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Journal of Neuroscience Research 67:143–148 (2002) Mini-Review Pharmacodynamics of Citicoline Relevant to the Treatment of Glaucoma Pawel Grieb1* and Robert Rejdak2,3 1 Laboratory of Experimental Pharmacology, Medical Research Center, Polish Academy of Sciences, Warsaw, Poland 2 Department of Pathophysiology of Vision and Neuro-Ophthalmology, University Eye Hospital, Tubingen, Germany 3 Second Ophthalmology Clinic, Medical School of Lublin, Lublin, Poland Citicoline (exogenous CDP-choline) is a nontoxic and well-tolerated drug used in pharmacotherapy of brain insufficiency and some other neurological disorders, such as stroke, brain trauma, and Parkinson’s disease. A few reports indicate that citicoline treatment may also be beneficial in glaucoma. Currently glaucoma is considered a neurodegenerative disease in which retinal ganglion cells (RGC) slowly die, likely in the apoptotic mechanism. Endogenous CDP-choline is a natural precursor of cellular synthesis of phospholipids, mainly phosphatydylcholine (PtdCho). Enhancement of PtdCho synthesis may counteract neuronal apoptosis and provide neuroprotection. Citicoline, when administered, undergoes a quick transformation to cytidine and choline, which are believed to enter brain cells separately and provide neuroprotection by enhancing PtdCho synthesis; similar effect may be expected to occur in glaucomatous RGC. Furthermore, citicoline stimulates some brain neurotransmitter systems, including the dopaminergic system, and dopamine is known as a major neurotransmitter in retina and postretinal visual pathways. In a double-blind, placebo-controlled study, treatment of glaucoma resulted in functional improvement in the visual system noted with electrophysiological methods. Development of citicoline as a treatment for glaucoma is indicated. © 2002 Wiley-Liss, Inc. Key words: citicoline; dopamine; glaucoma; neuroprotection; retinal ganglion cells Citicoline is the International Nonproprietary Name of cytidine-5⬘-diphosphocholine (CDPCho). This compound is marketed in several countries either as a prescription drug (e.g., in Japan, Italy, France, and Spain) or as an OTC substance (e.g., in the United States). According to a recent metaanalysis of several double-blind, placebocontrolled trials (Fioravanti and Yanagi, 2000), citicoline is moderately effective in cognitive and behavioral disturbances associated with chronic cerebral disorders in the © 2002 Wiley-Liss, Inc. DOI 10.1002/jnr.10129 elderly. Some beneficial effects have also been documented in stroke (Tazaki et al., 1988), brain trauma (Calatayud et al., 1991), Parkinson’s disease (Cubells and Hernando, 1988), and Alzheimer’s disease (Alvarez et al., 1999a). The negligible toxicity of this drug is notable. The LD50 is 4.6 g/kg in mice and 4.15 g/kg in rats following intravenous administration and approximately 8 g/kg in both species when it is ingested (Grau et al., 1983). Acute toxicity of citicoline has been found to be two orders of magnitude lower than that of choline (LD50 by the i.v. route 4.6 g/kg and 53 mg/kg, respectively; Augt et al., 1983). In a phase IV study, almost 3,000 elderly patients (age ⬎50 years) with various chronic neurological diseases (senile involution, sequeals of cerebral vascular accidents, etc.) were treated orally with 600 mg/day for 15– 60 days, and the incidence of side effects was 5.01% (none of them serious; Lozano, 1983). Although none of the recent reviews on citicoline (Weiss, 1995; Secades and Frontera, 1995; D’Orlando and Sandage, 1995) mentioned its possible application for treatment of glaucoma, a few clinical trials reported to date ahve indicated some benefits of such treatment (Pecori Giraldi et al., 1989; Parisi et al., 1999; Virno et al., 2000). The aim of the present review is to provide a rationale for further development of this drug for glaucoma treatment. NEUROPROTECTIVE TREATMENT FOR GLAUCOMA Glaucoma is currently recognized as a chronic neurodegenerative disease in which selective death of retinal ganglion cells (RGC) associated with structural changes in the optic nerve head occurs (Osborne et al., 1999c; Naskar and Dreyer, 2001). Its most common form, primary open*Correspondence to: Pawel Grieb, Laboratory of Experimental Pharmacology, Medical Research Center, Polish Academy of Sciences, Pawiñskiego 5, 02-106 Warsaw, Poland. E-mail: [email protected] Received 10 October 2001; Accepted 14 October 2001 Published online 14 December 2001 144 Grieb and Rejdak angle glaucoma, is characterized by chronically elevated intraocular pressure (IOP). However, up to one-third of all glaucoma patients have normal IOP (Douglas, 1998), and conventional treatment of primary open-angle glaucoma able to control IOP retards, but does not stop, the progression of blindness (Nickells, 1996; Schwartz et al., 1996). Thus, although increased IOP is an important risk factor (Osborne et al., 1999a), pressure-independent mechanisms are undoubtedly involved (Hartwick, 2001). The evidence