Download Pharmacodynamics of citicoline relevant to the treatment of glaucoma

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. The possibility
that systemic citicoline treatment may protect RGC from
degeneration, enhance functions of failing retinal and postretinal visual patways, or promote the reversal of RGC
and axonal damage in glaucoma deserves further evaluation, both in animal models and in a clinical setting.
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