Targeting the Brain: Neuroprotection and Neurorestoration in Ischemic Stroke

Jeffrey L. Saver, M.D., FAHA, FAAN

Disclosures

Pharmacotherapy. 2010;30(7):62S-69S. 

In This Article

Choline Precursors as Potential Neuroreparative Agents

Choline precursors are exogenous agents that are converted to choline in the body and promote the maintenance, repair, and de novo formation of cell membrane phospholipids and the neurotransmitters acetylcholine and dopamine. A variety of choline precursor agents have been tested in clinical trials, including choline, lecithin, and choline alphoscerate, but by far the largest experience has been gained with citicoline.[22,23] Citicoline is currently available by prescription in over 50 countries and is available in the United States as an over-the-counter nutritional supplement.

Cell membranes and mitochondrial membranes are essential for maintaining cellular homeostasis, activity of membrane-associated enzymes, coupling of membrane receptor and intracellular signaling, nerve impulse conduction, and oxidative energy metabolism. The synthesis of 80% of central nervous system phospholipids can be altered by modulating the concentration of citicoline. In preclinical models, exogenously administered citicoline promotes rapid repair of injured cell surface and mitochondrial membranes and maintenance of cell integrity and bioenergetic capacity.

Early investigations of citicoline in stroke models focused on potential acute neuroprotective effects. Mechanistic studies showed that citicoline downregulates phospholipases to reduce apoptotic and necrotic cell death and decreases free fatty acid release from membranes and the formation of toxic oxygenated metabolites and free radicals. In animal models, acute administration of citicoline reduced infarct size and improved behavioral outcomes.

More recent studies have revealed substantial neuroplasticity-enhancing properties of citicoline. Because cell membrane phospholipids have a very high turnover rate, continuous synthesis of replacement compounds is required to maintain cell integrity, even in normal circumstances. Greater demand for phospholipid generation arises during the perinatal and the subacute poststroke period to support axonal sprouting, synaptogenesis, and neuronogenesis. As formation of citicoline is the rate-limiting step in the generation of phosphatidylcholine through the Kennedy cycle, exogenously administered citicoline can accelerate phospholipid synthesis and neural repair.

Two recent animal model studies illustrate the evidence for a neuroplasticity-enhancing effect of citicoline. In one investigation, middle cerebral artery infarcts were made in adult Sprague-Dawley rats.[24] Beginning 24 hours after infarct onset, beyond the acute neuroprotective period, animals received either citicoline or saline placebo for the next 28 days. Animals receiving citicoline behaviorally showed substantially greater recovery on tests of sensorimotor integration (staircase skilled reaching) and asymmetric motor behavior (elevated body swing test). Citicoline-treated animals also showed neuroanatomic evidence of enhanced motor plasticity and reorganization. Layer V pyramidal cells in the contralesional motor cortex exhibited more dendritic branches, greater branch complexity, and increased density of synaptic spines in terminal branches in animals receiving citicoline than in saline controls.

The effect of citicoline on brain plasticity during the perinatal period was investigated.[25] In the in vitro part of the study, citicoline-treated culture of somatosensory neurons developed longer neurites and more branch points, resulting in a larger arborized field. In the in vivo part of the study, citicoline was administered to Long Evans rats daily from conception until 2 months after birth and pyramidal neurons from supragranular layers 2 and 3, granular layer 4, and infragranular layer 5 of somatosensory cortex were analyzed. Among citicoline-treated animals, the length and complexity of both apical and dendritic branches were substantially enhanced.

The clinical trial experience with citicoline in stroke similarly provides a signal of potential neuroplasticity-enhancing benefit. In a recent meta-analysis of 10 randomized clinical trials enrolling 2279 patients with ischemic or hemorrhagic stroke, treatment with citicoline reduced the rate of death or dependency at longterm follow-up from 67.5% to 57.0% (odds ratio 0.64, 95% confidence interval, 0.54–0.77; p<0.00001).[23] Although the design of the trials does not allow definite disambiguation of neuroprotective and neuroreparative treatment effects, the time windows for enrollment and duration of therapy suggest that neuroplasticity enhancement would have predominated over acute neuroprotection. In all of the trials, treatment duration was for extended time periods, ranging from 10 days–6 weeks, subacute periods during which neuroplasticity enhancement effects would be expected to occur. Except for one small trial in patients with hemorrhagic stroke, the permitted time windows for patient entry were late. Across all studies, 83% of patients were enrolled in trials permitting enrollment up to 24 hours after onset and 15% of patients were in trials permitting enrollment up to 48 hours to 14 days after onset. With these long enrollment windows, likely very few patients would have received the study agent in the first 1–3 hours after onset, when neuroprotective effects would be greatest.

