J Clin Neurol.  2009 Mar;5(1):33-38.

Citicoline Protects Against Cognitive Impairment in a Rat Model of Chronic Cerebral Hypoperfusion

• Lee HJ
• Kang JS
• Kim YI

Abstract

BACKGROUND AND PURPOSE: Cerebral white matter (WM) lesions are frequently observed in human cerebrovascular diseases, and are believed to be responsible for cognitive impairment. Various neuroprotective agents can suppress this type of WM or neuronal damage. In this study, we investigated whether citicoline, a drug used to treat acute ischemic stroke, can attenuate WM lesions and cognitive decline caused by chronic hypoperfusion in the rat.
METHODS
Animals were divided into immediate- and delayed-treatment groups. Those in the immediate-treatment group received a sham operation, citicoline (500 mg/kg/day), or phosphate buffered saline (PBS) treatment. Citicoline or PBS was administered intraperitoneally for 21 days after occluding the bilateral common carotid arteries. Rats in the delayed-treatment group were intraperitoneally administered with either 500 mg/kg/day citicoline or PBS for 21 days beginning on the 8th day after the operation. From the 17th day of administration, the rats were placed in an eight-arm radial maze to examine their cognitive abilities. After completing the administration, tissues were isolated for Kluver-Barrera and the terminal deoxynucleotidyl transferase biotin-dUTP nick end labelling (TUNEL) staining.
RESULTS
In the immediate-treatment group, cognitive functions were preserved in the citicoline-treated group, and WM damage and TUNEL-positive cells differed significantly between the citicoline- and PBS-treated animals. In the delayed-treatment group, there was no decrease in WM damage and TUNEL-positive cells, but cognitive improvement was evident for citicoline treatment relative to PBS treatment.
CONCLUSIONS
These results show that citicoline can prevent WM damage and aid cognitive improvement, even after a certain extent of disease progression. Citicoline might be useful in patients with acute ischemic stroke as well as in chronic stroke accompanied with cognitive impairment.

Keyword

chronic cerebral hypoperfusion; rat; citicoline; white-matter damage; cognitive impairment

MeSH Terms

Animals
Carotid Artery, Common
Cytidine Diphosphate Choline
Disease Progression
DNA Nucleotidylexotransferase
Humans
Neurons
Neuroprotective Agents
Rats
Salicylamides
Stroke
Cytidine Diphosphate Choline
DNA Nucleotidylexotransferase
Neuroprotective Agents
Salicylamides

Figure

• 

  Fig. 1 Eight-arm radial maze test of immediate treatments with citicoline, PBS, and a sham operation. Number of TEs (A), number of RMEs (B), and time spent (C). †p<0.05 vs citicoline treatment, §p<0.05 vs citicoline treatment, *p<0.05, **p<0.01 vs. sham operation. PBS: phosphate buffered saline, TEs: total error, RMEs: reference memory errors.

• 

  Fig. 2 Eight-arm radial maze test of delayed treatments with citicoline, PBS, and a sham operation. Number of TEs (A), number of RMEs (B), time spent (C). *p<0.05, **p<0.01. PBS: phosphate buffered saline, TEs: total error, RMEs: reference memory errors.

• 

  Fig. 3 Klüver-Barrera staining for WM damage. Corpus callosum and optic tract of rats that received a sham operation, citicoline, or PBS in the immediate-treatment (A) and delayed-treatment (B) groups. Schematic representation of the rat brain at 3.14 mm posterior to the bregma (C). Grade of Klüver-Barrera staining for WM damage in the corpus callosum and optic tract in the immediate-treatment (D) and delayed-treatment (E) groups. The WM damage was greatest in the optic tract, with less intense changes observed in the medial part of the corpus callosum. Note that citicoline caused less serious WM damage than PBS in both the optic tract and corpus callosum in the immediate-treatment group, whilst there was no significant difference in the delayed-treatment group. Scale bars in A, B=60 µm. *p<0.01, **p<0.001. WM: white matter, PBS: phosphate buffered saline.

• 

  Fig. 4 TUNEL staining in the immediate-treatment group. TUNEL-positive cells were evident both in WM such as the optic tract (A) and internal capsule (B) and also in gray matter such as the infarcted cortex (C) and subventricular zone (D). We only counted positive cells that were also stained with DAPI (E). TUNEL-positive cells in the immediate-treatment (F) and delayed-treatment (G) groups. The number of TUNEL-positive cells was lower for citicoline treatment than for PBS treatment in the immediate-treatment group, whilst there was no significant difference in the delayed-treatment group. Scale bars in A-E=200 µm. *p<0.05, **p<0.001. TUNEL: the terminal deoxynucleotidyl transferase biotin-dUTP nick end labelling, WM: white matter.

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