Trimetazidine protects retinal ganglion cells from acute glaucoma via the Nrf2/Ho-1 pathway

Abstract

Acute glaucoma is one of the leading causes of irreversible vision impairment characterized by the rapid elevation of intraocular pressure (IOP) and consequent retinal ganglion cell (RGC) death. Oxidative stress and neuroinflammation have been considered critical for the pathogenesis of RGC death in acute glaucoma. Trimetazidine (TMZ), an anti-ischemic drug, possesses antioxidative and anti-inflammatory properties, contributing to its therapeutic potential in tissue damage. However, the role of TMZ in acute glaucoma and the underlying molecular mechanisms remain elusive. Here, we report that treatment with TMZ significantly attenuated retinal damage and RGC death in mice with acute glaucoma, with a significant decrease in reactive oxygen species (ROS) and inflammatory cytokine production in the retina. Furthermore, TMZ treatment directly decreased ROS production and rebalanced the intracellular redox state, thus contributing to the survival of RGCs in vitro. TMZ treatment also reduced the production of inflammatory cytokines in vitro. Mechanistically, the TMZ-mediated inhibition of apoptosis and inflammatory cytokine production in RGCs occurred via the regulation of the nuclear factor erythroid 2-related factor 2/heme oxygenase 1/caspase-8 pathway. Moreover, the TMZ-mediated neuroprotection in acute glaucoma was abrogated when an HO-1 inhibitor, SnPP, was used. Our findings identify potential mechanisms of RGC apoptosis and propose a novel therapeutic agent, TMZ, which exerts a precise neuroprotective effect against acute glaucoma.

LncRNA H19 initiates microglial pyroptosis and neuronal death in retinal ischemia/reperfusion injury

“…The retinal I/R model were established as previously described [48]. In brief, a 30-gauge needle containing a balanced salt solution was cannulated into the anterior chamber to maintain the IOP at 70 mmHg for 60 min.…”

“…In vivo RGC retrograde labeling was performed as previously described [48]. Bilateral holes were drilled, and 1 µL of a 4% (vol/vol) Fluorogold (FG, hydroxystilbamidine; Fluorochrome, USA) solution was injected into both superior colliculi.…”

“…Seven days after I/R damage, mice were overdosed with anesthesia and transcardially perfused with isotonic saline and 4% (wt/vol) paraformaldehyde (PFA). Mouse eyes were enucleated and stained with hematoxylin and eosin (H&E) [48]. To quantify retinal damage, the thickness of the inner plexiform layer (IPL) was measured within 1 mm of the optic nerve center using Axiovision Software (Carl Zeiss).…”

Cardioprotective effects of anisodamine against myocardial ischemia/reperfusion injury through the inhibition of oxidative stress, inflammation and apoptosis

“…Anisodamine is a cholinergic and α 1 adrenergic receptor antagonist, which has been used in China for the treatment of coronary heart disease, for the prevention and treatment of angina, pulmonary hypertension and chronic heart failure, in combination with cardiac glycosides or diuretic agents (15,16). The present study aimed to investigate the putative cardioprotective effects of anisodamine against myocardial I/R injury, and to explore the underlying molecular mechanisms, using an in vivo rat model of I/R injury.…”

Tetrahydrocurcumin Provides Neuroprotection in Experimental Traumatic Brain Injury and the Nrf2 Signaling Pathway as a Potential Mechanism

“…Nuclear factor erythroid 2 (NFE2)-related factor 2 (Nrf2) is an important transcription factor that regulates the cellular antioxidant mechanism in response to different types of stress, and plays a critical role in modulating inflammatory responses in many experimental models [6, 7]. Under physiological conditions, Nrf2 is localized in the cytoplasm where it is anchored by the Kelch-like ECH-associating protein (Keap1).…”