Joaquim Forés | Universitat de Barcelona (original) (raw)

Papers by Joaquim Forés

Research paper thumbnail of Network-based proteomic approaches reveal the neurodegenerative, neuroprotective and pain-related mechanisms involved after retrograde axonal damage

Scientific reports, 2015

Neurodegenerative processes are preceded by neuronal dysfunction and synaptic disconnection. Disc... more Neurodegenerative processes are preceded by neuronal dysfunction and synaptic disconnection. Disconnection between spinal motoneuron (MN) soma and synaptic target leads either to a retrograde degenerative process or to a regenerative reaction, depending injury proximity among other factors. Distinguished key events associated with one or other processes may give some clues towards new therapeutical approaches based on boosting endogenous neuroprotective mechanisms. Root mechanical traction leads to retrograde MN degeneration, but share common initial molecular mechanisms with a regenerative process triggered by distal axotomy and suture. By 7 days post-injury, key molecular events starts to diverge and sign apart each destiny. We used comparative unbiased proteomics to define these signatures, coupled to a novel network-based analysis to get biological meaning. The procedure implicated the previous generation of combined topological information from manual curated 19 associated biol...

Research paper thumbnail of Alignment of collagen and laminin-containing gels improve nerve regeneration within silicone tubes

Restorative neurology and neuroscience, 2002

Placement of extracellular matrix components has been used as a mean to enhance axonal growth acr... more Placement of extracellular matrix components has been used as a mean to enhance axonal growth across nerve long gaps repaired by tubulization. However, such matrices may impede axonal regeneration depending on its density and microgeometry. Silicone tubes were prefilled with collagen or laminin-containing gels and implanted into a 6 mm gap, a length considered limiting for regeneration, in the mouse sciatic nerve. Gels were polymerized prior to implantation either in horizontal position or subjected to gravitational (in vertical position) or to magnetic forces to induce longitudinal alignment of the fibrils. Recovery of motor, sensory and sudomotor functions in the hindpaw was evaluated during 4 months postoperation. Reinnervation started earlier and achieved slightly higher levels with aligned collagen gels than with the horizontal gel. For the three groups repaired with tubes with Matrigel, there was a gradation of the functional results, reinnervation started earlier and reached ...

Research paper thumbnail of El trasplante de células de la glía envolvente del bulbo olfatorio tras lesión de la médula espinal: Estudio experimental en ratas

Revista Española de Cirugía Ortopédica y Traumatología, 2005

Research paper thumbnail of Improved prediction of knee osteoarthritis progression by genetic polymorphisms: the Arthrotest Study

Rheumatology (Oxford, England), Jan 7, 2015

The aim of this study was to develop a genetic prognostic tool to predict radiographic progressio... more The aim of this study was to develop a genetic prognostic tool to predict radiographic progression towards severe disease in primary knee OA (KOA) patients. This investigation was a cross-sectional, retrospective, multicentric association study in 595 Spanish KOA patients. Caucasian patients aged ≥40 years at the time of diagnosis of primary KOA of Kellgren-Lawrence grade 2 or 3 were included. Patients who progressed to Kellgren-Lawrence score 4 or who were referred for total knee replacement within 8 years after diagnosis were classified as progressors to severe disease. Clinical variables of the initial stages of the disease (gender, BMI, age at diagnosis, OA in the contralateral knee, and OA in other joints) were registered as potential predictors. Single nucleotide polymorphisms and clinical variables with an association of P < 0.05 were included in the multivariate analysis using forward logistic regression. A total of 23 single nucleotide polymorphisms and the time of prima...

Research paper thumbnail of Transplanted olfactory ensheathing cells modulate the inflammatory response in the injured spinal cord

Neuron Glia Biology, 2004

Transplantation of olfactory ensheathing cells (OECs) into the injured spinal cord has been shown... more Transplantation of olfactory ensheathing cells (OECs) into the injured spinal cord has been shown to exert neuroprotective effects and promote functional recovery. In the present study, we investigated the potential modulatory effects of OECs on the inflammatory reaction developed after photochemical injury to the spinal cord. OEC cultures were obtained from olfactory bulbs of adult Sprague-Dawley rats. Photochemical spinal cord injury was induced in adult rats at T8. Thirty minutes after the insult, either a suspension of OECs (180 000 cells in 12 microl DMEM) or DMEM alone was injected into the lesioned spinal cord.At 3, 7 and 14 days post-operation (dpo), five animals from each group were processed for histology. Double-fluorescent labeling of transverse sections of the cord were made by combination of immunohistochemistry for inflammatory markers, interleukin 1b(IL-1b) and inducible nitric oxide synthase (iNOS), and for selective markers of astrocytes (glial fibrillar acidic protein; GFAP)and microglia/macrophages (tomato lectin; LEC). Differences in the intensity and time course of glial response, and IL-1band iNOS expression were found between the two groups of rats. The reactivity grade against IL-1beta, iNOS, GFAP and LEC in OEC-transplanted rats was higher at 7 dpo and lower at 14 dpo compared with DMEM-injected rats. These results indicate that the mechanisms underlying neuroprotection by OECs might be caused by earlier, higher and shorter duration of microglia/macrophage and astrocyte responses after injury.

