A chronic treatment with CDP-choline improves functional recovery and increases neuronal plasticity after experimental stroke O. Hurtado, b,1 A. Cárdenas, a,1 J.M. Pradillo, a J.R. Morales, a F. Ortego, a T. Sobrino, b J. Castillo, b M.A. Moro, a and I. Lizasoain a, ⁎ a Departamento de Farmacología, Facultad de Medicina, Universidad Complutense de Madrid, Av. Complutense s/n. 28040, Madrid, Spain b Servicio de Neurología, Hospital Clínico Universitario, Santiago de Compostela, Spain Received 17 August 2006; revised 20 November 2006; accepted 5 December 2006 Available online 16 January 2007 Chronic impairment of forelimb and digit movement is a common problem after stroke that is resistant to therapy. Although in the last years some studies have been performed to increase the efficacy of rehabilitative experience and training, the pharmacological approaches in this context remain poorly developed. We decided to study the effect of a chronic treatment with CDP-choline, a safe and well-tolerated drug that is known to stabilize membranes, on functional outcome and neuromorphological changes after stroke. To assess the functional recovery we have performed the staircase reaching test and the elevated body swing test (EBST), for studying sensorimotor integration and asymmetrical motor function respectively. The treatment with CDP- choline, initiated 24 h after the middle cerebral artery occlusion (MCAO) and maintained during 28 days, improved the functional outcome in both the staircase test (MCAO + CDP = 87.0 ± 6.6% pellets eaten vs. MCAO + SAL = 40.0 ± 4.5%; p <0.05) and the EBST (MCAO+CDP=70.0± 6.8% vs. MCAO + SAL = 88.0 ± 5.4%; contralateral swing p < 0.05). In addition, to study potential neuronal substrates of the improved function, we examined the dendritic morphology of layer V pyramidal cells in the undamaged motor cortex using a Golgi–Cox procedure. The animals treated with CDP-choline showed enhanced dendritic complexity and spine density compared with saline group. Our results suggest that a chronic treatment with CDP-choline initiated 24 h after the insult is able to increase the neuronal plasticity within noninjured and functionally connected brain regions as well as to promote functional recovery. © 2006 Elsevier Inc. All rights reserved. Keywords: Dendritic arborization; Dendritic spines; Forelimb; Plasticity; Sensorimotor; Stroke Introduction Stroke is a leading cause of death and long-lasting disability with a high socioeconomic burden; among 30-day survivors of first-ever stroke, about half survive for 5 years; of survivors, one-third remain disabled, and 1 in 7 are in permanent institutional care (Hankey et al., 2002). Taking into account that hemiparesis is the most common cause of disability after stroke (Duncan et al., 1992), it seems essential to develop effective therapies to improve the motor recovery of these patients. However, few advances have been done in this context and most of them only related to the constraint- induced therapy (Tarkka et al., 2005; Page et al., 2005) or the levo- dopa administration (Scheidtmann, 2004). Although the precise restorative mechanisms underlying motor recovery after stroke are poorly understood, it seems clear that a spontaneous and gradual return of some motor abilities occurs at weeks or months after the injury (Lashley, 1924; Travis and Woolsey, 1956) and that this functional return mainly depends on brain plasticity in both ipsilesional and contralesional hemispheres (reviewed in Lee and van Donkelaar, 1995; Seil, 1997; Steinberg and Augustine, 1997; Johansson, 2000; Hallett, 2001; Nelles, 2004). In this context, contralesional activation of the sensorimotor cortex has been demonstrated to occur as early as 24 h and remained at 3 days after stroke in animals (Abo et al., 2001; Dijkhuizen et al., 2001, 2003) and in humans (Nelles et al., 1999; Cuadrado et al., 1999; Marshall et al., 2000). Moreover, an increase in the dendritic arborization of pyramidal cells of layer V within the undamaged cortex together with an improvement in forelimb function have been demonstrated in rats with focal ischemic injury (Jones and Schallert, 1994; Biernaskie and Corbett, 2001; Biernaskie et al., 2004; Luke et al., 2004). Furthermore, the axonal reorganization in the rat brain after stroke has been associated with restored cortical control of the denervated forelimb (Bury and Jones, 2002; Cheng et al., 2002; Wiessner et al., 2003; Dijkhuizen et al., 2003; Luke et al., 2004). CDP-choline is an intermediate in membrane phospholipid synthesis that, when administered exogenously, increases phospha- tidylcholine and sphingomyelin membrane content on the first day of reperfusion after stroke (Adibhatla et al., 2001). Although it is generally assumed that it could be acting as a membrane stabilizer, to date there are no studies about the effect of CDP-choline in neuronal plasticity after stroke. The only previous evidence is the effect of the influence of CDP-choline on alcoholic fetopathy (Patt et al., 1989). www.elsevier.com/locate/ynbdi Neurobiology of Disease 26 (2007) 105 – 111 ⁎ Corresponding author. Fax: +34 91 3941464. E-mail address: ignacio.lizasoain@med.ucm.es (I. Lizasoain). 1 Both authors contributed equally to the present work. Available online on ScienceDirect (www.sciencedirect.com). 0969-9961/$ - see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.nbd.2006.12.005