Systemic Treatment with Pioglitazone Reverses Vision Loss in Preclinical Glaucoma Models

Zeng, Huilan; Dumitrescu, Alina V.; Wadkins, David; Elwood, Benjamin W.; Gramlich, Oliver W.; Kuehn, Markus H.

doi:10.3390/biom12020281

Cited by 5 publications

(5 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“… 67 – 69 Pioglitazone, an agonist of PPARγ used in the treatment of type 2 diabetes mellitus, has been shown to significantly protect RGCs and prevent axonal degeneration in the glaucomatous retina of mice. 70 Furthermore, treatment with pioglitazone preserved and partially reversed vision loss in spite of continuously elevated IOP. Similarly, two other PPARγ ligands protected transformed rat RGC against glutamate cytotoxicity.…”

Section: Discussionmentioning

confidence: 96%

Glaucoma Patients Have a Lower Abundance of Butyrate-Producing Taxa in the Gut

Vergroesen,

Jarrar,

Weiss

et al. 2024

Invest. Ophthalmol. Vis. Sci.

View full text Add to dashboard Cite

Purpose Glaucoma is an eye disease that is the most common cause of irreversible blindness worldwide. It has been suggested that gut microbiota can produce reactive oxygen species and pro-inflammatory cytokines that may travel from the gastric mucosa to distal sites, for example, the optic nerve head or trabecular meshwork. There is evidence for a gut-eye axis, as microbial dysbiosis has been associated with retinal diseases. We investigated the microbial composition in patients with glaucoma and healthy controls. Moreover, we analyzed the association of the gut microbiome with intraocular pressure (IOP; risk factor of glaucoma) and vertical cup-to-disc ratio (VCDR; quantifying glaucoma severity). Methods The discovery analyses included participants of the Rotterdam Study and the Erasmus Glaucoma Cohort. A total of 225 patients with glaucoma and 1247 age- and sex-matched participants without glaucoma were included in our analyses. Stool samples were used to generate 16S rRNA gene profiles. We assessed associations with 233 genera and species. We used data from the TwinsUK and the Study of Health in Pomerania (SHIP) to replicate our findings. Results Several butyrate-producing taxa (e.g. Butyrivibrio , Caproiciproducens , Clostridium sensu stricto 1 , Coprococcus 1 , Ruminococcaceae UCG 007 , and Shuttleworthia ) were less abundant in people with glaucoma compared to healthy controls. The same taxa were also associated with lower IOP and smaller VCDR. The replication analyses confirmed the findings from the discovery analyses. Conclusions Large human studies exploring the link between the gut microbiome and glaucoma are lacking. Our results suggest that microbial dysbiosis plays a role in the pathophysiology of glaucoma.

show abstract

Section: Discussionmentioning

confidence: 96%

Glaucoma Patients Have a Lower Abundance of Butyrate-Producing Taxa in the Gut

Vergroesen,

Jarrar,

Weiss

et al. 2024

Invest. Ophthalmol. Vis. Sci.

View full text Add to dashboard Cite

show abstract

“…In vivo retinal electrophysiology and data analysis. An optimized protocol for PERG (pattern electroretinogram) recording in mice was previously described [50,51]. Briefly, animals were anesthetized with ketamine/xylazine (80/10 mg/kg) and gently restrained in an animal holder.…”

Section: Methodsmentioning

confidence: 99%

Inflammasome-Dependent Dysfunction and Death of Retinal Ganglion Cells after Repetitive Intraocular Pressure Spikes

Spurlock,

An,

Reshetnikova

et al. 2023

Preprint

View full text Add to dashboard Cite

Dysfunction and selective loss of retinal ganglion cells (RGCs) is a known cause of vision loss in glaucoma and other neuropathies where ocular hypertension (OHT) is the major risk factor. We investigated the impact of transient non-ischemic OHT spikes (spOHT) on RGC function and viability in vivo to identify cellular pathways linking low-grade repetitive mechanical stress to RGC pathology. We found that repetitive spOHT had an unexpectedly high impact on intraocular homeostasis and RGC viability, while exposure to steady OHT (stOHT) of similar intensity and duration failed to induce pathology. The repetitive spOHT induced a rapid activation of the inflammasome, marked by the upregulation of NLRP1, NLRP3, AIM2, caspases -1, -3/7, -8, gasdermin D (GsdmD) and the release of interleukin-1β (IL-1β) and other cytokines into the vitreous. Similar effects were also detected after 5 weeks of exposure to chronic OHT in an induced glaucoma model. The onset of these immune responses in both spOHT and glaucoma models preceded a 50% deficit in pattern electroretinograms (PERG) amplitude, and significant loss of RGCs at 7 days post-injury. Inactivation of inflammasome complexes in NLRP1-/- , Casp1-/- and GsdmD-/- knockout animals, significantly suppressed the spOHT induced inflammatory response and protected RGCs. Our results demonstrate that mechanical stress produced by acute repetitive spOHT or chronic OHT is mechanistically linked to inflammasome activation, which leads to RGC dysfunction and death.

show abstract

“…Bilateral visual acuity was measured in subsets of 14 EAE mice, 15 GA-treated EAE mice, and 10 naive controls using the OptoDrum system (Striatech, Tübingen, Germany) [ 36 , 37 ]. Awake mice were placed on a platform in a closed chamber with a virtual cylinder projecting stripes of varying spatial frequencies at 99.8% contrast.…”

Section: Methodsmentioning

confidence: 99%

Targeting Cholesterol Homeostasis Improves Recovery in Experimental Optic Neuritis

et al. 2022

View full text Add to dashboard Cite

Acute optic neuritis (ON) is a common cause of vision loss and is often associated with multiple sclerosis (MS). Cholesterol recycling has been identified as a key limiting factor in recovery after demyelination events. Thus, the purpose of our study was to determine if the augmentation of cholesterol transport by gentisic acid (GA) benefits retinal ganglion cell (RGC) development and myelination in organoid systems and enables the recovery of the ocular phenotype upon systemic GA treatment in a MOG-induced experimental autoimmune encephalomyelitis (EAE) ON model. The retinal organoids treated with GA demonstrate an accelerated maturation when compared to the conventionally derived organoids, which was evidenced by the improved organization of Brn3a-GFP+RGC and increased synaptogenesis. A GA supplementation in brain organoids leads to a 10-fold increase in NG2 and Olig2 expression. Weekly GA injections of EAE mice significantly lessened motor-sensory impairment, protected amplitudes in pattern electroretinogram recordings, and preserved visual acuity over the study period of 56 days. Furthermore, GA-treated EAE mice revealed diminished GCL/IPL complex thinning when compared to the untreated EAE mice. An optic nerve histopathology revealed less severe grades of demyelination in the GA-treated EAE cohort and fewer infiltrating cells were observed. Interventions to improve cholesterol homeostasis may be a viable approach to promoting the rehabilitation of MS patients.

show abstract

Systemic Treatment with Pioglitazone Reverses Vision Loss in Preclinical Glaucoma Models

Cited by 5 publications

References 59 publications

Glaucoma Patients Have a Lower Abundance of Butyrate-Producing Taxa in the Gut

Glaucoma Patients Have a Lower Abundance of Butyrate-Producing Taxa in the Gut

Inflammasome-Dependent Dysfunction and Death of Retinal Ganglion Cells after Repetitive Intraocular Pressure Spikes

Targeting Cholesterol Homeostasis Improves Recovery in Experimental Optic Neuritis

Contact Info

Product

Resources

About