Combined use of neuroprotective agents: A new treatment strategy for patients with glaucoma

Abstract

Keywords: Glaucoma, Coenzyme Q10, Citicoline, Neuroprotection, Retinal ganglion cells.Glaucoma is a leading cause of irreversible blindness worldwide. Although the multifactorial genesis, by now, the main treatable risk factor is the elevated intraocular pressure. Nevertheless, some patients, whose intraocular pressure is considered at the target level, still experience a progression of the disease. New evidence strongly suggesting brain involvement in all aspects of the disease led to a growing interest in the pharmacological research of new neuroprotective agents with an intraocular pressure independent activity.Citicoline and coenzyme Q10 are among the most studied and used molecules in clinical practice for some forms of neurodegeneration. In particular, the neuromodulatory and neuroprotective properties of citicoline were extensively investigated either in vivo or in vitro studies. Among the activities of citicoline it has been proposed the capacity to increase neuronal viability as well as the vasomodulatory effect that results in an increased blood flow. Similarly, the neuroprotective effects of coenzyme Q10 has been proposed in experimental models of ocular neurodegeneration.The greater efficacy of the fixed combination over the single components could depend on the fact that each molecule exerts, at least in part, its activity on mitochondria. Coenzyme Q10 acts as an electron carrier from mitochondrial complexes I and II to III, while citicoline maintains proper levels of cardiolipin and sphingomyelin in the cellular and axon membranes. Thus, increasing the energetic rate of cells.Citicoline and coenzyme Q10 are reported to counteract excitotoxicity by respectively decreasing nitrosative stress and extracellular signal‐regulated kinases 1/2, and preventing the upregulation of NR1 and NR2A subunit receptors. In addition, coenzyme Q10 significantly prevents apoptosis by acting on Bax and pBad proteins expression and preserves mitochondrial DNA content and mitochondrial oxidative phosphorylation system in experimental models.Citicoline and coenzyme Q10 are also important in preventing retinal ganglion cells death possibly by acting on Bcl family regulation increasing retinal expression of Bcl‐2, and by significantly inducing Bcl‐xL protein expression, respectively.Citicoline and coenzyme Q10 also show an anti‐inflammatory effect; the first acting on inhibition of phospholipase A2 and downregulating synaptophysin, and the latter by downregulating tumour necrosis factor α and protein 1α, as well as acting on macrophage induced inflammation.Data on literature indicates that the combined use of molecules may be also beneficial for the metabolism of the molecules themselves. In fact, coenzyme Q10 increases the choline oxidase activity in ubiquinone‐depleted mitochondria, thus underling the importance of the presence of good plasmatic choline and coenzyme Q10 levels for energetic production.Overall, evidence seems to suggest the usefulness of coenzyme Q10 and citicoline, eventually combined, in the prevention of glaucomatous neurodegeneration.