the stroke unit, and was then the center of several studies: its adaptation into other languages, the comparison of aphasia and hemiplegia, determining aphasiological profiles kinds...The field of aphasiology is very broad and there are still many areas of research to pursue. Our screening tool of aphasia could participate to prove the benefit of an early treatment of aphasia, and could also allow proposing a new classification of aphasia.

The role of CEA for stroke prevention in the presence of symptomatic carotid artery stenosis is well established. In order to maximize the benefit of surgery, several perioperative processes of care have been under scrutiny, of which one is the choice of anaesthetic method. The differing effects of GA vs. LA on the cerebral circulation after CEA may be of significance, since changes in the cerebral circulation post-CEA may give rise to cerebral hyperperfusion and intracerebral haemorrhage. This work assessed the effect of GA vs. LA on cerebral haemodynamic control after CEA using transcranial Doppler (TCD) techniques, and correlated these changes with serum markers of cerebral injury. Subjects undergoing CEA had perioperative TCD monitoring of middle cerebral artery blood flow velocity (MCAV). Pre- and postoperative (within 48 hours of surgery) testing of cerebral autoregulation [CA] (tilt-testing) and cerebral vasoreactivity to CO2 [CVR] (rebreathing expired air) was conducted. Cerebral haemodynamic parameters and clinical outcome were correlated with changes in jugular venous and peripheral levels of protein S100β and neurone-specific enolase (NSE).The change in CA and CVR was not different between GA (n=16) and LA (n=20). Overall, CA and CVR improved significantly within 48 hours of CEA for patients with preoperative impairment of these parameters, although some patients with normal baseline CA and CVR exhibited postoperative impairment. Increase of MCAV >100% from baseline after restoration of carotid blood flow was observed in patients with impaired CVR, but resolved by the first postoperative day. Transient elevation in jugular venous (but not peripheral) S100β during surgery was seen. Both jugular and peripheral NSE levels dropped during surgery. Neither anaesthetic method nor CA or CVR status had any effect on changes in serum S100β or NSE. Cerebral autoregulatory parameters thus improve rapidly after CEA, but appear unaffected by anaesthetic technique. This supports the concept that cerebral hyperperfusion is dependent on factors in addition to impaired CA or CVR. Changes in serum S100β or NSE do not reflect cerebral haemodynamic changes. However, the variability encountered between patients warrants further investigation. The implications for clinical practice and directions for further research are discussed.

Les micro-saignements cérébraux (MSC) sont des dépôts d’hémosidérine particulièrement visibles sur des séquences IRM sensibles à la susceptibilité magnétique, comme par exemple la séquence en écho de gradient pondérée (GRE) en T2*. Néanmoins, leur détection in-vivo à partir de l’image d'amplitude GRE T2* obtenue en routine clinique est peu exacte et très sensible aux paramètres d’acquisition. Une détection automatique des MSC permettrait d’augmenter la portée et la pertinence de cette séquence, mais il est avant tout nécessaire de mieux caractériser les MSC pour augmenter la spécificité de détection. Cette thèse présente une nouvelle méthode pour extraire l’information d’intérêt (la carte champ interne) à partir d’images de phase obtenues avec les mêmes acquisitions cliniques GRE T2*. En effet, l’image de phase T2* contient directement une information sur la susceptibilité et pourrait donc améliorer la détection des MSC. Cette méthode a été évaluée avec succès sur des données multicentriques de qualité compatible avec la routine clinique pour des sujets avec un nombre très variable de MSC et a permis de différencier les MSC des micro-calcifications. Une étude de validation a également été menée pour évaluer l’utilité clinique de la carte de champ interne pour la détection par un expert, par rapport à d’autres types d’images et reconstructions utilisées en clinique. Elle a montré une amélioration de la spécificité. La thèse comprend également une preuve de concept d’une méthode d’identification automatique utilisant l’information provenant de plusieurs types d’image et de reconstruction afin d’augmenter la spécificité de l’identification. L’évaluation est menée sur les sujets précédemment décrits. Cette preuve de concept est basée sur un algorithme d’apprentissage supervisé ; cela consiste à combiner les informations issues des différents types d’image à partir desquels des descripteurs d’intensités et de forme ont été extraits pour créer un modèle de prédiction permettant discriminer les MSC. / CMBs, small hypo-intense foci with a maximum diameter of 10 millimeters, were first thought clinically silent. They are now considered as an imaging marker of cerebral small vessel diseases and their clinical involvement is increasingly recognized; they may be associated with an increased risk of hemorrhagic stroke, ischemia and dementia such as Alzheimer's disease. However, their relation with pathology and its causality remains largely to be understood, partly because of their tricky characterization in-vivo. Large scale studies or meta-analyses are made difficult because their identification varies with MRI sequence parameters and suffers from reproducibility issues and is time-consuming. Automatic identification methods have been proposed to address these issues but they all require manual post processing selection steps, because of a very high number of false positives. This suggests that a better characterization of CMBs may be the key to improve their detection, as it would allow better identifying them from misleading structures and lesions.This PhD focused on achieving a better characterization of CMBs to better detect them with an automatic method. It covers multiple aspects to improve CMBs identification. First, MR phase image was taken into account in addition to the standard MR magnitude image, because of its sensitivity to CMBs. A new MR phase image processing technique was thus developed to obtain the magnetic field of interest free of contamination from background sources in datasets equivalent to clinical routine. A comparison study was carried-out to evaluate the outcome of this tool for CMBs detection in a standardized dataset in a clinical environment. A proof-of-concept is given to illustrate the advantages of new features for automatically identifying CMBs.

