| 1. |
|
|
| 2. |
- Coutard, B., et al.
(författare)
-
The VIZIER project : Preparedness against pathogenic RNA viruses
- 2008
-
Ingår i: Antiviral Research. - : Elsevier BV. - 0166-3542 .- 1872-9096. ; 78:1, s. 37-46
-
Tidskriftsartikel (refereegranskat)abstract
- Life-threatening RNA viruses emerge regularly, and often in an unpredictable manner. Yet, the very few drugs available against known RNA viruses have sometimes required decades of research for development. Can we generate preparedness for outbreaks of the, as yet, unknown viruses? The VIZIER (VIral enZymes InvolvEd in Replication) (http://www.vizier-europe.org/) project has been set-up to develop the scientific foundations for countering this challenge to society. VIZIER studies the most conserved viral enzymes (that of the replication machinery, or replicases) that constitute attractive targets for drug-design. The aim of VIZIER is to determine as many replicase crystal structures as possible from a carefully selected list of viruses in order to comprehensively cover the diversity of the RNA virus universe, and generate critical knowledge that could be efficiently utilized to jump-start research on any emerging RNA virus. VIZIER is a multidisciplinary project involving (i) bioinformatics to define functional domains, (ii) viral genomics to increase the number of characterized viral genomes and prepare defined targets, (iii) proteomics to express, purify, and characterize targets, (iv) structural biology to solve their crystal structures, and (v) pre-lead discovery to propose active scaffolds of antiviral molecules.
|
|
| 3. |
- Rocha-Ferreira, Eridan, 1983, et al.
(författare)
-
Neuroprotective exendin-4 enhances hypothermia therapy in a model of hypoxic-ischaemic encephalopathy
- 2018
-
Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 141:10, s. 2925-2942
-
Tidskriftsartikel (refereegranskat)abstract
- Hypoxic-ischaemic encephalopathy remains a global health burden. Despite medical advances and treatment with therapeutic hypothermia, over 50% of cooled infants are not protected and still develop lifelong neurodisabilities, including cerebral palsy. Furthermore, hypothermia is not used in preterm cases or low resource settings. Alternatives or adjunct therapies are urgently needed. Exendin-4 is a drug used to treat type 2 diabetes mellitus that has also demonstrated neuroprotective properties, and is currently being tested in clinical trials for Alzheimer's and Parkinson's diseases. Therefore, we hypothesized a neuroprotective effect for exendin-4 in neonatal neurodisorders, particularly in the treatment of neonatal hypoxic-ischaemic encephalopathy. Initially, we confirmed that the glucagon like peptide 1 receptor (GLP1R) was expressed in the human neonatal brain and in murine neurons at postnatal Day 7 (human equivalent late preterm) and postnatal Day 10 (term). Using a well characterized mouse model of neonatal hypoxic-ischaemic brain injury, we investigated the potential neuroprotective effect of exendin-4 in both postnatal Day 7 and 10 mice. An optimal exendin-4 treatment dosing regimen was identified, where four high doses (0.5 mu g/g) starting at Oh, then at 12h, 24h and 36h after postnatal Day 7 hypoxic-ischaemic insult resulted in significant brain neuroprotection. Furthermore, neuroprotection was sustained even when treatment using exendin-4 was delayed by 2 h post hypoxic-ischaemic brain injury. This protective effect was observed in various histopathological markers: tissue infarction, cell death, astrogliosis, microglial and endothelial activation. Blood glucose levels were not altered by high dose exendin-4 administration when compared to controls. Exendin-4 administration did not result in adverse organ histopathology (haematoxylin and eosin) or inflammation (CD68). Despite initial reduced weight gain, animals restored weight gain following end of treatment. Overall high dose exendin-4 administration was well tolerated. To mimic the clinical scenario, postnatal Day 10 mice underwent exendin-4 and therapeutic hypothermia treatment, either alone or in combination, and, brain tissue loss was assessed after 1 week. Exendin-4 treatment resulted in significant neuroprotection alone, and enhanced the cerebroprotective effect of therapeutic hypothermia. In summary, the safety and tolerance of high dose exendin-4 administrations, combined with its neuroprotective effect alone or in conjunction with clinically relevant hypothermia make the repurposing of exendin-4 for the treatment of neonatal hypoxic-ischaemic encephalopathy particularly promising.
|
|
| 4. |
|
|
| 5. |
- Poupon-Bejuit, Laura, et al.