is accumulating that in glaucomatous eyes ganglion cells die by apoptosis (Nickels, 1996; Tatton et al., 2001). The nature of the insult(s) initiating the apoptotic process is debated. One hypothesis supported by some experimental (Bunt-Milam et al., 1987) and clinicopathological (Quigley, 1995) evidence indicates axons as the primary site of injury. Apoptotic RGC degeneration may occur in response to the blockage of retrograde axonal transport (likely at the level of lamina cirrhosa), causing deprivation of trophic factors essential for maintenance of neuronal systems (such as brain-derived neurotrophic factor, BDNF; Pease et al., 2000). However, there is some evidence that RGC receive BDNF mainly from intraretinal sources (Herzog and von Bartheld, 1998) and that retrograde BDNF cannot rescue these cells in the long term (Isenmann et al., 1999). According to the other hypothesis, RGC apoptosis is triggered by a particular form of ischemia (Osborne et al., 1999b). This concept corresponds with findings that patients with both primary open-angle and normal-tension glaucoma frequently display various ocular blood flow deficits (Harris et al., 1999). These conditions may produce either recurring episodes of acute retinal ischemia or a chronic, albeit incomplete, retinal ischemia. RGC display a variety of glutamate receptors (Aizenman et al., 1988), and they actually were the first neurons in which glutamate-induced cell death was demonstrated (Lucas and Newhouse, 1957). Several lines of evidence are suggestive of the involvement of glutamate excitotoxicity in the pathogenesis of glaucoma (Vorwerk et al., 1999). In humans a twofold elevation of glutamate has been detected in the vitreous body of glaucomatous eyes compared with the control cataract eyes (average values 27 M and 11 M, respectively; Dreyer et al., 1996). A similar phenomenon has been found in dogs with breed-related primary open glaucoma (glutamate level in the vitreous 31.7 M vs. 6.9 M in normal control dogs; Brooks et al., 1997). Even larger rises in glutamate have been detected in macaque monkeys in which glaucoma was experimentally induced (Dreyer et al., 1996) and in rabbits subjected to optic nerve ischemia induced either by local endothelin-1 infusion (Kim et al., 2000) or by transient simultaneous ligature of the optic nerve, ciliary arteries, and extraocular muscles (Kageyama et al., 2000). On the other hand, numerous in vitro studies have shown that increased glutamate and the glutamate agonists kainate and N-methyl-D-aspartate (NMDA) are selectively toxic to some RGC, and in adult pig retina (thought to resemble human retina closely) this toxicity appears to be me- diated by both NMDA and non-NMDA receptor pathways (Luo et al., 2001). Intravitreal injections of NMDA have induced caspase- and poly(ADP-ribose) polymerasedependent apoptosis of retinal cells (Lam et al., 1999). Of particular relevance is the in vivo study showing that a moderate (⬍30 M) increase in vitreal glutamate, when maintained chronically, is toxic to RGC (Vorwerk et al., 1996). It should be mentioned, however, that, in the rat, protection of retinal cells against NMDA toxicity by intraocular pretreatment with the specific metabotropic glutamate receptor agonist (1S,3R)-1-aminocyclopentane1,3-dicarboxylic acid has been found in one study (Siliprandi et al., 1992). There is also some indication that both hypotheses may be correct, because in the etiology of glaucoma inadequate supply of neurotrophic factors may synergize with exitotoxicity. In human glaucomatous eyes, a downregulation of retinal excitatory amino acid transporter EAAT1 expression (concurrent with a down-regulation of the NMDAR1 glutamate receptor) has been found (Naskar et al., 2000). It is possible that increased glutamate in vitreous fluid results from failure of glutamate transporters, and it may also lead to a perturbation in glutamate receptors. Interestingly, in the rat, injection of eyes with glial-derived neurotrophic factor (GDNF) elevated both EEAT1 and NMDAR1 in retina (Naskar et al., 2000), and intravitreal BDNF injections protected retinas from NMDA-induced retinal degeneration (Kido et al., 2000). To explain the chronic character of RGC death in glaucoma, Osborne et al. (1999c) have proposed three models: 1) All ganglion cells are initiated to die at the same time, but their death is variable because of differences in individual susceptibility to the initiating insult; 2) the cells die at similar rates, but their deaths are triggered by a series of insults occurring at different times; and 3) the initiating insult eliminates a subgroup of the most susceptible cells and disrupts the internal balance in the retina, and a subsequent secondary degenerative death of the other cells follows. In any case, it usually takes years for some ganglion cells to degenerate, leaving plenty of time for pharmacological interventions aimed at preventing their death. Although many compounds have been shown to protect brain neurons against lethality of various insults