Influence de la chimiokine CCL2 sur la modulation des canaux Nav1.8 et lors la douleur inflammatoire

Il est de nos jours clairement établi que la chimiokine CCL2 est exprimée à l état basal et est sécrétée par les neurones des ganglions rachidiens et de la moelle épinière. Lors de douleurs chroniques, cette chimiokine participe à la mise en place des mécanismes pronociceptifs. Le premier objectif de notre recherche a eu pour but d étudier les effets de CCL2 sur l activité du canal sodique Nav1.8 par la technique de patch clamp sur cellules entières sur les neurones nociceptifs primaires de petit diamètre. En effet, il est clairement établi que l activité du Nav1.8 fait l objet d importants changements au sein de ces neurones lors du développement de douleur chronique inflammatoire. Ainsi les résultats de cette étude électrophysiologique, démontrent que CCL2 (100 nM) augmente de manière significative l amplitude des courants des canaux sodiques TTX Résistant (Nav1.8) en altérant leur cinétique d activation. L implication spécifique du récepteur CCR2 dans ces effets, ne fait aucun doute puisque le traitement par un antagoniste sélectif de ce récepteur (INCB 3344) bloque l hyperexcitabilité du Nav1.8 des neurones sensitifs primaires induite par le CCL2. De plus, afin de valider l implication des sous-unités Gi/o dans les mécanismes associés à l effet de CCL2 sur l activité des canaux Nav1.8, la toxine pertussique (PTX) été utilisée. Les résultats révèlent qu en présence de PTX, aucune altération induite par le CCL2 des courants et propriétés biophysiques de Nav1.8 n est observable. L ensemble de résultats obtenus au cours de cette première étude, nous a permis de démontrer que CCL2 module, de façon spécifique, l activité des courants Nav1.8, au niveau des neurones sensitifsPARIS-BIUSJ-Biologie recherche (751052107) / SudocSudocFranceF

The underlying physiological basis of the desert rodent Meriones shawi's survival to prolonged water deprivation: Central vasopressin regulation on peripheral kidney water channels AQPs-2

International audienceMerlons shawl (M. shawl) is a particular semi-desert rodent known by its resistance to long periods of thirst. The aim of the present investigation is to clarify the underlying mechanisms allowing M. shawl to resist to hard conditions of dehydration. For this reason we used two different approaches: i) a morphometric study, which consists In measuring the effect of dehydration on body and kidneys weights as well as the report kidney weight/body weight, ii) By immunohistochemistry, we proceed to study the effect of dehydration on the immunoreactivity of central vasopressin (AVP) and the kidney aquaporin-2 (AQP-2) which is a channel protein that allows water to permeate across cell membranes. Our results showed both a body mass decrease accompanied by a remarkable kidneys hypertrophy. The immunohistochemical study showed a significant increase of AQP-2 immunoreactivity in the medullar part of Meriones kidneys allowing probably to Meriones a great ability to water retention. Consistently, we demonstrate that the increased AQP-2 expression occurred together with an increase in vasopressin (AVP) expression in both hypothalamic supraoptic (SON) and paraventricular nucleus (PVN), which are a major hub in the osmotic control circuitry. These various changes seen either in body weight and kidneys or at the cellular level might be the basis of peripheral control of body water homeostasis, providing to M. shawia strong resistance against chronic dehydration

Management of Ischemic Stroke during cardiac catheterization: A case report and review of literature

Stroke following coronary interventions is a devastating and most dreaded complication with signiβicant morbidity and mortality. Various factors have been ascribed for this complication including the technical errors [1]. A small percentage of strokes are iatrogenic, including those associated with invasive cardiac procedures. According to the literature, it is a rare complication of left heart catheterization [2]. Percutaneous coronary intervention is increasingly used to treat patients with diffuse atherosclerosis, acute coronary syndromes and even high-risk patients such as low ejection fraction [1]. The authors describe a patient who underwent percutaneous coronary intervention in the context of inferior infarction, which was complicated by ischemic stroke during cardic catheterization

Brain targeting with docosahexaenoic acid as a prospective therapy for neurodegenerative diseases and its passage across blood brain barrier

International audienceDocosahexaenoic acid (DHA, 22:6n-3) is the main omega-3 polyunsaturated fatty acid in brain tissues necessary for common brain growth and function. DHA can be provided to the body through two origins: an exogenous origin, from direct dietary intakes and an endogenous one, from the bioconversion of the essential a-linolenic acid (ALA, 18:3n-3) in the liver. In humans, the biosynthesis of DHA from its precursor ALA is very low. A reduction in the cerebral amount of DHA is detected in patients suffering from neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. Considering the vital functions of DHA for the brain, new methodologies to target the brain with DHA offers encouraging perceptions in the improvement of precautionary and therapeutic approaches for neurodegenerative diseases. The aim of the present review was to provide better understanding of the cerebral uptake of DHA in different form including free fatty acids, Lysophosphatidylcholines LysoPC-DHA as well as structured phospholipids. First, we explored the special structure of the blood-brain barrier BBB, BBB being a physical and metabolic barrier with restrictive properties. Then, we discussed the incorporation of DHA into the membrane phospholipids of the brain, the neuroprotective and therapeutic effect of DHA for neurological diseases. (C) 2020 Elsevier B.V. and Societe Francaise de Biochimie et Biologie Moleculaire (SFBBM)