Les Accidents Vasculaires Cérébraux (AVC) sont un groupe de maladies à morbi-mortalité élevée, classés parmi les causes les plus communes de décès et de handicap acquis dans le monde. Ainsi, leur épidémiologie jouerait un rôle crucial dans la diminution de leur impact sur la population. Les pays en voie de développement sont aujourd'hui les plus responsables de l'augmentation de la fréquence de la maladie, vu que la sensibilisation des gens et l'amélioration de la prise en charge dans les pays développés a permis de contrôler à un certain degré l'incidence et la mortalité de la maladie dans ces pays. Au Liban, un pays en voie de développement du Moyen Orient, les études épidémiologiques concernant les AVC sont relativement rares, malgré que nécessaires. En effet, le pays confronte le problème de vieillissement de sa population et des taux très élevés de tabagisme, et à un moindre degré d'obésité, hypertension et diabète, comparés aux autres pays. Dans ce contexte, il fallait initier ce travail qui surligne les grands titres de l'épidémiologie des AVC au Liban. Deux études ont été conduites, l'une communautaire transversale pour estimer la prévalence des AVC et la deuxième hospitalière rétrospective pour évaluer d'une part la prévalence des sous-types et leur association aux facteurs de risque et, d'une autre part, la prise en charge précoce de la maladie. Malgré que les résultats obtenus soient peu généralisables, on pourrait dire que la prévalence estimée (5‰ [95% CI= 3.3-6.6‰]) serait liée à l'incidence élevée de la maladie (notamment des athéroscléroses des gros vaisseaux) plutôt qu'à une meilleure prise en charge des AVC en phase aiguë. Des campagnes de sensibilisation des gens au risque et symptômes des AVC surtout parmi les fumeurs aideraient à limiter l'incidence et la sévérité de la maladie. De plus, l'implantation d'unités neurovasculaires diminuerait le taux de mortalité à court terme et les handicaps à long terme. / Stroke is a group of cerebrovascular diseases with high morbidity and mortality rates, classified among the most common causes of death and acquired disability worldwide. Thus, assessing its epidemiology may play a crucial role in reducing its impact on the population. Stroke late burden is attributable to developing countries mainly, as people in developed countries have a better access to optimal care and an increased awareness of stroke symtpoms and risk factors. However, in less developed countries, where population confronts the huge impact of urbanization and globalization with a great increase in the prevalence of cardiovascular risk factors, the incidence of stroke remains high. Lebanon, a developing country of the Middle East region, lacks epidemiological data on stroke burden. Moreover, he confronts the aging problem and very high rates of smoking, and to a lesser degree of obesity, hypertension and diabetes, compared to other countries. In this context, it was necessary to initiate this work to highlight some features of the disease epidemiology in the country. Two studies were conducted, the first one was a community-based cross-sectional study to assess stroke prevalence in the country, whereas the second one was a retrospective hospital-based study to assess stroke prevalence by subtypes and associations with risk factors, and to evaluate stroke acute management in hospitals. Despite that the obtained results were not generalizable, we could state the following: The estimated prevalence of stroke (5 ‰ [95% CI= 3.3-6.6‰]) may be linked to a high incidence of the disease (especially large artery atherosclerosis) rather than a better acute stroke care. Awareness campaigns on stroke risk and symptoms especially among smokers would help limit the incidence and severity of the disease, while the establishment of stroke units may reduce short-term mortality and long term disabilities.

