The Role of Citicoline in Neuroprotection and Neurorepair in Ischemic Stroke
Abstract
:1. Introduction
2. Ischemic Neuroprotection: Brain Protection
- There is a need to protect the entire neurovascular unit that comprises neurons, glia, pericytes and blood vessels [26,27]. For many years the goal was to salvage neurons in the ischemic penumbra but recently it became clear that this goal is insufficient and that all the elements of the neurovascular unit must be rescued from ischemia [28].
- Many of the potential targets have a biphasic cycle whereby the same mediator or molecule plays a different role under pathologic or physiological conditions. For instance, in the earliest phase of ischemic stroke the excitatory glutamate NMDA receptors become hyperactive and mediate cell death, but these same receptors are critical for neurogenesis and neuronal plasticity during the recovery phase of stroke. A similar mechanism occurs with metalloproteases [29,30,31,32,33,34] that contribute to the breakdown of the blood brain barrier (BBB) enlarging the ischemic lesion but are critical also for angiogenesis during the rec
3. Citicoline Neuroprotection in Experimental Stroke
4. Clinical Experience with Citicoline in Stroke Patients
5. Data Pooling Analyses
6. The ICTUS Trial
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- Citicoline had no significant effect on the risk of hemorrhage from rtPA and had a comparable safety and tolerability profile compared to placebo.
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- Global recovery at 90 days was similar in patients who received citicoline and in those who received placebo. Results were also neutral in the secondary endpoints and in the predetermined protocol analyses.
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- Under the circumstances of the ICTUS trial, citicoline is safe but does not provide efficacy evidence for the treatment of moderate-to-severe acute ischemic stroke.
- Patients had more severe strokes in the ICTUS trial, as demonstrated by the NIH-SS 15 [11,12,13,14,15,16,17,18,19] vs. 14 [10,11,12,13,14,15,16,17,18] in previous studies; this renders more difficult the demonstration of a favorable effect; the main end-point required global improvement of both neurological and functional measurements. In fact, in the ICTUS trial the mRs 0–2 was 29% vs. 39% for pooled cases.
- It is conceivable that larger doses for a longer period could have had a positive effect. In the previously noted meta-analysis of experimental data [41] greater reduction of infarct volume occurred in rats treated with larger doses of citicoline (300–500 mg/kg), along with superior recovery (27%; 95% CI 9–46) in comparison with animals treated with lower doses (100–300 mg/kg) with 18% recovery (95% CI 5–32; p > 0.001). Larger reduction of stroke volume was also documented in another study [61]; moreover, citicoline at high doses is as effective as i.v. thrombolysis in experimental stroke [62].
- Patients enrolled in the ICTUS trial were not required to have neuroimaging studies of ischemic penumbra. Therefore, it was impossible to determine if at the onset of therapy salvageable brain tissue was present; moreover, this lack of images prevented accurate evaluation of stroke evolution. The latter is highly relevant given that in the ECCO 2000 Citicoline Trial—DWI Sub-study a comparison of DW-MRIs obtained at baseline with T2 MR images at week 12 of treatment with citicoline (2 g/day for six weeks) showed a significant decrease in volume of the cortical lesion [53]; this reduction in lesions size was associated with better clinical outcome, as mentioned above.
- Finally, a substantial number of patients received i.v. rtPA rendering the analysis of the results more difficult since many patients reached the maximum possible recovery with the thrombolytic treatment. Thus, a ceiling effect resulting from an already maximal improvement due to rtPA effect cannot be ruled out. Almost half of the patients (47%) in the ICTUS trial received i.v. rtPA compared with only 13% in the pooled data analyses. Additionally, the trials were done 10 years apart, a period of time during which the standard of stroke care has improved substantially.
7. Hemorrhagic Stroke
8. Brain Neurorepair
9. Neurorepair Therapies
10. Citicoline and Brain Neurorepair
11. Citicoline in Post-Stroke Cognitive Decline
12. Expert Opinion
Conflicts of Interest
References
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Álvarez-Sabín, J.; Román, G.C. The Role of Citicoline in Neuroprotection and Neurorepair in Ischemic Stroke. Brain Sci. 2013, 3, 1395-1414. https://doi.org/10.3390/brainsci3031395
Álvarez-Sabín J, Román GC. The Role of Citicoline in Neuroprotection and Neurorepair in Ischemic Stroke. Brain Sciences. 2013; 3(3):1395-1414. https://doi.org/10.3390/brainsci3031395
Chicago/Turabian StyleÁlvarez-Sabín, José, and Gustavo C. Román. 2013. "The Role of Citicoline in Neuroprotection and Neurorepair in Ischemic Stroke" Brain Sciences 3, no. 3: 1395-1414. https://doi.org/10.3390/brainsci3031395