Evidence from magnetic resonance imaging (MRI) in clinical trials of citicoline similarly supports a predominant neurorepair rather than neuroprotective effect when the agent is administered to patients relatively late after stroke onset. In a pooled analysis of patients enrolled in two trials, among 214 analyzed patients, citicoline reduced the growth of ischemic lesion volume from study entry to 12 weeks in a dose-dependent fashion: 82% growth with placebo versus 34% growth with citicoline 500 mg/day and 2% growth with citicoline 2000 mg/day (p=0.015).[26] A more fine-grained analysis can be made of the Citicoline 010 trial, which randomized patients up to 24 hours from stroke symptom onset to citicoline or placebo for 6 weeks.[27] The MRI ischemic lesion volume measures were performed at entry, week 1, and week 12, permitting separate analysis of early and late lesion evolution. Strikingly, citicoline did not attenuate the volume of infarct growth in week 1 (increase of 28.4 ml for citicoline vs 25.7 ml for placebo), but did enhance lesion reduction between weeks 1 and 12 (−17.2 ml for citicoline and −6.9 ml for placebo, p<0.01), potentially consistent with a late neuroreparative effect as perilesional tissue more vigorously filled in the infarct bed (Figure 2).[27]

Figure 2.

Evolution of lesion volume among 81 patients randomized to citicoline or placebo within 24 hours of onset of ischemic stroke. Absolute change from baseline to week 1 did not significantly differ between treatment groups, but from week 1 to week 12, reduction in lesion volume was greater in the citicoline group (−17.2 ml vs −6.9 ml, p<0.01). (From reference 27.)

Additional support for a neuroreparative effect of citicoline in ischemic stroke comes from a recent trial comparing a standard and a prolonged citicoline dosage regimen. Spanish investigators performed a randomized, open-label trial to determine if prolonged citicoline therapy improves cognitive outcome after first ever ischemic stroke.[28] All patients received citicoline 2000 mg/day for 6 weeks, started within 24 hours of stroke onset. Patients were then randomized to discontinue therapy or to receive citicoline 1000 mg/day until 6 months after stroke. Among the 310 patients completing follow-up, neuropsychologic testing showed fewer abnormalities in orientation (19.5% vs 29.5%, p=0.042) and attentional and executive function (33.8% vs 46.8%, p=0.019) after 6 months compared with 6 weeks of treatment. In other cognitive domains, point estimates also favored the prolonged-therapy group but the difference between groups did not reach statistical significance. Of course, the benefits from therapy extension beyond 6 weeks cannot be attributed to acute neuroprotection and are consistent with a neuroreparative treatment effect.

These tantalizing suggestions of a neuroreparative benefit from citicoline in ischemic stroke, from both basic science studies and modest-sized clinical trials, require confirmation. Presently under way in Europe is a much-needed, large, pivotal trial—the International Citicoline Trial on Acute Stroke (ICTUS)—that will confirm or disconfirm the signals of benefit. In ICTUS, 2600 patients with acute ischemic stroke within 24 hours of onset are being randomized to high-dose citicoline 2000 mg/day or placebo, with treatment initiated intravenously for the first 3 days, then continued orally until 6 weeks.[29] Among the first 550 patients enrolled, median time from stroke onset to treatment start was 4.5 hours, suggesting that ICTUS results will reflect combined neuroprotective and neuroreparative effects of citicoline. Additional studies of citicoline's effects specifically on late brain reorganization are warranted, including functional MRI and voxel-based morphometry MRI investigations, trials testing whether citicoline may potentiate constraint-induced recovery techniques in patients with chronic stroke, staggered-start trials comparing acute versus subacute initiation of citicoline (disentangling acute neuroprotection from subacute neurorepair), and staggered-end trials comparing standard versus prolonged continuation of therapy (determining the duration of the subacute window during which neuroplasticity enhancement may be effective).

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