Research paper thumbnail of Acute and delayed transplantation of olfactory ensheathing cells promote partial recovery after complete transection of the spinal cord

Neurobiology of Disease, 2006

The present study was undertaken to determine whether olfactory ensheathing cells (OECs) from the... more The present study was undertaken to determine whether olfactory ensheathing cells (OECs) from the olfactory bulb were capable to promote axonal regeneration and functional recovery when transplanted either acutely or 1 week delayed into the T8 transected rat spinal cord. OEC transplants increased recovery of functional outcomes, as shown electrophysiologically by return of motor evoked potentials and by reduction of hindlimb hyperreflexia, and behaviorally by recovery of movements of hindlimb joints. Axonal regeneration was proven histologically by demonstrating long axonal outgrowth of raphespinal, coerulospinal, and corticospinal tracts within the caudal cord stump. Expression of GFAP and NG2 was down-regulated in perilesional cord segments in transplanted animals, indicating a more suitable environment for axonal regeneration. Overall, earlier recovery and better functional and histological results were observed in rats receiving acute than delayed OEC transplants. The beneficial effects obtained with transplantation after transection are encouraging for the application of OECs in the human injured spinal cord.

Research paper thumbnail of Olfactory ensheathing glia graft in combination with FK506 administration promote repair after spinal cord injury

Neurobiology of Disease, 2006

The aim of this study was to determine whether a combination of olfactory ensheathing cell (OEC) ... more The aim of this study was to determine whether a combination of olfactory ensheathing cell (OEC) graft with the administration of FK506, two experimental approaches that have been previously reported to exert protective/regenerative effects after spinal cord injury, promotes synergic restorative effects after complete or partial spinal cord injuries. In partial spinal cord injury, combination of an OEC graft and FK506 reduced functional deficits evaluated by the BBB score, motor-evoked potentials (MEPs) and H reflex tests, diminished cavitation, astrogliosis and increased sparing/regeneration of raphespinal fibers compared to untreated and single-treatment groups of rats. After complete spinal cord transection, the combined treatment significantly improved functional outcomes, promoted axonal regeneration caudal to the lesion, and diminished astrogliosis compared only to non-transplanted animals. Slightly, but nonsignificant, better functional and histological results were found in OEC-grafted animals treated with FK506 than in those given saline after spinal cord transection. Nevertheless, the combined treatment increased the percentage of rats that recovered MEPs and promoted a significant reduction in astrogliosis. In conclusion, this study demonstrates that OEC grafts combined with FK506 promote additive repair of spinal cord injuries to those exerted by single treatments, the effect being more remarkable when the spinal cord is partially lesioned.

Research paper thumbnail of Cytoskeletal and activity-related changes in spinal motoneurons after root avulsion

Journal of Neurotrauma, 2009

Compelling evidence shows that after root avulsion motoneurons attempt to survive and regenerate ... more Compelling evidence shows that after root avulsion motoneurons attempt to survive and regenerate before dying. In order to study these mechanisms, unilateral avulsion of L4-L5 spinal roots was performed in adult rats, and the ventral spinal cords were studied from 3 to 28 days post-operation (dpo). Electrophysiological results indicated complete denervation of L4-L5 muscles in the injured limb without functional effects on the contralateral hindlimb. Estimated cell counts showed progressive loss of avulsed motoneurons; at 28 dpo, the number of surviving motoneurons averaged 13% (AE3), 22% (AE0.9), and 29% (AE0.7) in samples stained with cresyl violet, immunostained for choline acetyltransferase (ChAT) and for SMI32, respectively. Regarding glial reactivity, we found an early microglial response, with the highest increase of isolectin B4 (IB4) and Iba1 expression at 3 days, and a slower and progressive response of astrocytes, shown by increasing expression of glial fibrillary acidic protein (GFAP) during the 28 days studied. Accumulation of phosphorylated (RT97þ) and non-phosphorylated (SMI32þ) neurofilaments was observed in the soma of axotomized motoneurons from 3 dpo. RT97 expression was present in approximately 80% (AE3.7) of surviving motoneurons at 7 dpo, and it was related to the regenerative response of motoneurons, as revealed by decreased ChAT expression and co-localization with GAP43. Intense SMI32 immunostaining was observed during the first week after avulsion, appearing in 37% (AE0.9) of surviving motoneurons, but it was not associated with GAP43 expression. Calcitonin gene-related peptide (CGRP) expression in motoneurons was markedly reduced from the second week after avulsion. This study presents a detailed description of motoneuron reaction after root avulsion, which suggests an early time-window during the first 2 weeks for attempts to repair the injury and promote motoneuron survival and regeneration.

