Aim: Both hyperbaric oxygenation (HBO) and inhibition of the c-Jun N-terminal kinases (JNKs) by the peptide inhibitor XG-102 (D-JNKI-1) are efficient protective strategies against ischaemia-induced neurodegeneration. The present study investigated whether the combination of HBO and JNK inhibitor, XG-102, provides additive neuroprotection against cerebral ischaemia.
Methods: Rat middle cerebral artery was occluded (MCAO) for 90 min. XG-102 [2 mg/kg, intraperitoneally] or HBO (3 ATA, 60 min) was applied 3 h after the onset of MCAO. For the combination treatment, HBO was started 10 min after the injection of XG-102. Twenty-four hours after MCAO, the infarct area, the neurological score and the immunohistochemistry staining in brain slices for cleaved-PARP, transferase-mediated biotinylated UTP nick end labelling, c-Jun and phosphorylated (activated) c-Jun were observed.
Results: XG-102 or HBO alone reduced the total infarct area by 43% and 63%, respectively. The combination diminished total infarct area by 78%, improved the neurological function and reduced brain oedema. Co-application of HBO and XG-102 also significantly reduced the cleavage of PARP, by 96% and 91% in cortical penumbra and ischaemic core, respectively. Moreover, cotreatment significantly attenuated the number of cells labelled with transferase-mediated biotinylated UTP nick end labelling and phosphorylated c-Jun.
Conclusion: Our study demonstrates that HBO reinforces the efficiency of neuroprotective drugs such as XG-102 and vice versa. Both treatments, physical HBO and pharmacological XG-102, are already in phase I/II studies and promising strategies for clinical use.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1111/j.1365-2990.2009.01047.x | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
The Ameliorative Effect of JNK Inhibitor D-JNKI-1 on Neomycin-Induced Apoptosis in HEI-OC1 Cells.
Front Mol Neurosci
March 2022
Department of Otolaryngology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China.
Aminoglycosides can cause ototoxicity and lead to hair cell damage. Neomycin-induced ototoxicity is related to increased production of reactive oxygen species (ROS) and triggering hair cell apoptosis. The c-Jun-N-terminal kinase (JNK) pathway plays an essential role during hair cell damage.
View Article and Find Full Text PDFc-Jun N-terminal kinase 1 (JNK1) modulates oligodendrocyte progenitor cell architecture, proliferation and myelination.
Sci Rep
March 2021
Department of Neuroscience Rita Levi-Montalcini, University of Turin, Turin, Italy.
Article Synopsis
- * The study found that knocking out the MAPK isoform JNK1 significantly reduces myelin in the cerebral cortex and corpus callosum during postnatal and adult stages, leading to higher OPC density and proliferation early in life.
- * JNK1 knockout OPCs have smaller territories and simpler structures, and although differentiation seems normal, both knockout and treated OLs have reduced surface area, highlighting JNK1's crucial role in OPC function and myelination.
Efficacy and Safety of AM-111 in the Treatment of Acute Unilateral Sudden Deafness-A Double-blind, Randomized, Placebo-controlled Phase 3 Study.
Otol Neurotol
June 2019
Auris Medical AG, Basel, Switzerland.
Objective: To confirm the efficacy and safety of AM-111 (brimapitide), a cell-penetrating c-Jun N-terminal Kinase (JNK) inhibitor, in patients suffering from severe to profound acute unilateral idiopathic sudden sensorineural hearing loss (ISSNHL).
Study Design: Prospective, double-blind, randomized, placebo-controlled phase 3 study with follow-up visits on Days 3, 7, 28, and 91.
Setting: Fifty-one European and Asian sites (tertiary referral centers, private ENT practices).
A novel nanoparticle delivery system for targeted therapy of noise-induced hearing loss.
J Control Release
June 2018
Department of Otorhinolaryngology - Head and Neck Surgery, Perelman School of Medicine at the University of Pennsylvania, 421 Curie Blvd, BRB 1220, Philadelphia, PA 19104, USA. Electronic address:
Hearing loss is the most prevalent sensory disability worldwide and may be caused by age, drugs or exposure to excessive noise. We have previously developed a minimally-invasive nanohydrogel drug delivery system that successfully delivers nanoparticles into the inner ear. We have substantially extended this technique by functionalizing the nanoparticles and introducing a targeting peptide which recognizes prestin, a transmembrane electromotile protein uniquely expressed in outer hair cells (OHCs) of the inner ear.
View Article and Find Full Text PDFBrimapitide Reduced Neuronal Stress Markers and Cognitive Deficits in 5XFAD Transgenic Mice.
J Alzheimers Dis
June 2019
Inserm UMR-S 942, Paris, France.
Alzheimer's disease (AD) is characterized by accumulations of amyloid-β (Aβ42) and hyperphosphorylated tau proteins, associated with neuroinflammation, synaptic loss, and neuronal death. Several studies indicate that c-Jun N-terminal kinase (JNK) is implicated in the pathological features of AD. We have investigated in 5XFAD mice, the therapeutic effects of Brimapitide, a JNK-specific inhibitory peptide previously tested with higher concentrations in another AD model (TgCRND8).
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!