Tackling issues in the path toward clinical translation in brain conditioning: Potential offered by nutraceuticals

International audienceBrief periods of ischemia have been shown in many experimental setups to provide tolerance against ischemia in multiple organs including the brain, when administered before (preconditioning) or even after (postconditioning) the normally lethal ischemia. In addition to these so-called ischemic conditionings, many pharmacological and natural agents (e.g., chemicals and nutraceuticals) can also act as potent pre-and post-conditioners. Deriving from the original concept of ischemic preconditioning, these various conditioning paradigms may be promising as clinical-stage therapies for prevention of ischemic-related injury, especially stroke. As no proven experimentally identified strategy has translated into clinical success, the experimental induction of neuroprotection using these various conditioning paradigms has raised several questions, even before considering translation to clinical studies in humans. The first aim of the review is to consider key questions on preclinical studies of pre-or post-conditioning modalities including those induced by chemical or nutraceuticals. Second, we make the argument that several key issues can be addressed by a novel concept, nutraceutical preconditioning. Specifically, α-linolenic acid (alpha-linolenic acid [ALA] an omega-3 polyunsaturated fatty acid), contained in plant-derived edible products, is essential in the daily diet, and a body of work has identified ALA as a pre-and post-conditioner of the brain. Nutritional intervention and functional food development are an emerging direction for preventing stroke damage, offering the potential to improving clinical outcomes through activation of the endogenous protective mechanisms known collectively as conditioning

Alpha-linolenic acid: A promising nutraceutical for the prevention of stroke

International audienceStroke is a worldwide main cause of mortality and morbidity. Most of the preventive and neuroprotective treatments identified in preclinical studies failed in clinical trials. Although there is a consensus that nutrition is important for health, its role is underestimated in stroke. Indeed an increase consumption of salt and fatty foods may promote hypertension and obesity, which are well known risk factors of stroke. In contrast it is more difficult to identify a risk factor arising from a deficiency in an essential nutrient in the diet. Western modern diets are deficient in omega-3 polyunsaturated fatty acids, which are essential for brain health. Such deficiency may constitute by itself a risk factor for stroke. Furthermore, an imbalance in the consumption of omega-6 and omega-3 progressively took place in the past 40 years leading to omega-6/omega-3 ratios that are far above the WHO healthy recommendations. A consequence of this imbalanced ratio has been the fostering of elevations in and increased prevalence of inflammatory cardiovascular diseases and obesity. In this context, this review outlines a promising therapeutic opportunity by integrating a nutritional-based approach focusing on omega-3 alpha-linolenic acid as nutraceutical to prevent the devastating damage caused by brain ischemia

Conditioning Medicine A new pharmacological preconditioning-based target: from drosophila to kidney transplantation

International audienceOne of the biggest challenges in medicine is to dampen the pathophysiological stress induced by an episode of ischemia. Such stress, due to various pathological or clinical situations, follows a restriction in blood and oxygen supply to tissue, causing a shortage of oxygen and nutrients that are required for cellular metabolism. Ischemia can cause irreversible damage to target tissue leading to a poor physiological recovery outcome for the patient. Contrariwise, preconditioning by brief periods of ischemia has been shown in multiple organs to confer tolerance against subsequent normally lethal ischemia. By definition, preconditioning of organs must be applied preemptively. This limits the applicability of preconditioning in clinical situations, which arise unpredictably, such as myocardial infarction and stroke. There are, however, clinical situations that arise as a result of ischemia-reperfusion injury, which can be anticipated, and are therefore adequate candidates for preconditioning. Organ and more particularly kidney transplantation, the optimal treatment for suitable patients with end stage renal disease (ESRD), is a predictable surgery that permits the use of preconditioning protocols to prepare the organ for subsequent ischemic/reperfusion stress. It therefore seems crucial to develop appropriate preconditioning protocols against ischemia that will occur under transplantation conditions, which up to now mainly referred to mechanical ischemic preconditioning that triggers innate responses. It is not known if preconditioning has to be applied to the donor, the recipient, or both. No drug/target pair has been envisioned and validated in the clinic. Options for identifying new target/drug pairs involve the use of model animals, such as drosophila, in which some physiological pathways, such as the management of oxygen, are highly conserved across evolution. Oxygen is the universal element of life existence on earth. In this review we focus on a very specific pathway of pharmacological preconditioning identified in drosophila that was successfully transferred to mammalian models that has potential application in human health. Very few mechanisms identified in these model animals have been translated to an upper evolutionary level. This review highlights the commonality between oxygen regulation between diverse animals

Omega-3 Alpha-linolenic acid supplementation as disease-modifier promoting functional recovery and targeting toxic CCL2 post-stroke inflammatory response

