The Role of Citicoline and Coenzyme Q10 in Retinal Pathology

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TL;DR

This narrative review summarizes evidence that citicoline and coenzyme Q10 (CoQ10) have neuroprotective, antioxidant, and anti-inflammatory effects in retinal neurodegenerative diseases such as glaucoma, diabetic retinopathy, age-related macular degeneration, and Leber's hereditary optic neuropathy. In glaucoma, citicoline improved visual field, retinal nerve fiber layer thickness, and electrophysiological responses, while CoQ10/idebenone showed benefits in animal models and some human studies, particularly for LHON. The review concludes that both molecules show promise as adjuvant therapies, but more human studies are needed to establish clinically significant effects.

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**Background:** Retinal neurodegenerative diseases, including glaucoma, age-related macular degeneration (AMD), diabetic retinopathy (DR), and non-arteritic ischemic optic neuropathy (NAION), are leading causes of visual impairment worldwide. Current treatments often fail to halt neurodegeneration, prompting interest in neuroprotective agents. Citicoline (cytidine-5'-diphosphocholine) is a precursor of phosphatidylcholine and acetylcholine, stabilizing neuronal membranes and reducing oxidative stress. Coenzyme Q10 (CoQ10) is a mitochondrial electron carrier and antioxidant that protects against oxidative damage and apoptosis. This narrative review summarizes the published evidence on citicoline and CoQ10 in retinal pathologies, focusing on the last ten years.

**Methods:** The authors conducted a narrative review of the literature, primarily covering studies published in the last decade. They searched for experimental and clinical studies evaluating citicoline or CoQ10 in retinal diseases. The review includes in vitro, animal model, and human studies, with a focus on glaucoma, DR, AMD, NAION, Leber's hereditary optic neuropathy (LHON), and retinitis pigmentosa (RP). The authors extracted data on study design, population, dose, route of administration, and outcomes.

**Key Results:** - **Citicoline and Glaucoma:** In a 3-year randomized double-blind trial (n=78 OAG patients), topical citicoline (0.2 g/day) significantly improved visual field (VF) and retinal nerve fiber layer (RNFL) thickness compared to placebo. Oral citicoline (500-600 mg/day) improved pattern electroretinogram (pERG) and visual evoked potential (VEP) responses, contrast sensitivity, and quality of life (GQL-15) in multiple studies. In a rat glaucoma model, oral citicoline (500 mg/kg) reduced histological alterations in the visual pathway and increased visual acuity. - **Citicoline and NAION:** In 36 NAION patients, oral citicoline (500 mg/day for 6 months) significantly improved visual acuity, pERG, VEP, RNFL thickness, and VF, with effects maintained after a 3-month washout. - **Citicoline and DR:** In db/db mice, topical 2% citicoline improved electroretinogram (ERG) B-wave amplitude and prevented glial activation and apoptosis. In humans with non-proliferative DR (NPDR), topical citicoline 2% plus vitamin B12 for 3 years reduced microvascular damage and neuroretinal degeneration and improved multifocal ERG responses. - **Citicoline and AMD:** In an in vitro model using transmitochondrial AMD RPE cybrid cells, citicoline (1 mM) decreased apoptotic cell death, enhanced cell viability, reduced reactive oxygen species (ROS), and lowered HIF-1α and VEGF gene expression. - **CoQ10 and Glaucoma:** In a rat glaucoma model, topical CoQ10 (0.1%) with α-tocopherol polyethylene glycol succinate (TPGS) (0.5%) reduced RGC loss and gliosis. In OAG patients, topical COQUN® (CoQ10 + vitamin E) improved pERG and VEP in 60% and 50% of patients, respectively. In DBA/2J mice, oral CoQ10 (1,600-2,000 mg/kg) promoted 29% RGC survival, decreased Bax expression, increased pBad, reduced oxidative stress, and preserved mitochondrial DNA. - **CoQ10 and AMD:** In ARPE-19 cells, idebenone (1-100 μM) decreased ROS formation and increased cell survival. In early AMD patients, a combination of fatty acids (1320 mg/day), acetyl-L-carnitine (500 mg/day), CoQ10 (30 mg/day), and vitamin E (30 mg/day) for 3 months improved visual function and reduced drusen area in a randomized double-blind placebo-controlled trial (n=106). - **CoQ10 and LHON:** In the RHODOS trial (n=85), idebenone (900 mg/day) improved mean visual acuity at 24 weeks and tritan color contrast at 12 weeks. A retrospective study (n=111) reported clinically relevant recovery (CRR) of best-corrected visual acuity (BCVA) in 46% of patients, with an average gain of 0.72 logMAR. In chronic LHON patients (onset >5 years), idebenone improved VA by 2-3 logMAR lines. - **CoQ10 and RP:** In Rd10 mice, dietary CoQ10 preserved ERG a-waves and synaptic contacts. In 3 RP patients, oral CoQ10 (100 mg/day for 2.5 months) increased brain energy reserve in 2 patients. - **CoQ10 and DR:** In a rat model of type 2 diabetes, topical idebenone (0.03 M) restored vision from 35% to 58-80% after 3 weeks. In NPDR patients, oral CoQ10 (400 mg/day) improved oxidative and antioxidant biomarkers.

**Clinical Implications:** The review suggests that citicoline and CoQ10 may serve as neuroprotective adjuncts in retinal diseases, particularly glaucoma, DR, AMD, and LHON. Citicoline's effects on membrane stability and neurotransmission, and CoQ10's antioxidant and mitochondrial stabilizing properties, address key pathogenic mechanisms. However, most evidence comes from small human studies or animal models. The authors note that idebenone, a CoQ10 analog, is approved in the EU for LHON, but caution that idebenone and CoQ10 have different pharmacokinetics and may not be interchangeable. They call for larger, well-designed human trials and clinical guidelines for nutraceutical use.