in vitro and in vivo, none of them has been tested in glaucoma (Ritch, 2000). Probably the only exception is ␣2adrenergic agonist brimonidine, which, along with its primary effect of reducing IOP, may display some independent neuroprotective properties in retina (Cantor, 2000). Osborne et al. (1999b) postulated that a putative neuroprotectant is likely to attenuate ganglion cell death and benefit glaucoma patients provided that it can be administered in such a way that it reaches the retina in appropriate amounts and has insignificant side effects. Citicoline may have the potential to fulfill these requirements. INTRACELLULAR CDP-CHOLINE AND METABOLISM OF PHOSPHATIDYLCHOLINE Citicoline is not a xenobiotic substance. CDPCho is a natural constituent of all cells, where it serves as the Citicoline for Glaucoma intermediate in phosphatidylcholine (PtdCho) synthesis via the Kennedy pathway (Kent and Carman, 1999). CDPCho is formed from phosphocholine (PCho) and cytidine-5⬘-triphosphate (CTP) in a reversible reaction catalyzed by the CTP:phosphocholine cytidyltransferase (CT). PCho is supplied by phosphorylation of choline (Cho) entering cells via the adenosine triphosphate (ATP)dependent Cho transporter present in the cell membrane [although intracellular Cho and PCho recycling may also take place (Jansen et al., 2001)]. CTP is derived from uridine-5⬘-triphosphate or may be formed by phosphorylation of Cyt. The second step is catalyzed by CDPcholine:1,2-diacylglicerol choline-phosphotransferase (CPT). In this pathway, CT is the regulatory enzyme, and PtdCho synthesis is dependent on the supply of Cho and Cyt from extracellular sources (Kent and Carman, 1999). PtdCho comprises numerous molecular species of phospholipids, which differ in hydrocarbon chains attached to glycerophosphocholine. In mammals, PtdCho accounts for more than half of all cellular phospholipids, in particular in the brain (Sastry, 1985). They not only are important structural components of the membranes but also serve as major reservoirs of free fatty acids (FFA), such as arachidonic acid (AA) and diacylglycerols (DAG), released by various phospholipases. Catabolism of PtdCho plays an important physiological role in cellular transduction processes in which AA and DAG act as intracellular messengers (Exton, 1995), including light transduction in retina (Giusto et al., 1997; Lee et al., 2001). However, massive degradation of phospholipids following various insults is detrimental to the cells. Brain PtdCho catabolism is enhanced following ischemia, seizures, or trauma; the effect is attributed mainly to the activation of phospholipase A2 (PLA2; Farooqui et al., 1997). Resulting accumulation of AA and other FFA may be an important contributor to cell death. Mitochondrial dysfunction, possibly related to the degradation of inner mitochondrial membrane cytoskeleton by PLA2 and followed by cell calcium overload and energy failure, has been discussed as a probable mechanism (Kristan and Siesjo, 1998). The same may also occur in glaucomatous RGC (Tatton et al., 2001). We were unable to find any data concerning FFA in glaucomatous vs. normal eyes, but a recent observation that polyunsaturated FFA (mainly AA and docosahexanoic acid) accumulate in human retina with age (Nourooz-Zadeh and Pereira, 1999) may be relevant, in that age is the major risk factor for glaucoma. Inhibition of PtdCho breakdown or stimulation of PtdCho synthesis may spare cells from apoptotic death. In fibroblasts, activation of the proapoptotic ceramide liberation from sphingolipids inhibited PtdCho synthesis, and the maintenance of glycerophospholipid, in particular PtdCho, synthesis seemed to be essential in preventing cells from undergoing apoptosis (Bladergroen et al., 1999). NEUROPROTECTION BY CITICOLINE Results obtained with double-labeled 3H-CDPmethyl-14C-Cho (Galetti et al., 1985; 1991) indicated that citicoline given i.v. or orally undergoes a quick hydrolysis 145 to cytidine-5⬘-monophosphate (CMP) and PCho. In the perfused liver system, citicoline completely disappeared from perfusate within 10 min, whereas PCho and, in particular, CMP were much more stable. However, because phosphorylated substances are unable to cross biological membranes, it is usually assumed that CMP and PCho derived from the hydrolysis of citicoline are further dephosphorylated by phosphatases before they enter brain cells. In agreement with this assumption, direct measurements have shown that citicoline given orally produced an increase of plasma Cyt and Cho levels in rodents, and the effect of the former was more pronounced than that of the later (Lopez-Coviella et al., 1995). In humans receiving oral citicoline, a dose-dependent increase in plasma Cho has also been found, but elevation of plasma uridine instead of Cyt was seen. It seems likely that the circulating substrates through which oral citicoline may increase membrane phospholipid synthesis in human neural tissues involve uridine and choline (Wurtman et al., 2000). Citicoline increases the