Research paper thumbnail of Functional and Electrophysiological Characterization of Photochemical Graded Spinal Cord Injury in the Rat

Journal of Neurotrauma, 2003

This study characterizes by functional and electrophysiological methods changes following photoch... more This study characterizes by functional and electrophysiological methods changes following photochemically induced injuries to the spinal cord in adult rats. The spinal cord was exposed by laminectomy and bathed with 1.5% rose bengal solution for 10 min (T12-L1 vertebrae). The excess dye was removed by saline rinse and the spinal cord was irradiated with &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;cold&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; light for 0, 1, 2.5, 5, and 10 min in different groups of rats. During the first 15 days postlesion, locomotion activity, pain sensibility, motor and somatosensory evoked potentials, and motor and nerve action potentials were evaluated. Graded locomotor and nociceptive recovery was observed in irradiated rats depending on the photoinduction time. At 15 days, the amplitude of motor and sensory evoked potentials was significantly lower in irradiated groups with respect to control rats. The amplitude of compound muscle action potentials and of reflex H wave after sciatic nerve stimulation decreased significantly in irradiated animals with respect to control rats, while the latency did not show significant differences. In irradiated groups, significant differences were seen between pre- and postoperative values for most functional and electrophysiological parameters analyzed. A significant negative relationship was found between the area of cystic cavity of the spinal cord and the functional and electrophysiological impairment.

Research paper thumbnail of Increased Expression of Cyclo-Oxygenase 2 and Vascular Endothelial Growth Factor in Lesioned Spinal Cord by Transplanted Olfactory Ensheathing Cells

Journal of Neurotrauma, 2004

Olfactory ensheathing cells (OECs) were transplanted in adult rats after photochemical injury of ... more Olfactory ensheathing cells (OECs) were transplanted in adult rats after photochemical injury of the spinal cord. Rats received either 180,000 OECs suspended in DMEM or DMEM alone. Locomotor ability scored by the BBB-scale, pain sensibility, and motor and somatosensory evoked potentials were evaluated during the first 14 days post-surgery. At 3, 7, and 14 days, 5 rats per day of both groups were perfused and transverse sections from proximal, lesioned and distal spinal cord blocks were stained for COX-2, VEGF, GFAP and lectin. The BBB-score and the amplitude of motor and somatosensory evoked potentials were significantly higher in OEC- than in DMEM-injected animals throughout follow-up, whereas the withdrawal latency to heat noxious stimulus was lower in OEC- than in DMEM-injected rats. The area of preserved spinal cord and the levels of COX-2 and VEGF staining were significantly higher in OEC- than in DMEM-injected rats. GFAP- but no LEC-positive cells expressed COX-2 staining in OEC-transplanted rats. The density of blood vessels was also significantly increased in OEC- with respect to DMEM-injected rats. Our results show that OECs promote functional and morphological preservation of the spinal cord after photochemical injury, increasing neoangiogenesis and up-regulation of COX-2 and VEGF expression in astrocytes.

Research paper thumbnail of Morphological Characterization of Photochemical Graded Spinal Cord Injury in the Rat

Journal of Neurotrauma, 2003

This study characterizes the histological and immunohistochemical changes in the adult rat spinal... more This study characterizes the histological and immunohistochemical changes in the adult rat spinal cord following photochemically induced spinal cord lesions. The spinal cord was exposed by laminectomy (T12-L1 vertebrae) and bathed with 1.5% rose bengal solution for 10 min. The excess dye was removed by saline rinse and the spinal cord was irradiated with &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;cold&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; light for 0, 1, 2.5, 5, and 10 min in different groups of rats. After 15 days a graded loss of spinal tissue was observed according to photoinduction times. Animals irradiated for 1 min showed spinal cavities involving the dorsal funiculi. The cavity became progressively larger, involving dorsal horns in animals irradiated for 2.5 min, together with the dorsolateral funiculi in animals irradiated for 5 min and the ventrolateral funiculi in those irradiated for 10 min, with loss of gray matter in these three groups. Changes in GFAP-, CGRP-, proteoglycan- and calbindin-immunoreactivity were observed in all lesioned groups when compared with control spinal cords. Hypertrophied and heavily GFAP- and proteoglycan-stained astrocytes were seen in irradiated spinal cords. Reactive microglial cells were also found. Both astroglial and microglial reactions paralleled the severity of the spinal cord lesion. A significant loss of CGRP-immunoreactive somas was seen in animals irradiated for 10 min, whereas the wider distribution of calbindin-positive neurons was found in lesioned rats. In spinal cord sections from animals illuminated for 5 min and perfused 60 min postillumination, light and electron microscopy showed cytotoxic edema with astrocytic swelling, red blood cell extravasation, and myelin degradation.

