Background and Purpose-The neuroprotective potential of citicoline in acute ischemic stroke has been shown in many experimental studies and, although the exact mechanisms are still unknown, a clinical Phase III trial is currently underway. Our present study was designed to check whether citicoline also enhances neuroregeneration after experimental stroke. Methods-Forty Wistar rats were subjected to photothrombotic stroke and treated either with daily injections of citicoline (100 mg/kg) or vehicle for 10 consecutive days starting 24 hours after ischemia induction. Sensorimotor tests were performed after an adequate training period at Days 1, 10, 21, and 28 after stroke. Then brains were removed and analyzed for infarct size, glial scar formation, neurogenesis, and ligand binding densities of excitatory and inhibitory neurotransmitter receptors. Results-Animals treated with citicoline showed a significantly better neurological outcome at Days 10, 21, and 28 after ischemia, which could not be attributed to differences in infarct volumes or glial scar formation. However, neurogenesis in the dentate gyrus, subventricular zone, and peri-infarct area was significantly increased by citicoline. Furthermore, enhanced neurological outcome after citicoline treatment was associated with a shift toward excitation in the perilesional cortex. Conclusions-Our present data demonstrate that, apart from the well-known neuroprotective effects in acute ischemic stroke, citicoline also possesses a substantial neuroregenerative potential. Thanks to its multimodal effects, easy applicability, and history as a well-tolerated drug, Key Words: citicoline Ⅲ neurogenesis Ⅲ receptor autoradiography Ⅲ regeneration Ⅲ stroke A lthough most patients with stroke show some degree of spontaneous functional improvement, 1 recovery is generally far from complete. Therefore, there is an urgent need to identify therapeutic strategies to support endogenous poststroke repair mechanisms. One candidate stroke drug for ischemic stroke with an extended therapeutic window, which is currently under investigation in a randomized, doubleblind, placebo-controlled, multicenter clinical Phase III trial (International Citicoline Trial on Acute Stroke [ICTUS]), is citicoline (also known as cytidine-5-diphosphocholine or CDP-choline). Although citicoline seems to display a multitude of beneficial effects, the exact mechanisms of action are still enigmatic.Citicoline, a naturally occurring endogenous compound, is an essential intermediate in the biosynthesis of phosphatidylcholine. 2 Citicoline has been shown to have neuroprotective effects in a variety of central nervous system injury models, including cerebral ischemia. [3][4][5][6] The suggested mechanisms that may explain the neuroprotective actions of citicoline include prevention of fatty acid release, 7 stimulation of phosphatidylcholine synthesis, 2 preservation of cardiolipin and sphingomyelin levels, 7 increase of glutathione synthesis and glutathione reductase activity, 8 restoration of Na ϩ /K ϩ -ATPase ac...