This is indicative that citicoline enhances bioenergetics and phospholipid membrane turnover in the brain Mitofilin, the principal mitochondrial inner membrane protein which plays a crucial role in the preservation of mitochondrial cristae morphology, reduces in the condition of oxidative stress.

In this condition CoQ10 showed partial preservation of mitochondrial morphology, increased mitochondrial numbers and mitochondrial volume density. This is possibly due to CoQ10 ability to promote mitofilin protein expression, providing protection to the mitochondria and ultimately OXPHOS capacity against oxidative stress In addition, CoQ10 plays a vital role in ATP production.

Thus supporting the bioenergetic role of CoQ As seen, citicoline not only exerts a neuroprotective effect but also boosts the synthesis of dopamine, acetylcholine, noradrenaline and serotonin.

Studies reported that after citicoline administration retinal dopamine levels significantly increased thus possibly in part justifying the improvement of visual function in glaucomatous patients in terms of visual field and electrophysiological tests results One additional target on which citicoline may act is remyelination.

Disruption of the axonal membranes in glaucoma has been previously described since the early stages of the disease 19 , 24 , Citicoline, is a precursor for phosphatidylcholine, phosphatidylethanolamine, sphingomyelin and cardiolipin, which are fundamental structural and functional components of cell membranes that ensure the correct enzymatic viability for the transport of substances across the membrane and are essential in signal transduction.

Being a protagonist in maintaining membrane integrity, citicoline also plays a pivotal role in counteracting axonal degeneration in glaucoma 46 , 58 — Citicoline has been shown to have a positive protective effect on inflammatory diseases Citicoline has been shown to counteract the pathological downregulation of synaptophysin in the retina, restoring its anti-inflammatory properties.

Moreover, citicoline is able to reduce retinal reactive gliosis, prevent apoptosis of the entire retinal components, such as photoreceptors, bipolar cells, and RGCs.

Similarly, the administration of citicoline resulted to be protective in transient cerebral ischemia through the inhibition of phospholipase A2 PLA2 , with a consequent reduction of tissue inflammation and redox imbalance Coenzyme Q10 claims some anti-inflammatory properties as well.

A recent systematic review and meta-analysis reported that improving the serum level of CoQ10 induced a significant reduction of TNF-α level in the CoQ10 supplementation group compared with placebo.

This may be due to the potential role of CoQ10 in lessening the production of pro-inflammatory cytokines by preventing NF-κB gene expression, reducing miRa and IL-1 receptor associated kinase modulation.

CoQ10 may also act by lowering the production of macrophage inflammatory protein-1 alpha Citicoline was shown to improve cerebral blood flow and velocities compared to placebo. This is possibly due to the effect on calcium release from endothelial cells that regulate nitric oxide synthesis consequently enhancing endothelial function.

The proper functioning of the microvasculature and the right tissue perfusion is crucial for neuronal viability. In this context, restoring endothelial dysfunction leads to healthier microvasculature and improved blood flow, avoiding neuronal apoptosis 60 , 63 , Data on literature, suggests that the combined use of molecules may be also beneficial for the metabolism of the molecules themselves.

Barrett and Dawson 58 reported that rat liver mitochondria treated extensively with n-pentane are incapable of oxidizing choline.

Choline oxidization is restored by the addition of ubiquinone-2 or ubiquinone to the oxidase assay medium. The necessity for ubiquinone of the Lglycerophosphate oxidase of pig brain mitochondria has been also previously confirmed Ubiquinone is also fundamental for Nicotinamide adenine dinucleotide NADH and succinate oxidase Previous studies showed that solubilized choline dehydrogenase is capable to reduce ubiquinone-6 and that, in mitochondria incubated with choline until the anaerobic state was achieved, endogenous ubiquinone was reduced The choline dehydrogenase is a respiratory-chain-linked enzyme that supplies electrons into the respiratory chain.

Remarkably, Barrett and Dawson 58 observed that most of the choline oxidase activity was reduced because of ubiquinone depletion. In this regard, CoQ10 was found to increase the choline oxidase activity in ubiquinone-depleted mitochondria, thus suggesting the importance of the presence of good levels of plasmatic choline and CoQ10 for energetic production Qu et al.

This may have two main consequences: a decrease in antioxidant ability and a decrease in the rate of ATP synthesis in the retina. This would make the RGCs more vulnerable to pro-apoptotic insults. Moreover, a study on an experimental animal model of non-alcoholic steatohepatitis NASH in albino rats induced by a methionine and choline-deficient MCD diet showed a significant increase in the brain contents of ammonia and NOx.