Mechanisms of DHA transport to the brain and potential therapy to neurodegenerative diseases

Docosahexaenoic acid (DHA; 22:6 omega-3) is highly enriched in the brain and is required for proper brain development and function. Its deficiency has been shown to be linked with the emergence of neurological diseases. Dietary omega-3 fatty acid supplements including DHA have been suggested to improve neuronal development and enhance cognitive functions. However, mechanisms of DHA incorporation in the brain remain to be fully understood. Findings suggested that DHA is better incorporated when esterified within lysophospholipid rather than under its non-esterified form. Furthermore, DHA has the potential to be converted into diverse oxylipins with potential neuroprotective effects. Since DHA is poorly synthesized de novo, targeting the brain with specific carriers of DHA might provide novel therapeutic approaches to neurodegenerative diseases

The pleiotropic effects of omega-3 docosahexaenoic acid on the hallmarks of Alzheimer's disease

Among omega-3 polyunsaturated fatty acids (PUFAs), docosahexaenoic acid (DHA, 22:6n-3) is important for adequate brain development and cognition. DHA is highly concentrated in the brain and plays an essential role in brain functioning. DHA, one of the major constituents in fish fats, readily crosses the blood brain barrier from blood to the brain. Its critical role was further supported by its reduced levels in the brain of Alzheimer's disease (AD) patients. This agrees with a potential role of DHA in memory, learning and cognitive processes. Since there is yet no cure for dementia such as AD, there is growing interest in the role of DHA-supplemented diet in the prevention of AD pathogenesis. Accordingly, animal, epidemiological, preclinical and clinical studies indicated that DHA has neuroprotective effects in a number of neurodegenerative conditions including AD. The beneficial effects of this key omega-3 fatty acid supplementation may depend on the stage of disease progression, other dietary mediators and the apolipoprotein ApoE genotype. Herein, our review investigates, from animal and cell culture studies, the molecular mechanisms involved in the neuroprotective potential of DHA with emphasis on AD

Functional up-regulation of Nav1.8 sodium channel in Aβ afferent fibers subjected to chronic peripheral inflammation.

International audienceBACKGROUND: Functional alterations in the properties of Aβ afferent fibers may account for the increased pain sensitivity observed under peripheral chronic inflammation. Among the voltage-gated sodium channels involved in the pathophysiology of pain, Nav1.8 has been shown to participate in the peripheral sensitization of nociceptors. However, to date, there is no evidence for a role of Nav1.8 in controlling Aβ-fiber excitability following persistent inflammation. METHODS: Distribution and expression of Nav1.8 in dorsal root ganglia and sciatic nerves were qualitatively or quantitatively assessed by immunohistochemical staining and by real time-polymerase chain reaction at different time points following complete Freund's adjuvant (CFA) administration. Using a whole-cell patch-clamp configuration, we further determined both total INa and TTX-R Nav1.8 currents in large-soma dorsal root ganglia (DRG) neurons isolated from sham or CFA-treated rats. Finally, we analyzed the effects of ambroxol, a Nav1.8-preferring blocker on the electrophysiological properties of Nav1.8 currents and on the mechanical sensitivity and inflammation of the hind paw in CFA-treated rats. RESULTS: Our findings revealed that Nav1.8 is up-regulated in NF200-positive large sensory neurons and is subsequently anterogradely transported from the DRG cell bodies along the axons toward the periphery after CFA-induced inflammation. We also demonstrated that both total INa and Nav1.8 peak current densities are enhanced in inflamed large myelinated Aβ-fiber neurons. Persistent inflammation leading to nociception also induced time-dependent changes in Aβ-fiber neuron excitability by shifting the voltage-dependent activation of Nav1.8 in the hyperpolarizing direction, thus decreasing the current threshold for triggering action potentials. Finally, we found that ambroxol significantly reduces the potentiation of Nav1.8 currents in Aβ-fiber neurons observed following intraplantar CFA injection and concomitantly blocks CFA-induced mechanical allodynia, suggesting that Nav1.8 regulation in Aβ-fibers contributes to inflammatory pain. CONCLUSIONS: Collectively, these findings support a key role for Nav1.8 in controlling the excitability of Aβ-fibers and its potential contribution to the development of mechanical allodynia under persistent inflammation

Multifunctional Curcumin-Nanocarriers Based on Host-Guest Interactions for Alzheimer Disease Diagnostic

International audienc