L’accident vasculaire cérébral (AVC) est l’une des principales causes de mortalité dans le monde. Sile taux de de mortalité associé à l’AVC a sensiblement diminué dans les dernières décennies, cela estprincipalement du à l’amélioration globale de l’état de santé de la population et non à la découverte d’untraitement thérapeutique contre l’AVC et de nombreux survivants garderont des séquelles. Dans ce contexte,l’influence de la nutrition qui pourrait jouer un rôle central dans la résistance à l’AVC reste très peu étudier.Pourtant de nombreuses études épidémiologiques confèrent des propriétés protectrices à certaines moléculesnaturelles comme les acides gras polyinsaturés oméga-3.Dans un modèle murin d’AVC, notre laboratoire ayant montré que la consommation d’un régimeenrichi en acide a-linolénique (ALA), l’oméga-3 végétal, réduisait le volume d’infarctus cérébral, mestravaux ont porté sur l’effet de la supplémentation nutritionnelle en ALA. J’ai montré que la supplémentationen ALA par voie orale ou intraveineuse favorise la récupération cognitive post-AVC. Ces bénéfices sontassociés à la préservation des neurones de l’hippocampe, une structure cérébrale impliquée dans la mémoire.Par la suite, je me suis intéressé à l’effet de l’ALA sur la réponse inflammatoire pos-AVC, une composantemajeure dans l’étendue des séquelles. J’ai pu ainsi caractériser le rôle neurotoxique de la chimiokine CCL2 etd’identifier la réduction de son expression post-AVC, comme un facteur clé de la protection cérébrale induitepar la supplémentation en ALA. De plus, une étude collaborative nous a permis de mettre en évidencel’implication de la voie de signalisation de cette chimiokine dans la perte de poids induite par uneinflammation du système nerveux central. Mes travaux soulignent l’importance de la supplémentation en ALA pour réduire les conséquences d’un AVC, en ciblant la réponse pro-inflammatoire post-ischémique, apportant une preuve supplémentaire del’intérêt de l’ALA contre l’une des priorités les plus urgentes de la médecineStroke is a worldwide major cause of mortality and morbidity without any therapeutic opportunities.While improvements in population health - in the control of major risk factors of stroke - over the pastdecades have contributed to reduced stroke mortality, numerous therapeutics applied acutely after stroke havefailed to improve long-term clinical outcomes. Weirdly, how nutrition may affect stroke damage and recoveryhas not yet been intensely investigated, which is surprising given its great influence as risk factor. Therefore,our lab is investigating an emerging view that is the health potential of a-linolenic acid (ALA is the omega-3contained in plant-derived edible products) in stroke.Our laboratory has previously shown that ALA injections or dietary supplementation reduces strokedamage by direct neuroprotection in rodent models of stroke. As successful translation of putative therapieswill depend on demonstration of efficacy on stroke-induced motor and cognitive deficits, my PhD work hasevaluated the value of ALA supplementation in stroke recovery. I demonstrated that oral and intravenoussupplementation of ALA improved cognitive recovery, which was associated to a better preservation ofhippocampus, a brain structure involved in memory. Looking for mechanistic insights, I also investigated theeffect of ALA supplementation by modification of the daily diet on post-stroke inflammatory response. Wefirst demonstrated a neurotoxic role of the chemokine CCL2 after stroke and identified its reduction, as a keyfactor in brain protection induced by ALA supplementation. In addition, I also contributed to a collaborativestudy deciphering the role of CCL2 in weight loss induced by inflammation of the central nervous system.To conclude, my PhD highlights the importance of ALA supplementation to reduce the consequencesof stroke, targeting post-ischemic pro-inflammatory response and prepare the ground of clinical trial onnutritional interventions that are yet to be evaluate

L’Acide Alpha-Linolénique, précurseur végétal des oméga-3 pour lutter contre les dommages liés à l’accident vasculaire cérébral