These substances were significantly reduced by treatment with CoQ Concomitantly the brain-derived neurotrophic factor content, which was reduced by the diet, increased. Overall, CoQ10 showed a neuroprotective activity, in the case of choline depletion, by inhibiting the release of glutamate in rat cerebrocortical nerve terminals The greater efficacy of the fixed combination over the single components could therefore depend on the fact that each molecule exerts, at least in part, their activity on mitochondria CoQ10 acts as an electron accepter from mitochondrial complexes I and II, thus increasing the energetic rate of cells.

Additionally, citicoline maintains proper levels of cardiolipin and sphingomyelin in the cellular and axon membranes and stimulates cardiolipin production within the mitochondrial membranes.

Cardiolipin is essential for the optimal activity of the enzyme complexes of the electron transport chain and for ATP production Overall, these data suggest the possible usefulness of the combined use of citicoline and CoQ10 both in terms of a putative synergistic effect and in terms of combined action on the different pathogenetic targets causing the onset and progression of glaucoma.

Using combined treatment may downregulate more pro-apoptotic pathways as well as it may boost the effect on one or more pathways on which the different molecules act.

All authors listed have made a substantial, direct, and intellectual contribution to the work, and approved it for publication. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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Effect of oral citicoline therapy on retinal nerve fiber layer and ganglion cell-inner plexiform layer in patients with primary open angle glaucoma. Neurodegenerative diseases, including glaucoma, 3 , 21 involve cell loss by apoptosis as the main pathogenetic event.

Notwithstanding a substantial amount of research that is focused on this area, effective treatments for most neurodegenerative diseases do not yet exist.

Previously, we have shown that CoQ10 prevented apoptosis of corneal keratocytes both in vitro 12 and in vivo 13 in response to therapeutic excimer laser irradiation with markedly higher efficacy compared with that of other antioxidants vitamins A, C, and E.

We then demonstrated that keratocyte apoptosis prevention by CoQ10 also occurred in response to apoptotic stimuli that do not induce the formation of free radicals such as ceramide, hypoxia, and growth factor withdrawal and that this was consequent to the ability of CoQ10 to inhibit mitochondrial depolarization.

The effects of CoQ10 on the vision and, in particular, on the health of the retina have not been widely investigated. Only a few studies have indicated that oral or intravitreal administration of CoQ10 significantly improves eyesight 18 , 25 , 26 and protects RGCs against oxidative stress 27 or high IOP-induced ischemia.

Although the involvement of RGC excitotoxicity as a pathogenetic mechanism of glaucoma is debated, it has been proven that in most cases it could play a key role. In particular, Sucher et al. Mali et al. In a parallel study, Kumada et al.

A very recent study reports that KA induces a reactive gliosis that leads to RGC apoptosis by activating retinal matrix metalloproteinase-9, tPA, and uPA. Here, we demonstrate that CoQ10 protects RGCs from apoptosis independently from its antioxidant properties, in keeping with the previous results we obtained with corneal keratocytes.

Our results also indicate that CoQ10 increases RGC viability and inhibits apoptosis in response to different apoptotic stimuli such as glutamate, chemical hypoxia Antimycin A , and serum withdrawal FBS 0.

On the basis of these observations, the effectiveness of corneal application of CoQ10 eye drops in protecting RGCs from KA-induced apoptosis in our study indicates that CoQ10 may act by mechanisms that are downstream of and overcome all the above pathways. Finally, the ability of CoQ10 eye drops to deliver CoQ10 to the retina and to protect the retinal layers from apoptosis in the mouse model of KA-induced retinal damage reminiscent of glaucoma suggests that CoQ10 eye drops have a promising therapeutic applicability.

The ability of CoQ10 to reach the retina following corneal application is supported by an observation of Fato et al. Our results are in keeping with a report of Qu et al. These authors speculate that enhancing CoQ10 levels in the retina of elderly patients could have therapeutic value.

In conclusion, we propose that CoQ10 eye drops may be evaluated as a novel, simple, and noninvasive therapy for topical treatment of retinopathies with apoptosis as the main pathogenetic mechanism.

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Disclosure: M. Lulli , None; E. Witort , None; L. Papucci , None; E. Torre , None; C. Schipani , None; C. Bergamini , None; M.

Dal Monte , None; S. Capaccioli , P. Copyright © Association for Research in Vision and Ophthalmology. View Metrics. Related Articles The Role of Apoptosis within the Retina of Coronavirus-Infected Mice. Light-Induced Apoptosis in the Neonatal Mouse Retina and Superior Colliculus.

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