CITICOLINE

GUEST AUTHOR

MOHSINA

Ajmal Khan Tibiya College

Aligarh

India

• INTRODUCTION

• The eye is regarded as a continuation of the central nervous system (CNS) and correspondingly, glaucoma can be considered a neurodegenerative disorder of the brain.

• Retinal Ganglion Cell (RGC) survival is believed to depend upon a fine balance between survival signals and neurotoxic stimuli.

•  Apoptosis occurs when this balance is disturbed.

• Neuroprotective agents act by either increasing the survival stimuli and/or by hindering the neurotoxic signals and more in general by targeting the mechanisms that trigger the apoptotic cascade.

•  There are experimental and clinical evidences regarding the protective role of Citicoline on RGCs and its neuromodulator effect in glaucoma.

•  This post takes a look at this endogenous compound: Citicoline. 

 CITICOLINE

•  Cytidine 5’ diphosphocholine is a promising molecule for the treatment of glaucoma. It is more commonly known as Citicoline.

• This mononucleotide is composed of ribose, cytosine, pyrophosphate and choline which are intermediate endogenous compounds in the synthesis of membrane phospholipids.

• This molecule acts by stimulating synthesis of phospholipids and phosphotidylcholine, attenuating free fatty acid release and re-establishing cardiolipin phospholipid compound levels in the inner mitochondrial membrane.

•  Citicoline enhances tyrosine hydroxylase activity and inhibits dopamine re-uptake to increase the dopamine level.

• Citicoline also increases the level of other neurotransmitters such as noradrenaline, serotonin and acetylcholine.

• USES AND EFFECTIVENESS

•  1. CEREBROVASCULAR DISEASES

•  Citicoline has a protective role in cerebrovascular and neurodegenerative diseases.

•  2. STROKE RECOVERY

• Citicoline has been effective in reducing infarct volume, brain edema and also in improving the neurological deficit in stroke as well as enhancing the level of consciousness after ischemia.

•  Stroke patients who take Citicoline orally within 24 hours of having an ischemic stroke (a cerebrovascular accident caused by a clot) are more likely than other stroke patients to have a complete recovery within 3 months.

•  3. ALZHEIMER’S DISEASE

• Citicoline has also shown efficacy in Alzheimer’s disease and improving mental performance and brain electrical activity.

• 4. NEUROLOGICAL IMPROVEMENT

•  The use of Citicoline is also associated with significant improvement in the neurological signs and symptoms such as rigidity, bradykinesia and tremors in Parkinson’s disease.

•  5. VISION LOSS

•  Early research suggests that taking Citicoline for 60 days may improve vision in patients with ischemic optic neuropathy.

• 6. GLAUCOMA

• Developing evidence suggests that Citicoline might improve vision in some people with glaucoma.

• CITICOLINE AS NEUROPROTECTANT

• A few experimental and clinical studies have shown that Citicoline can serve as a neuroprotectant.

•  EXPERIMENTAL STUDIES

• Rejadak: Compared intraperitoneal injection of Citicoline (50 g/kg BW) twice daily in albino rats versus vehicle injection in control group. At the end of the study dopamine levels were higher in animals treated with Citicoline compared to control group, adrenaline concentration was slightly higher and noradrenaline remained unchanged.

• Oshitari: Studied the effect of Citicoline on damaged RGCs using quantitative analysis of TdT-dUTP terminal nick-end labeling (TUNEL) positivity in the ganglion cell layer (GCL) and the assessment of the amount of regenerating neuritis. The proportion of TUNEL-positive clls in the GCL was very low in mouse retina treated with 0.1-10 mmol/L compared to the control group (p<0.05). the authors postulated an antiapoptotic effect of Citicoline in mitochondria-dependent cell death mechanism and its ability in supporting axon regeneration.

• Shuettaf: Intraperitoneal injection of vehicle, Citicoline, lithium or Citicoline-lithium combination was studied in adult rats. The density of RGCs connected with the superior colliculus was higher in animals treated with Citicoline compared to those treated with vehicle.

• Park: In a rat model of Kainic acid-induced retinal damage, animals injected with intraperitoneal Citicoline had significant attenuated reduction in retinal thickness.

• Matteucci: Cell culture studies using embryonic rat retina found the apoptotic rate significantly reduced in those treated with Citicoline.

• Zerbini & also Oshitari: Retinal nerve fibers treated with Citicoline eyedrops showed decreased number of apoptotic cells and suppression of caspase-3 and -9 activities.

• CLINICAL STUDIES

•  Giraldi: A study conducted in 1989 reported improvement of visual fields in 75% eyes on serial visual field analysis in patients with open angle glaucoma following intramuscular injection of Citicoline. The drug was given in a dose of 1 gm for 10 consecutive days. The patients were examined at baseline, 15 days and 3 months after the injection. The authors noted an improvement in visual fields in 75% of the 34 examined eyes based on the reduction in the scotomatous area and mean defect.

• A follow-up study after 10 years of these patients showed significant improvement of retinal sensitivity.

• Parisi: Intramuscular Citicoline (combined with hypotensive medication) treated eyes have significant improvement in Visually-Evoked-Potentials (VEP) and Pattern-Electroretinogram (PERG) parameters.

• Rejadek: His study found treatment with oral Citicoline may normalize VEPs in glaucoma patients.

• Parisi: Another study by this author reported improved retinal parameters evaluated on PERG and VEP after intra-muscular and oral routes.

• Ottobelli: Citicoline oral solution significantly reduced mean rate of VF progression and IOP at the end of the study period.

• Parisi: Recently a study has reported that administration of Citicoline eyedrops three times a day significantly improved the PERG and VEP values with respect to control and baseline. In particular patients who displayed the worst retinal function at baseline had the greatest benefit from the Citicoline eyedrop treatment.

• PHARMACOKINETICS

•  Citicoline is water soluble with more than 90% oral bioavailability.

•  Plasma levels peak one hour after oral ingestion and a majority of Citicoline is excreted as carbon dioxide in respiration and again 24 hours after ingestion where the remaining Citicoline is excreted through urine.

• DOSE

•  ORAL
• 1000-2000 mg per day: For decline of thinking skills.
• 600 mg per day: In chronic cerebrovascular disease.
• 500-2000 mg per day (starting within 24 hours of the CVA): In ischemic stroke.

• INTRAVENOUS

• This route can be used in cases of age-related decline in thinking skills and for chronic cerebrovascular disease.

•  SIDE-EFFECTS

• Citicoline reportedly has a very low toxicity profile in animal and human studies.

• Clinically doses of 2000mg per day have been used in human studies and approved for use.

• Minor transient adverse effects are rare and commonly include stomach pain and diarrhea.