Research paper thumbnail of FK506 reduces tissue damage and prevents functional deficit after spinal cord injury in the rat

Journal of Neuroscience Research, 2005

We examined the efficacy of FK 506 in reducing tissue damage after spinal cord injury in comparis... more We examined the efficacy of FK 506 in reducing tissue damage after spinal cord injury in comparison to methylprednisolone (MP) treatment. Rats were subjected to a photochemical injury (T8) and were given a bolus of MP (30 mg/kg), FK 506 (2 mg/kg), or saline. An additional group received an initial bolus of FK 506 (2 mg/kg) followed by daily injections (0.2 mg/kg intraperitoneally). Functional recovery was evaluated using open-field walking, inclined plane tests, motor evoked potentials (MEPs), and the H-reflex response during 14 days postoperation (dpo). Tissue sparing and glial fibrillary acidic protein (GFAP), biotinylated tomato lectin LEC, cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and interleukin 1 beta (IL-1 beta) immunoreactivity were quantified in the injured spinal cord. FK 506-treated animals demonstrated significantly better neurologic outcome, higher MEP amplitudes, and lower H-wave amplitude compared to that of saline-treated rats. In contrast, administration of MP did not result in significant differences with respect to the saline-treated group. Histologic examination revealed that tissue sparing was largest in FK 506-treated compared to saline and MP-treated animals. GFAP and COX-2 reactivity was decreased in animals treated with FK 506 compared to that in animals given MP or saline, whereas IL-1 beta expression was similarly reduced in both FK 506- and MP-treated groups. Microglia/macrophage response was reduced in FK 506 and MP-injected animals at 3 dpo, but only in MP-treated animals at 7 dpo with respect to saline-injected rats. Repeated administrations of FK 506 improved functional and histologic results to a greater degree than did a single bolus of FK 506. The results indicate that FK 506 administration protects the damaged spinal cord and should be considered as potential therapy for treating spinal cord injuries.

Research paper thumbnail of Spinal cord injury induces endoplasmic reticulum stress with different cell-type dependent response

Journal of Neurochemistry, 2007

The mechanisms of injury-induced apoptosis of neurons within the spinal cord are poorly understoo... more The mechanisms of injury-induced apoptosis of neurons within the spinal cord are poorly understood. In this study, we show that spinal cord injury (SCI) induces endoplasmic reticulum stress revealed by the activation of an unbalanced unfolded protein response (UPR). Using a weight-drop contusion model of SCI, the UPR activation was characterized by a quick transient phosphorylation of alpha subunit of eukaryotic initiation factor 2 soon restored by the up-regulation of its regulator Gadd34; an effective cleavage/activation of the ATF6a transcription factor leading to up-regulation of the canonical UPR target genes Chop, Xbp1 and Grp78; the presence of the processing of Xbp1 mRNA indicative of inositol requiring kinase 1 activation, and a gradual accumulation of C/EBP homologous transcription factor protein (CHOP) with concomitant caspase-12 activation. Interestingly, the subcellular distribution of CHOP was found in the nucleus of neurons and oligodendrocytes but in the cytoplasm of astrocytes. Considering the pro-apoptotic action attributed to this transcription factor, this phenomenon might account for the different susceptibility of cell types to dye after SCI.

Research paper thumbnail of Chronic transplantation of olfactory ensheathing cells promotes partial recovery after complete spinal cord transection in the rat

Glia, 2007

The goal of this study was to ascertain whether olfactory ensheathing cells (OECs) were able to p... more The goal of this study was to ascertain whether olfactory ensheathing cells (OECs) were able to promote axonal regeneration and functional recovery when transplanted 45 days after complete transection of the thoracic spinal cord in adult rats. OECs promoted partial restitution of supraspinal pathways evaluated by motor evoked potentials and modest recovery of hindlimb movements. In addition, OEC grafts reduced lumbar reflex hyperexcitability from the first month after transplantation. Histological results revealed that OECs facilitated corticospinal and raphespinal axons regrowth through the injury site and into the caudal spinal cord segments. Interestingly, raphespinal but not corticospinal fibers regenerated long distances through the gray matter and reached the lower lumbar segments (L5) of the spinal cord. However, delayed OEC grafts failed to reduce posttraumatic astrogliosis. In conclusion, the beneficial effects found in the present study further support the use of OECs for treating chronic spinal cord injuries.

