A Hydroxypyrone-Based Inhibitor of Metalloproteinase-12 Displays Neuroprotective Properties in Both Status Epilepticus and Optic Nerve Crush Animal Models

Vinet, Jonathan; Costa, Anna-Maria; Salinas‐Navarro, Manuel; Leo, Giuseppina; Moons, Lieve; Arckens, Lutgarde; Biagini, Giuseppe

doi:10.3390/ijms19082178

Cited by 14 publications

(12 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The second pair was Timp2, expressed by resRGCs and Mmp12, expressed by susRGCs. Administration of a soluble inhibitor of MMP12 was recently shown to improve RGC survival after ONC (Vinet et al, 2018), a result we replicated, and Mmp12 deletion improves recovery from spinal cord injury (Wells et al, 2003). In vivo, MMP activity has been described to be closely controlled by endogenous tissue inhibitors (TIMP1-4) (Dzwonek et al, 2004) and AAV-mediated gene-transfer of Timp1 and Timp2 reduced neuronal damage in transient global ischemia, suggesting a neuroprotective role (Magnoni et al, 2007).…”

Section: Genes That Affect Resilience and Susceptibilitysupporting

confidence: 56%

Single-cell profiles of retinal neurons differing in resilience to injury reveal neuroprotective genes

Tran¹,

Shekhar

Whitney³

et al. 2019

Preprint

View full text Add to dashboard Cite

Neuronal types in the central nervous system differ dramatically in their resilience to injury or insults. Here we studied the selective resilience of mouse retinal ganglion cells (RGCs) following optic nerve crush (ONC), which severs their axons and leads to death of ~80% of RGCs within 2 weeks. To identify expression programs associated with differential resilience, we first used single-cell RNA-seq (scRNA-seq) to generate a comprehensive molecular atlas of 46 RGC types in adult retina. We then tracked their survival after ONC, characterized transcriptomic, physiological, and morphological changes that preceded degeneration, and identified genes selectively expressed by each type. Finally, using loss-and gain-of-function assays in vivo, we showed that manipulating some of these genes improved neuronal survival and axon regeneration following ONC. This study provides a systematic framework for parsing type-specific responses to injury, and demonstrates that differential gene expression can be used to reveal molecular targets for intervention.

show abstract

Section: Genes That Affect Resilience and Susceptibilitysupporting

confidence: 56%

Single-cell profiles of retinal neurons differing in resilience to injury reveal neuroprotective genes

Tran¹,

Shekhar

Whitney³

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…The presence of albumin following disruption of the BBB by seizures has been shown by several authors [19,20,51]. Previous report has shown that neuronal death and ischemic-like lesion that occur in the hippocampus following SE can be prevented by the specific inhibition of matrix metalloproteinase-12, a protein supposed to be involved in BBB leakage [52].…”

Section: Discussionmentioning

confidence: 94%

Altered Proteins in the Hippocampus of Patients with Mesial Temporal Lobe Epilepsy

et al. 2018

View full text Add to dashboard Cite

Mesial temporal lobe epilepsy (MTLE) is usually associated with drug-resistant seizures and cognitive deficits. Efforts have been made to improve the understanding of the pathophysiology of MTLE for new therapies. In this study, we used proteomics to determine the differential expression of proteins in the hippocampus of patients with MTLE compared to control samples. By using the two-dimensional electrophoresis method (2-DE), the proteins were separated into spots and analyzed by LC-MS/MS. Spots that had different densitometric values for patients and controls were selected for the study. The following proteins were found to be up-regulated in patients: isoform 1 of serum albumin (ALB), proton ATPase catalytic subunit A (ATP6V1A), heat shock protein 70 (HSP70), dihydropyrimidinase-related protein 2 (DPYSL2), isoform 1 of myelin basic protein (MBP), and dihydrolipoamide S-acethyltransferase (DLAT). The protein isoform 3 of the spectrin alpha chain (SPTAN1) was down-regulated while glutathione S-transferase P (GSTP1) and protein DJ-1 (PARK7) were found only in the hippocampus of patients with MTLE. Interactome analysis of the nine proteins of interest revealed interactions with 20 other proteins, most of them involved with metabolic processes (37%), presenting catalytic activity (37%) and working as hydrolyses (25%), among others. Our results provide evidence supporting a direct link between synaptic plasticity, metabolic disturbance, oxidative stress with mitochondrial damage, the disruption of the blood–brain barrier and changes in CNS structural proteins with cell death and epileptogenesis in MTLE. Besides this, the presence of markers of cell survival indicated a compensatory mechanism. The over-expression of GSTP1 in MTLE could be related to drug-resistance.