Stroke is a worldwide major cause of mortality and morbidity without any therapeutic opportunities.While improvements in population health - in the control of major risk factors of stroke - over the pastdecades have contributed to reduced stroke mortality, numerous therapeutics applied acutely after stroke havefailed to improve long-term clinical outcomes. Weirdly, how nutrition may affect stroke damage and recoveryhas not yet been intensely investigated, which is surprising given its great influence as risk factor. Therefore,our lab is investigating an emerging view that is the health potential of a-linolenic acid (ALA is the omega-3contained in plant-derived edible products) in stroke.Our laboratory has previously shown that ALA injections or dietary supplementation reduces strokedamage by direct neuroprotection in rodent models of stroke. As successful translation of putative therapieswill depend on demonstration of efficacy on stroke-induced motor and cognitive deficits, my PhD work hasevaluated the value of ALA supplementation in stroke recovery. I demonstrated that oral and intravenoussupplementation of ALA improved cognitive recovery, which was associated to a better preservation ofhippocampus, a brain structure involved in memory. Looking for mechanistic insights, I also investigated theeffect of ALA supplementation by modification of the daily diet on post-stroke inflammatory response. Wefirst demonstrated a neurotoxic role of the chemokine CCL2 after stroke and identified its reduction, as a keyfactor in brain protection induced by ALA supplementation. In addition, I also contributed to a collaborativestudy deciphering the role of CCL2 in weight loss induced by inflammation of the central nervous system.To conclude, my PhD highlights the importance of ALA supplementation to reduce the consequencesof stroke, targeting post-ischemic pro-inflammatory response and prepare the ground of clinical trial onnutritional interventions that are yet to be evaluatedL’accident vasculaire cérébral (AVC) est l’une des principales causes de mortalité dans le monde. Sile taux de de mortalité associé à l’AVC a sensiblement diminué dans les dernières décennies, cela estprincipalement du à l’amélioration globale de l’état de santé de la population et non à la découverte d’untraitement thérapeutique contre l’AVC et de nombreux survivants garderont des séquelles. Dans ce contexte,l’influence de la nutrition qui pourrait jouer un rôle central dans la résistance à l’AVC reste très peu étudier.Pourtant de nombreuses études épidémiologiques confèrent des propriétés protectrices à certaines moléculesnaturelles comme les acides gras polyinsaturés oméga-3.Dans un modèle murin d’AVC, notre laboratoire ayant montré que la consommation d’un régimeenrichi en acide a-linolénique (ALA), l’oméga-3 végétal, réduisait le volume d’infarctus cérébral, mestravaux ont porté sur l’effet de la supplémentation nutritionnelle en ALA. J’ai montré que la supplémentationen ALA par voie orale ou intraveineuse favorise la récupération cognitive post-AVC. Ces bénéfices sontassociés à la préservation des neurones de l’hippocampe, une structure cérébrale impliquée dans la mémoire.Par la suite, je me suis intéressé à l’effet de l’ALA sur la réponse inflammatoire pos-AVC, une composantemajeure dans l’étendue des séquelles. J’ai pu ainsi caractériser le rôle neurotoxique de la chimiokine CCL2 etd’identifier la réduction de son expression post-AVC, comme un facteur clé de la protection cérébrale induitepar la supplémentation en ALA. De plus, une étude collaborative nous a permis de mettre en évidencel’implication de la voie de signalisation de cette chimiokine dans la perte de poids induite par uneinflammation du système nerveux central. Mes travaux soulignent l’importance de la supplémentation en ALA pour réduire les conséquences d’un AVC, en ciblant la réponse pro-inflammatoire post-ischémique, apportant une preuve supplémentaire del’intérêt de l’ALA contre l’une des priorités les plus urgentes de la médecin

Alpha-linolenic acid: A promising nutraceutical for the prevention of stroke

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Alpha-Linolenic Acid: An Omega-3 Fatty Acid with Neuroprotective Properties—Ready for Use in the Stroke Clinic?

International audienceAlpha-linolenic acid (ALA) is plant-based essential omega-3 polyunsaturated fatty acids that must be obtained through the diet. This could explain in part why the severe deficiency in omega-3 intake pointed by numerous epidemiologic studies may increase the brain's vulnerability representing an important risk factor in the development and/or deterioration of certain cardio- and neuropathologies. The roles of ALA in neurological disorders remain unclear, especially in stroke that is a leading cause of death. We and others have identified ALA as a potential nutraceutical to protect the brain from stroke, characterized by its pleiotropic effects in neuroprotection, vasodilation of brain arteries, and neuroplasticity. This review highlights how chronic administration of ALA protects against rodent models of hypoxic-ischemic injury and exerts an anti-depressant-like activity, effects that likely involve multiple mechanisms in brain, and may be applied in stroke prevention. One major effect may be through an increase in mature brain-derived neurotrophic factor (BDNF), a widely expressed protein in brain that plays critical roles in neuronal maintenance, and learning and memory. Understanding the precise roles of ALA in neurological disorders will provide the underpinnings for the development of new therapies for patients and families who could be devastated by these disorders

A functional cerebral endothelium is necessary to protect against cognitive decline

A vascular insult occurring early in disease onset may initiate cognitive decline leading to dementia, while pharmacological and lifestyle interventions can prevent this progression. Mice with a selective, tamoxifen-inducible deletion of NF-κB essential modulator (Nemo) in brain endothelial cells were studied as a model of vascular cognitive impairment. Groups included Nemo(Fl) controls and three Nemo(beKO) groups: One untreated, and two treated with simvastatin or exercise. Social preference and nesting were impaired in Nemo(beKO) mice and were not countered by treatments. Cerebrovascular function was compromised in Nemo(beKO) groups regardless of treatment, with decreased changes in sensory-evoked cerebral blood flow and total hemoglobin levels, and impaired endothelium-dependent vasodilation. Nemo(beKO) mice had increased string vessel pathology, blood-brain barrier disruption, neuroinflammation, and reduced cortical somatostatin-containing interneurons. These alterations were reversed when endothelial function was recovered. Findings strongly suggest that damage to the cerebral endothelium can trigger pathologies associated with dementia and its functional integrity should be an effective target in future therapeutic efforts