Citicoline for Glaucoma

Article by Vincenzo Parisi, submitted to FitEyes by Robert Ritch MD

The natural history of glaucoma involves the early impairment of the innermost retinal layers, which may precede the onset of visual field defects,(Parisi et al. 2006) subsequently followed by damage due to transynaptic degeneration in post-retinal visual pathways and, in particular, at the level of the lateral geniculate nucleus.(Yücel et al. 2003) Glaucoma must not be considered exclusively as a disease involving ocular structures, but a pathology in which regions of the brain involved in vision are also compromised.

The possibility of inducing an improvement of glaucomatous visual function pharmacologically with cytidine-5’-diphosphocholine (citicoline) was suggested in 1989.(Pecori Giraldi et al. 1989) A similar treatment was used in different brain disorders ascribed to vascular, traumatic or degenerative processes.(Zappia et al. 1985; Cacabelos et al. 1996)

Citicoline (exogenous CDP-choline) is a nontoxic and well-tolerated substance that acts as an intermediary in the synthesis of phosphatidylcholine, a major phospholipid in the neuronal membrane, through = activation of the biosynthesis of structural membrane phospholipids. It increases the metabolism of cerebral structures and inhibits phospholipid degradation. Enhancement of phosphatidylcholine synthesis may counteract neuronal apoptosis and provide neuroprotection.(Grieb &  Rejdak 2002) Citicoline has been reported to have a neuroprotective effect on kainic acid-induced neurotoxicity in the retina.(Han et al. 2005)

Citicoline may therefore have potential neuroprotective and neuromodulator roles, as demonstrated in conditions of cerebral hypoxia and ischemia.(Secades &  Frontera 1995; Weiss 1995) In addition, it induces an increase in the levels of different neurotransmitters and neuromodulators, including noradrenaline, in the central nervous system. Several studies suggest that citicoline successfully increases the level of consciousness in different brain disorders ascribed to vascular, traumatic or degenerative processes.(Zappia et al. 1985; Cacabelos et al. 1996) When administered, citicoline is rapidly transformed to cytidine and choline, which are believed to provide neuroprotection by enhancing phosphatidylcholine synthesis; a similar effect may occur in glaucomatous retinal ganglion cells.(Grieb &  Rejdak 2002)

The first studies reported that treatment with citicoline could induce an improvement of glaucomatous visual field defects.(Pecori Giraldi et al. 1989) Subsequent studies questioned whether this improvement was related to a real enhancement of ganglion cell function and neural conduction along the visual pathways, or whether it was due to the associated effects of citicoline on the level of consciousness and attention.(Cacabelos et al. 1996)

To explore these hypotheses, further studies evaluated the effects of oral (1600 mg/die) or intramuscular (1000 mg/die) citicoline treatment, administered for 60 days, on retinal function and neural conduction in the visual pathways of glaucoma patients with moderate visual defects; these studies used an electrophysiological approach, pattern electroretinograpy, to evaluate ganglion cell function and visual evoked potentials to evaluate neural conduction along visual pathways.(Parisi et al. 1999; Parisi et al. 2008) Oral or intramuscular treatment with citicoline induced an improvement of both PERG and VEP responses, with an increase in amplitudes and a shortening in times-to-peaks.

Nevertheless, the beneficial effects of citicoline were treatment-dependent. In particular, 300 days after the end of treatment, no differences were detected with respect to pre-treatment conditions. When a second period of citicoline administration was performed, it was observed that even after a long period of wash-out (120 days), the improvement in visual function was once again evident, suggesting that repeated treatments may inhibit the development of the visual impairment.(Parisi et al. 1999; Parisi et al. 2008)

The effects of citicoline on the neural visual system were revealed by improvement in visual acuity,(Porciatti et al. 1998) in VEP responses, and in contrast sensitivity in amblyopic subjects after treatment. Since similar results were obtained in amblyopic subjects with levodopa,(Leguire et al. 1993) and in studies of patients with Parkinson’s disease, citicoline was recommended as a complement to levodopa therapy.(Birbamer et al. 1990) The addition of CDP-choline to patching therapy was no more effective than patching alone after 30-days, but that adding CDP-choline to patching stabilised the effects obtained during treatment of amblyopia.(Fresina et al. 2008) A dopaminergic-like activity could be suggested to explain PERG and VEP results after treatment with citicoline.

These results raise an interesting question: can oral or intramuscular citicoline effects be considered as “neuroprotective”, preventing the development of glaucoma? Considering that after the first period of wash-out there were no differences with respect to pre-treatment conditions, one cycle of treatment with citicoline is not sufficient to induce changes in the natural history of glaucoma. On the other hand, we observed that the second treatment period with oral citicoline induced an improvement which persisted after 120 days of wash-out.

The results obtained in the first study(D'Andrea et al. 1989) were further explored in a restricted cohort of selected patients (12 OAG patients only), in which a series of 60 day-periods of treatment each followed by 120 days of wash-out, were carried out during a total period of 8 years.(Parisi 2005) This study showed that after 8 years, glaucomatous patients subjected to citicoline treatment displayed a stable or improved electrophysiological and visual field condition compared to pre-treatment (8 years before), while in similar glaucoma patients without  citicoline treatment, there was worsening of the electrophysiological and visual field impairment with respect to pre-treatment conditions (8 years before).

Indeed, the data observed in glaucoma patients treated with beta-blockers plus several periods of treatment with intramuscular citicoline with respect to results in glaucoma patients treated with beta-blockers only may suggest the potential use of citicoline in order to obtain the stabilisation or improvement of visual function in glaucoma.

In agreement with similar studies,(Secades &  Frontera 1995; Weiss 1995; Porciatti et al. 1998; Parisi et al. 1999; Parisi 2005) an important aspect is the lack of adverse pharmacological side effects in all participating subjects, even after long-term administration of the drug.

All this indicates the potential use of citicoline in the medical treatment of glaucoma, as a complement to hypotensive therapy, with a possible direct neuroprotective effect.

Here is a related abstract:

Evidence of the neuroprotective role of citicoline in glaucoma patients.

Prog Brain Res. 2008;173:541-54. doi: 10.1016/S0079-6123(08)01137-0.
 

Vincenzo Parisi, Coppola G, Centofanti M, Oddone F, Angrisani AM, Ziccardi L, Ricci B, Quaranta L, Manni G.

The glaucomatous disease is currently considered a disease involving ocular and visual brain structures. This new approach to glaucoma introduces the possibility of inducing an improvement by means of a pharmacological approach similar to that used in different degenerative brain disorders. In line with this hypothesis, we studied the effects of oral (1600 mg/die, Cebrolux, Tubilux Pharma, Pomezia, Rome, Italy) or intramuscular (1000 mg/die, Cebroton, Tubilux Pharma) cytidine-5'-diphosphocholine (citicoline) treatment on retinal function and neural conduction in the visual pathways of glaucoma patients with moderate visual defects. Improvement of retinal function (objectively evaluated by pattern electroretinogram recordings) and of neural conduction along visual pathways (objectively evaluated by visual evoked potential recordings) were observed in glaucoma patients after two 60-day periods of oral or intramuscular treatment with citicoline. However, partial regression of this improvement was detected after two 120-day periods of washout. This suggests that the beneficial effects observed are in part treatment-dependent. The extension of citicoline treatment up to a period of 8 years lead to the stabilization or improvement of the glaucomatous visual dysfunction. These results suggest potential neuroprotective effects of citicoline in the glaucomatous disease.

PMID: 18929133

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