formation of PtdCho and other phospholipids in brain in vitro as well as in vivo (Lopez-Coviella et al., 1995; Wang and Lee, 2000) and at the same time prevents ischemia-triggered tissue accumulation of FFA (Trovarelli et al., 1981). As discussed in the previous section, these effects should be antiapoptotic and neuroprotective. Indeed, neuroprotective effects of citicoline administration have been observed, e.g., in the gerbil model of delayed death of hippocampal CA1 neurons following transient forebrain ischemia (Rao et al., 1999; Grieb et al., 2001), experimental stroke (Aronowski et al., 1996; Schabitz et al., 1996), hyperglycemic oligemiahypoxia (Rejdak et al., 2001), and neuronal apoptosis induced by -amyloid precursor protein deposits plus hypoperfusion (Alvarez et al., 1999b). Neuroprotection following citicoline may be the consequence of stimulation of brain PtdCho synthesis (Rao et al., 2001). Citicoline may act also through stimulating S-adenosyl-Lmethionine to stabilize membranes and prevent AA release (Rao et al., 1999). In the gerbil model of transient forebrain ischemia, the choline moiety of citicoline seems to be critical for rescuing CA1 hippocampal neurons from the delayed death (Grieb et al., 2001). One may argue that, in a chronic neurodegenerative disease such as glaucoma, enhancing PtdCho synthesis by citicoline might be detrimental in that it could fuel further PtdCho degradation and stimulate the accumulation of toxic FFA. However, such a possibility seems unlikely in view of the observation that citicoline (given orally) abolished brain PLA2 stimulation following cryogenic brain injury (Arrigoni et al., 1987). Averting postinsult brain PLA2 activation may be an important mechanism of neuroprotection provided by citicoline (Rao et al., 2001). Ischemic release of glutamate from neurons may be secondary to phospholipase-induced disruption of plasma membranes (Phillis and O’Regan, 1996), so citicoline may also attenuate glutamate excitotoxicity. 146 Grieb and Rejdak CITICOLINE AND DOPAMINERGIC NEUROTRANSMISSION Along with its neuroprotective properties, citicoline is known to increase in some brain areas the levels and enhance the rate of synthesis of acetylcholine, dopamine, noradrenalin, and serotonin (Seccades and Frontera, 1995; Weiss, 1995; and references therein). Choline is the precursor of acetylcholine, and this may explain the cholinergic effect of the drug. Mechanisms leading to the stimulation of brain catecholamines by citicoline remain much less well understood. However, the dopamine-stimulating effect seems clearly responsible for the beneficial neurologic responses seen in patients with Parkinson’s disease (PD) treated with citicoline alone (Agnoli et al., 1982) or combined with levodopa (Eberhardt et al., 1990). Dopamine is a major neurotransmitter in mammalian retina, where it acts both within synapses and by diffusion to more distant targets (Witkovsky and Dearry, 1991), and certain ganglion cells may also use DA to communicate with central visual areas (Simon and Nguyen-Legros, 1995). It is worthwhile noting that, although PD is primarily a disorder of the motor system, a decrease of DA in retina (Nguyen-Legros et al., 1993) and a loss of absolute sensitivity in pattern-evoked electroretinograms (PERG; Gottlob et al., 1987) have been noted in this disease, and electrophysiological studies also demonstrated a dysfunction of higher level visual information processing (Antal et al., 1998). In a recent double-blind, placebo-controlled study involving electrophysiological methods (visual evoked potentials and PERG), functional improvement at the retinal and postretinal level in patients with glaucoma treated with citicoline has been shown (Parisi et al., 1999). Thus, stimulation of dopaminergic system by citicoline may be a common mechanism leading to improvement of motoric symptoms in PD patients and of performance of retinal and postretinal visual pathways in glaucoma. In agreement with this hypothesis is the finding that, for rabbits treated parenterally with citicoline, we have recently observed a significant increase of DA concentration in retina (unpublished results). It may also be worthwhile to determine whether citicoline improves visual performance in PD. CONCLUDING COMMENTS Although the evidence for beneficial effects of citicoline in glaucoma is sparse, results of two long-term, open trials have been suggestive that this drug acts positively on the glaucomatous optic nerve damage as assessed perimetrically (Pecori Giraldi et al., 1989; Virno et al., 2000), and one short-term, placebo-controlled study indicated that such a treatment leads to functional improvement in both retinal and suprartetinal pathways (Parisi et al., 1999). Although these observations are not yet sufficient for the introduction of citicoline in standard therapy for glaucoma, they nicely correspond with welldocumented neuroprotective and dopamine-enhancing properties of the drug at the brain level. 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