Use of thrombolysis in acute ischaemic stroke may be limited by a narrow benefit/risk ratio. Pharmacological inhibition of the ischaemic cascade may constitute an effective and safer approach to stroke treatment. This study compared the effects of high doses of cytidine diphosphate-choline (CDP-choline; 1000 mg/kg) with recombinant tissue plasminogen activator (rt-PA; 5 mg/kg) in an experimental animal model of embolic stroke. Fifteen rats were embolized in the right internal carotid artery with an autologous clot and were divided into three groups: (1) infarct; (2) intravenous rt-PA 5 mg/kg 30 minutes post-embolization; and (3) CDP-choline 1000 mg/kg, intraperitoneal, three doses, 30 minutes, 24 hours, and 48 hours post-embolization. Functional evaluation scores were evaluated using Rogers test, lesion volume by haematoxylin and eosin staining, cell death with transferase-mediated dUTP nick-end labelling, and plasma levels of interleukin-6 (IL-6) and tumor necrosis factor-alpha with enzyme-linked immunosorbent assay. In this study, CDP-choline and rt-PA produced a significant reduction in brain damage considering infarct volume, cell death, and inflammatory cytokines (tumour necrosis factor-alpha and IL-6) compared with the infarct group. Additionally, CDP-choline significantly decreased infarct volume, cell death, and IL-6 levels with respect to the rt-PA group. From these results, we conclude that high-dose CDP-choline may be an effective treatment for acute ischaemic stroke even in absence of thrombolysis.
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"Similar doubts may be raised against the recent report by Gutiérrez-Fernández et al. , who compared the effects of citicoline (1,000 mg/kg intraperitoneally) and recombinant tissue plasminogen activator [rt-PA] (5 mg/kg intravenously) in a rat model of embolic stroke. The problem with this paper was that whereas the rt-PA dose used per kg of bodyweight was 5 to 8 times the dose used in the treatment of human embolic stroke (0.6–1.1 mg/kg intravenously; see Wardlaw et al. ), the citicoline dose was 15 to 30 times the dose used in clinical trials of citicoline in stroke. "
[Show abstract][Hide abstract] ABSTRACT: Citicoline is the generic name of the pharmaceutical substance that chemically is cytidine-5'-diphosphocholine (CDP-choline), which is identical to the natural intracellular precursor of phospholipid phosphatidylcholine. Following injection or ingestion, citicoline is believed to undergo quick hydrolysis and dephosphorylation to yield cytidine and choline, which then enter the brain separately and are used to resynthesize CDP-choline inside brain cells. Neuroprotective activity of citicoline has been repeatedly shown in preclinical models of brain ischaemia and trauma, but two recent, large, pivotal clinical trials have revealed no benefits in ischaemic stroke and traumatic brain injury. However, the substance seems to be beneficial in some slowly advancing neurodegenerative disorders such as glaucoma and mild vascular cognitive impairment. This paper critically discusses issues related to the clinical pharmacology of citicoline, including its pharmacokinetics/biotransformation and pharmacodynamics/mode of action. It is concluded that at present, there is no adequate description of the mechanism(s) of the pharmacological actions of this substance. The possibility should be considered and tested that, in spite of apparently fast catabolism, the intact citicoline molecule or the phosphorylated intermediate products of its hydrolysis, cytidine monophosphate and phosphocholine, are pharmacologically active.
[Show abstract][Hide abstract] ABSTRACT: Advances in acute stroke therapy resulting from thrombolytic treatment, endovascular procedures, and stroke units have improved significantly stroke survival and prognosis; however, for the large majority of patients lacking access to advanced therapies stroke mortality and residual morbidity remain high and many patients become incapacitated by motor and cognitive deficits, with loss of independence in activities of daily living. Therefore, over the past several years, research has been directed to limit the brain lesions produced by acute ischemia (neuroprotection) and to increase the recovery, plasticity and neuroregenerative processes that complement rehabilitation and enhance the possibility of recovery and return to normal functions (neurorepair). Citicoline has therapeutic effects at several stages of the ischemic cascade in acute ischemic stroke and has demonstrated efficiency in a multiplicity of animal models of acute stroke. Long-term treatment with citicoline is safe and effective, improving post-stroke cognitive decline and enhancing patients' functional recovery. Prolonged citicoline administration at optimal doses has been demonstrated to be remarkably well tolerated and to enhance endogenous mechanisms of neurogenesis and neurorepair contributing to physical therapy and rehabilitation.