Treatment of Rat Spinal Cord Injury with the Neurotrophic Factor Albumin-Oleic Acid: Translational Application for Paralysis, Spasticity and Pain Gerardo Avila-Martin1, Iriana Galan-Arriero1, Julio Go´ mez-Soriano1,2, Julian Taylor1* 1 Neurolog´ıa Experimental, Hospital Nacional de Paraple´jicos, Servicio de Salud de Castilla-La Mancha, Toledo, Castilla La-Mancha, Spain, 2 Escuela de Enfermer´ıa y Fisioterapia de Toledo, Universidad de Castilla La-Mancha, Toledo, Castilla-La Mancha, Spain Abstract Sensorimotor dysfunction following incomplete spinal cord injury (iSCI) is often characterized by the debilitating symptoms of paralysis, spasticity and pain, which require treatment with novel pleiotropic pharmacological agents. Previous in vitro studies suggest that Albumin (Alb) and Oleic Acid (OA) may play a role together as an endogenous neurotrophic factor. Although Alb can promote basic recovery of motor function after iSCI, the therapeutic effect of OA or Alb-OA on a known translational measure of SCI associated with symptoms of spasticity and change in nociception has not been studied. Following T9 spinal contusion injury in Wistar rats, intrathecal treatment with: i) Saline, ii) Alb (0.4 nanomoles), iii) OA (80 nanomoles), iv) Alb-Elaidic acid (0.4/80 nanomoles), or v) Alb-OA (0.4/80 nanomoles) were evaluated on basic motor function, temporal summation of noxious reflex activity, and with a new test of descending modulation of spinal activity below the SCI up to one month after injury. Albumin, OA and Alb-OA treatment inhibited nociceptive Tibialis Anterior (TA) reflex activity. Moreover Alb-OA synergistically promoted early recovery of locomotor activity to 50610% of control and promoted de novo phasic descending inhibition of TA noxious reflex activity to 4765% following non-invasive electrical conditioning stimulation applied above the iSCI. Spinal L4–L5 immunohistochemistry demonstrated a unique increase in serotonin fibre innervation up to 4.261.1 and 2.360.3 fold within the dorsal and ventral horn respectively with Alb-OA treatment when compared to uninjured tissue, in addition to a reduction in NR1 NMDA receptor phosphorylation and microglia reactivity. Early recovery of voluntary motor function accompanied with tonic and de novo phasic descending inhibition of nociceptive TA flexor reflex activity following Alb-OA treatment, mediated via known endogenous spinal mechanisms of action, suggests a clinical application of this novel neurotrophic factor for the treatment of paralysis, spasticity and pain. Citation: Avila-Martin G, Galan-Arriero I, Go´ mez-Soriano J, Taylor J (2011) Treatment of Rat Spinal Cord Injury with the Neurotrophic Factor Albumin-Oleic Acid: Translational Application for Paralysis, Spasticity and Pain. PLoS ONE 6(10): e26107. doi:10.1371/journal.pone.0026107 Editor: Robyn Klein, Washington University, United States of America Received July 21, 2011; Accepted September 19, 2011; Published October 26, 2011 Copyright: 2011 Avila-Martin et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This study was supported by the following research projects: ISCIII FIS-07/0806, INNPACTO Ministerio de Ciencia e Innovacio´ n IPT 01000-2010-016, Fundacio´ n Mutua Madrilen˜ a 2007 and 2010, FISCAM 2007/33, ‘‘Consolider-Ingenio 2010’’ from the ‘‘Ministerio Ciencia e Innovacio´ n’’ [CSDOOC-09-61313]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: jscott@sescam.org Introduction Many patients develop change in sensorimotor function below spinal cord injury (SCI), which include debilitating symptoms of spasticity [1,2] and changes in pain processing at the spinal level [3–5]. These symptoms may combine to impede the successful rehabilitation of residual voluntary motor function following incomplete spinal cord injury (iSCI) [6]. The presence of multiple spinal pathophysiological mechanisms after SCI [7–10] require that novel treatments simultaneously modulate neuronal hyperexcitabil- ity, neuroinflammation and adaptive or maladaptive neuroplasticity of both segmental and residual descending control systems across the lesion site [9,11–13]. Indeed the increase in neuronal NMDA receptor phosphorylation or glutamate receptor upregulation [14,15], microglial and astrocyte reactivity [15,16] and change in descending serotoninergic innervation of spinal activity below the injury [17,18] have been implicated in symptoms of pain, spasticity and paralysis following iSCI. Albumin (Alb) is necessary for oleic acid (OA) production by astrocytes [19] and extracellular Alb and OA are incorporated into neurons leading to dendritic growth, GAP-43 and microtubule- associated protein (MAP-2) upregulation in vitro [20]. Moreover Alb promotes motor recovery of SCI by neuroprotection against glutamate [21]. While omega-3 fatty acids can promote gain in function [22], no modulation of sensorimotor activity has been observed with omega-9 such as OA following iSCI [22]. However as Alb contains three primary specific binding sites for OA [23], the administration of this serum protein with the omega-9 fatty acid in vivo, either individually or in combination, may reveal recovery of unidentified specific sensorimotor function and symptoms following iSCI. Several clinical studies have identified Tibialis Anterior (TA) hyperreflexia or flexor reflex function as an indirect marker of change in spinal nociceptive function [24–26], paralysis [6] and spasticity [26–28]. The measurement of cutaneous nociceptive flexor reflex activity in animal models is used routinely to assess pharmacological modulation of spinal excitability [29,30], including the modulatory role of both tonic and phasic descending modulatory pathways [31–34]. Although functional plasticity of descending antinociceptive pathways has not been studied after experimental SCI, their role has been established in phasic inhibition of lumbar PLoS ONE | www.plosone.org 1 October 2011 | Volume 6 | Issue 10 | e26107