(författare)
-
Diabetes drugs activate neuroprotective pathways in models of neonatal hypoxic-ischemic encephalopathy
- 2024
-
Ingår i: EMBO MOLECULAR MEDICINE. - 1757-4676 .- 1757-4684. ; 16:6, s. 1284-1309
-
Tidskriftsartikel (refereegranskat)abstract
- Hypoxic-ischaemic encephalopathy (HIE) arises from diminished blood flow and oxygen to the neonatal brain during labor, leading to infant mortality or severe brain damage, with a global incidence of 1.5 per 1000 live births. Glucagon-like Peptide 1 Receptor (GLP1-R) agonists, used in type 2 diabetes treatment, exhibit neuroprotective effects in various brain injury models, including HIE. In this study, we observed enhanced neurological outcomes in post-natal day 10 mice with surgically induced hypoxic-ischaemic (HI) brain injury after immediate systemic administration of exendin-4 or semaglutide. Short- and long-term assessments revealed improved neuropathology, survival rates, and locomotor function. We explored the mechanisms by which GLP1-R agonists trigger neuroprotection and reduce inflammation following oxygen-glucose deprivation and HI in neonatal mice, highlighting the upregulation of the PI3/AKT signalling pathway and increased cAMP levels. These findings shed light on the neuroprotective and anti-inflammatory effects of GLP1-R agonists in HIE, potentially extending to other neurological conditions, supporting their potential clinical use in treating infants with HIE. Hypoxic-ischaemic encephalopathy (HIE) is caused by complications during labor or the umbilical cord causing reduced oxygen to the baby's brain. This leads to brain injury and lifelong disability or death. Administration of GLP1 receptor agonists to a mouse model of HIE reduces brain damage and improves multiple readouts of efficacy.A single peripheral administration of a GLP1 receptor agonist, used in the clinic to treat diabetes, significantly reduced brain infarct size and improved survival and locomotor function in a mouse model of neonatal HIE. GLP1 receptor agonists activated neuroprotective pathways and reduced markers of inflammatory response in the brain. This study is supportive of further investigating the clinical application of GLP1 receptor agonist for HIE but also more widely for other neurological diseases. Hypoxic-ischaemic encephalopathy (HIE) is caused by complications during labor or the umbilical cord causing reduced oxygen to the baby's brain. This leads to brain injury and lifelong disability or death. Administration of GLP1 receptor agonists to a mouse model of HIE reduces brain damage and improves multiple readouts of efficacy.
|
|
| 6. |
- Poupon-Bejuit, Laura, et al.
(författare)
-
Neuroprotective Effects of Diabetes Drugs for the Treatment of Neonatal Hypoxia-Ischemia Encephalopathy.
- 2020
-
Ingår i: Frontiers in cellular neuroscience. - : Frontiers Media SA. - 1662-5102. ; 14
-
Tidskriftsartikel (refereegranskat)abstract
- The perinatal period represents a time of great vulnerability for the developing brain. A variety of injuries can result in death or devastating injury causing profound neurocognitive deficits. Hypoxic-ischemic neonatal encephalopathy (HIE) remains the leading cause of brain injury in term infants during the perinatal period with limited options available to aid in recovery. It can result in long-term devastating consequences with neurologic complications varying from mild behavioral deficits to severe seizure, intellectual disability, and/or cerebral palsy in the newborn. Despite medical advances, the only viable option is therapeutic hypothermia which is classified as the gold standard but is not used, or may not be as effective in preterm cases, infection-associated cases or low resource settings. Therefore, alternatives or adjunct therapies are urgently needed. Ongoing research continues to advance our understanding of the mechanisms contributing to perinatal brain injury and identify new targets and treatments. Drugs used for the treatment of patients with type 2 diabetes mellitus (T2DM) have demonstrated neuroprotective properties and therapeutic efficacy from neurological sequelae following HIE insults in preclinical models, both alone, or in combination with induced hypothermia. In this short review, we have focused on recent findings on the use of diabetes drugs that provide a neuroprotective effect using in vitro and in vivo models of HIE that could be considered for clinical translation as a promising treatment.
|
|