La maladie de Parkinson (MP) est un trouble neurodégénératif caractérisé par une perte progressive de neurones dopaminergiques (DA) de la substance noire pars compacta (SNpc). Différents mécanismes sont associés à la neuropathogénèse de la MP et en particulier le dysfonctionnement de la chaîne respiratoire mitochondriale, le stress oxydatif, l’apoptose et les processus neuro-inflammatoires. L'octadécaneuropeptide (ODN) est un peptide dérivé du diazepam-binding inhibitor (DBI) exprimé par les cellules astrogliales, qui exerce une action neuroprotectrice dans un modèle cellulaire in vitro de la MP. A ce jour, aucune étude in vivo n’a été réalisée, afin de déterminer si les données obtenues sur les modèles cellulaires in vitro peuvent être transposées in vivo. Le projet de cette thèse consiste ainsi à mettre en évidence l’action protectrice de l’ODN sur la survie des neurones DA de la SNpc dans un modèle murin de la MP et à rechercher les conséquences de l’invalidation du gène du précurseur de l’ODN (DBI) sur la vulnérabilité des neurones DA. Les résultats obtenus montrent qu’une seule injection intra-cérébroventriculaire d’une faible quantité d’ODN (10 ng), 1 h après la dernière administration systémique de 1-méthyl-4-phényl-1,2,3,6-tétrahydropyridine (MPTP) prévient significativement la perte des neurones DA dans la substance noire et la dégénérescence de leurs prolongements nerveux vers le striatum comme mesuré par des marquages et des mesures d’expression de la tyrosine hydroxylase. Cet effet neuroprotecteur de l’ODN est accompagné par une réduction du nombre d’astrocytes réactifs, une forte inhibition de l'expression de gènes pro-inflammatoires tels que les interleukines (IL) IL-1β et IL-6, et tumor necrosis factor-α. De plus, l'ODN bloque l'inhibition du gène anti-apoptotique Bcl-2 et la stimulation des gènes pro-apoptotiques Bax et caspase-3, induite par le MPTP dans la SNpc et le striatum. L'ODN réduit également l’accumulation d'espèces réactives de l'oxygène (ROS) et de produits d'oxydation lipidique dans les neurones DA. Par ailleurs, les souris knock-out DBI (DBI-/-) sont plus vulnérables que les animaux sauvages (DBI+/+) vis-à-vis de la neurotoxicité du MPTP. L’absence de production d’ODN endogène, chez les souris DBI-/- parkinsoniennes, augmente les dommages cellulaires induits par le MPTP, la réactivité gliale, les taux de ROS, l’expression de cytokines pro-inflammatoires et l'activité de la caspase-3 dans la région nigro-striée. L’ensemble de ces résultats montre que le gliopeptide ODN exerce un puissant effet neuroprotecteur contre la dégénérescence des neurones DA de la SNpc induite par le MPTP, chez la souris. Cette action protectrice met en jeu des mécanismes impliquant l’inhibition des processus neuro-inflammatoires, oxydatifs et apoptotiques. D’autre part, la déficience en ODN potentialise les effets délétères du MPTP, suggérant que ce peptide joue un rôle clé lors de la réponse à un stress cellulaire. / Parkinson's disease (PD) is a neurodegenerative disorder characterized by a progressive loss of loss of dopaminergic (DA) neurons within the substantia nigra pars compacta (SNpc). Different mechanisms are associated with the neuropathogenesis of PD including dysfunction of the mitochondrial respiratory chain, oxidative stress, apoptosis and neuroinflammatory processes. Octadecaneuropeptide (ODN) is a diazepam-binding inhibitor (DBI)-derived peptide, expressed by astrocytes, which protects neurons against oxidative cell damages and apoptosis in an in vitro model of PD. Nevertheless, its protective action in vivo has never been investigated. Therefore, the aim of the project of this thesis was to investigate whether intracerebroventricular (i.c.v) injection of ODN could prevent DA neuron degeneration in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD, and to explore the vulnerability of ODN precursor knockout (DBI KO) mice to MPTP-induced neurotoxicity. The results show that a single i.c.v injection of 10 ng/μl ODN, 1 h after the last systemic administration of MPTP, prevents the reduction of the number of tyrosine hydroxylase (TH)-positive cell bodies and fibers in the SNpc and striatum, respectively. Immunofluorescence imaging, Western blot analysis and Q-PCR studies revealed that ODN totally abolished MPTP-induced decrease of TH positive cells, mRNA expression and protein levels. This neuroprotective effect of ODN is accompanied by a reduction in the number of reactive astrocytes, an inhibition of the expression of pro-inflammatory genes such as interleukins (IL) IL-1β and IL-6, and a decrease of tumor necrosis factor -α. In addition, ODN blocks the inhibition of the anti-apoptotic Bcl-2 gene and the stimulation of Bax and caspase-3 expression induced by MPTP in the SNpc and striatum. ODN also reduces the accumulation of reactive oxygen species (ROS) and lipid oxidation products in DA neurons. Furthermore, DBI-/- mice exhibited more vulnerability to MPTP than wild-type animals (DBI+/+). Thus, ODN KO mice are more sensitive to MPTP-induced inflammatory and oxidative brain damages, suggesting that the endogenous OD may also be neuroprotective. These results indicate that, based on its anti-oxidative, anti-inflammatory and anti-apoptotic effect, the gliopeptide ODN could lead to the development of effective therapeutic agents for the treatment of cerebral injuries involving oxidative neurodegeneration.