show abstract

“…Brain tissue sections (30 µm thickness) were pretreated with 3% hydrogen peroxide to eliminate endogenous peroxidase activity, blocked/permeabilized in 10% goat serum/0.1% Triton X-100 in phosphate-buffered saline (PBS) before added the anti-tyrosine hydroxylase antibody (R&D Systems, Inc., Minneapolis, MN, USA; MAB7566), and then visualized with 0.01% hydrogen peroxide and 0.05% 3,3 -diaminobenzidine (Sigma-Aldrich, St. Louis, MO, USA) as described previously [3]. Immunohistochemistry images were quantified using ImageJ software (National Institutes of Health, Bethesda, MD, USA) according to Vinet et al (2018) [29] 2.9. RNA Extraction, Reverse-Transcription, and Real-Time Quantitative PCR Total RNA for gene expression was extracted from cells or tissues according to the NucleoSpin ® RNA protocol (MACHEREY-NAGEL GmbH & Co. KG, Düren, Germany).…”

Section: Immunohistochemistry Staining Of Tyrosine Hydroxylasementioning

confidence: 99%

Celastrol Inhibits Dopaminergic Neuronal Death of Parkinson’s Disease through Activating Mitophagy

Lin

Chen

et al. 2019

Antioxidants

View full text Add to dashboard Cite

Parkinson’s disease (PD) is a neurodegenerative disease, which is associated with mitochondrial dysfunction and abnormal protein accumulation. No treatment can stop or slow PD. Autophagy inhibits neuronal death by removing damaged mitochondria and abnormal protein aggregations. Celastrol is a triterpene with antioxidant and anti-inflammatory effects. Up until now, no reports have shown that celastrol improves PD motor symptoms. In this study, we used PD cell and mouse models to evaluate the therapeutic efficacy and mechanism of celastrol. In the substantia nigra, we found lower levels of autophagic activity in patients with sporadic PD as compared to healthy controls. In neurons, celastrol enhances autophagy, autophagosome biogenesis (Beclin 1↑, Ambra1↑, Vps34↑, Atg7↑, Atg12↑, and LC3-II↑), and mitophagy (PINK1↑, DJ-1↑, and LRRK2↓), and these might be associated with MPAK signaling pathways. In the PD cell model, celastrol reduces MPP+-induced dopaminergic neuronal death, mitochondrial membrane depolarization, and ATP reduction. In the PD mouse model, celastrol suppresses motor symptoms and neurodegeneration in the substantia nigra and striatum and enhances mitophagy (PINK1↑ and DJ-1↑) in the striatum. Using MPP+ to induce mitochondrial damage in neurons, we found celastrol controls mitochondrial quality by sequestering impaired mitochondria into autophagosomes for degradation. This is the first report to show that celastrol exerts neuroprotection in PD by activating mitophagy to degrade impaired mitochondria and further inhibit dopaminergic neuronal apoptosis. Celastrol may help to prevent and treat PD.

show abstract

A Hydroxypyrone-Based Inhibitor of Metalloproteinase-12 Displays Neuroprotective Properties in Both Status Epilepticus and Optic Nerve Crush Animal Models

Cited by 14 publications

References 59 publications

Single-cell profiles of retinal neurons differing in resilience to injury reveal neuroprotective genes

Single-cell profiles of retinal neurons differing in resilience to injury reveal neuroprotective genes

Altered Proteins in the Hippocampus of Patients with Mesial Temporal Lobe Epilepsy

Celastrol Inhibits Dopaminergic Neuronal Death of Parkinson’s Disease through Activating Mitophagy

Contact Info

Product

Resources

About