- 2019 Feb;14(2):197-200.
PMID:
30530997
PMCID:
PMC6301180
DOI:
10.4103/1673-5374.244781
The specific loss of RGCs is a common feature of mitochondrial diseases (Lee et al., 2011). Indeed, inherited mitochondrial defects are associated with a number of optic neuropathies including Leber’s hereditary optic neuropathy and autosomal dominant optic atrophy, but also with more severe central nervous system (CNS) involvement in many other syndromic mitochondrial diseases, which are characterized by selective RGC death (Carelli et al., 2009; Lee et al., 2011; Ito and Di Polo, 2017).
The selective loss of neuronal populations and the cell damage pattern in glaucoma also resemble those of other neurodegenerative diseases (Nucci et al., 2016, 2018; Mancino et al., 2018a, b) and increasing evidence supports a causative role of the glutamate-induced excitotoxic mechanism in RGCs loss in in vitro and in vivo experimental conditions (Nucci et al., 2007). Several free radical scavengers and/or agents, that ameliorate mitochondrial function, have been candidate as treating agents to prevent cell death in various neurodegenerative conditions, such as Alzheimer’s disease and Parkinson, and glaucoma (Spindler et al., 2009; Ahmadinejad et al., 2017). CoQ10 is both a ubiquitous free radical scavenger and a recognised electron transporter in complexes I, II, and III of mitochondrial respiratory chain. CoQ10 is an important antioxidant and has a fundamental role in cellular bioenergetics. This led to consider glaucoma as a neurodegenerative disease and promoted clinical studies on new neuroprotective strategies not only targeted to IOP reduction (Nucci et al., 2016, 2018).
Interestingly, increasing evidence indicates that age-related mitochondrial defects play a central role in the pathogenesis of glaucoma (Nucci et al., 2007; Russo et al., 2008, 2009; Lee et al., 2014). Levels of CoQ10 in the human retina have been reported to declines with age (Qu et al., 2009). In this regard, it is well known the existence of a link between older age and the prevalence of glaucoma, thus suggesting a possible increased vulnerability of RGCs in glaucomatous neurodegeneration due to a lack of CoQ10 in older age (Bhagavan and Chopra, 2006; Lee et al., 2014).
This opens new opportunities of investigation for the development of novel neurotherapeutic agents for the treatment of glaucoma and other major retinal pathologies (Russo et al., 2008, 2009; Zhang et al., 2017).
CoQ10 poor aqueous solubility (Fato et al., 2010) and low bioavailability, partially due to the interactions with the multi-drug efflux pump P-glycoprotein expressed in both corneal epithelial cells and RGCs, have limited the development of topically active formulations of this molecule (Davis et al., 2017). To enhance the topical delivery and pharmacological effects of CoQ10, the co-administration with a P-glycoprotein inhibitor, such as D-α-Tocopherol polyethylene glycol 1000 succinate (TPGS), has been proposed (Davis et al., 2017). Interestingly, it has been successfully demonstrated both in vitro and in vivo mitochondrial-mediated neurotoxicity models that twice daily topical instillation of CoQ10/TPGS micelles was found to be significantly neuroprotective against RGCs loss than TPGS alone. The findings, in agreement with previous work, also suggest that the antioxidant activity of TPGS alone was insufficient to protect an immortalised neuronal cell line from insults generating mitochondrial oxidative stress, such as dimethyl sulfoxide and paraquat (Davis et al., 2017).
Topical ocular administration, in a model of high IOP–induced transient ischemia in rat, of CoQ10 0.1% + vitamin E (Vit E) 0.5% showed the ability to minimize DNA fragmentation and retinal cell apoptosis (Nucci et al., 2007) (Figure 1). This study confirmed, for the first time, that, during the reperfusion phase, the ischemic insult induces a significant increase of glutamate with consequent RGCs apoptosis. Thus, providing evidence of the usefulness of CoQ10 as a neuroprotective agent. In these conditions, administration of CoQ10 prevents glutamate increase, minimizing RGCs death in rats. It is plausible that the CoQ10 free radical scavenging mechanism may have a minor role in this process and that CoQ10 ability to restrains extracellular glutamate accumulation, may reduce the harmful effect of ischemia/reperfusion on mitochondrial energy metabolism and, accordingly, on the glutamate transporters function, preventing RGC apoptosis in the rats (Nucci et al., 2007). Excessive activation of glutamate receptors via the excitotoxic cascade leads to the MPTP formation and release of a proapoptotic factor, the cytochrome C, from the mitochondrial intermembrane space into the cytosol. Remarkably, CoQ10 inhibits this cascade by maintaining MPTP in the closed conformation, preventing apoptosis (Papucci et al., 2003).
The main concern about the topical administration was the concentration of CoQ10 at the retinal and vitreal level reached after the instillation of the eye drops. In this regard, it has been reported that when CoQ10 in association with Vit E eye drops are topically applied to the cornea, CoQ10 reaches the retina, substantially increasing local CoQ10 concentration and protecting retinal layers from apoptosis, in a mouse model of kainate-induced retinal damage. In addition, patients undergoing pars plana vitrectomy, who were administered CoQ10 in association with Vit E eye drops 1 hour before surgery, showed the presence of CoQ10 in the collected vitreous samples, thus confirming the ability of CoQ10 to reach the posterior ocular tissues (Fato et al., 2010; Lulli et al., 2012).
Oral administration of CoQ10 has also been reported to be neuroprotective in neurodegenerative diseases, as well as in cardiovascular diseases. CoQ10 supplementation has been reported to increase plasma CoQ10 concentrations, and the safety of high doses of orally-ingested CoQ10 over long periods has been well documented also in humans (Bhagavan and Chopra, 2006). Interestingly, it has been reported that CoQ10 is taken up by all tissues, including heart and brain mitochondria. This finding, together with growing evidence indicating that CoQ10 is neuroprotective in RGCs against IOP in vivo and in vitro, as well as against oxidative stress and excitotoxicity, suggests that CoQ10 could also be taken up by the retina and lead to a beneficial effect in glaucomatous retina (Lee et al., 2014). In a recent study on preglaucomatous DBA/2J and age-matched control DBA/2J-Gpnmb+ mice, diet supplementation with CoQ10 for 6 months was tested to assess the effects on glutamate excitotoxicity and oxidative stress-mediated RGC degeneration (Lee et al., 2014). Intriguingly, CoQ10 endorsed RGC survival, preserved the axons in the optic nerve head, and inhibited astroglial activation by reducing glial fibrillary acidic protein expression in the retina and optic nerve head of glaucomatous DBA/2J mice. Interestingly, CoQ10 significantly blocked the upregulation of N-methyl-D-aspartate receptor 1 and 2A, as well as of superoxide dismutase-2, heme oxygenase-1 protein expression in the retina of glaucomatous DBA/2J mice. Moreover, CoQ10 was able to prevent cell apoptosis by reducing Bax protein expression or by enhancing phosphorylated Bad protein expression. mtDNA content and mitochondrial transcription factor A/oxidative phosphorylation complex IV expression in the retina of glaucomatous DBA/2J mice were also preserved by CoQ10 supplementation. This suggest that CoQ10 may have a beneficial potential for ameliorating glutamate excitotoxicity and oxidative stress mediated glaucomatous neurodegeneration in the retina (Lee et al., 2014).
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