Research paper thumbnail of Olfactory ensheathing cells transplanted in lesioned spinal cord prevent loss of spinal cord parenchyma and promote functional recovery

Glia, 2003

We studied the effects of olfactory ensheathing cells (OECs) transplanted in a photochemical spin... more We studied the effects of olfactory ensheathing cells (OECs) transplanted in a photochemical spinal cord injury in adult rats. After dorsal laminectomy at T8 vertebra, subjacent spinal cord was bathed with rose Bengal for 10 min and illuminated with visible light by means of an optic fiber connected to a halogen lamp for 2.5 min at maximal intensity of 8 kLux. Eight injured rats received a suspension of OECs in DMEM, and another eight rats received DMEM alone. Locomotor ability scored by the BBB scale, pain sensibility by the plantar algesimetry test, and motor-and somatosensory-evoked potentials by electrophysiological techniques were evaluated for 3 months postsurgery. Finally, all rats were perfused with paraformaldehyde and transverse sections from the spinal cord segment at the lesion site were immunostained against GFAP. Area of the preserved spinal cord parenchyma was measured from the GFAPimmunolabeled cord sections. The BBB score and the amplitude of motor-and somatosensory-evoked potentials were higher in OECs-transplanted rats than in DMEMinjected animals throughout follow-up, whereas the withdrawal response to heat noxious stimulus was lower in OEC-than in DMEM-injected rats. The area of preserved spinal cord was significantly larger in OECs-transplanted rats than in DMEM-injected animals. These results indicate that OECs promote functional and morphological preservation of the spinal cord after photochemical injury. GLIA 42: [275][276][277][278][279][280][281][282][283][284][285][286] 2003.

Research paper thumbnail of Influence of Physical Parameters of Nerve Chambers on Peripheral Nerve Regeneration and Reinnervation

Experimental Neurology, 1996

We compared reinnervation of target organs after sciatic nerve section leaving gaps of 2, 4, 6, o... more We compared reinnervation of target organs after sciatic nerve section leaving gaps of 2, 4, 6, or 8 mm or gaps repaired with silicone tubes in different groups of mice. Functional reinnervation was assessed by noninvasive methods to determine recovery of sweating, nociceptive, and muscular functions in the hindpaw repeatedly during 3 months postoperation. The increase of gap length between nerve stumps delayed the beginning and reduced the degree of functional recovery achieved either with or without repair. When lesions were left unrepaired, functional reinnervation was only noticeable with a 2-mm gap and practically absent with longer gaps. With tube repair, reinnervation started earlier and achieved higher values than in the corresponding unrepaired groups. Tubulization was most effective with 4-mm gaps and comparatively less with shorter and longer gaps. With 4-mm gaps, recovery was higher when the silicone tube had a cross-sectional area 2.5 times that of the sciatic nerve than with narrower or wider tubes and when the wall was the thinnest available. In all cases muscle reinnervation showed a lower progression than sweating and nociceptive recovery.

Research paper thumbnail of Autophagy, and BiP level decrease are early key events in retrograde degeneration of motoneurons

Cell Death and Differentiation, 2011

Disconnection of the axon from the soma of spinal motoneurons (MNs) leads either to a retrograde ... more Disconnection of the axon from the soma of spinal motoneurons (MNs) leads either to a retrograde degenerative process or to a regenerative reaction, depending on the severity and the proximity to the soma of the axonal lesion. The endoplasmic reticulum (ER) is a continuous membranous network that extends from the nucleus to the entire cytoplasm of the neuronal soma, axon and dendrites. We investigated whether axonal injury is sensed by the ER and triggers the activation of protective mechanisms, such as the unfolded protein response (UPR) and autophagy. We found early (at 3 days) accumulation of beclin1, LC3II and Lamp-1, hallmarks of autophagy, in both degenerating MNs after spinal root avulsion and in non-degenerating MNs after distal nerve section, although Lamp-1 disappeared by 5 days only in the former. In contrast, only degenerating MNs presented early activation of IRE1a, revealed by an increase of the spliced isoform of Xbp1 and accumulation of ATF4 in their nucleus, two branches of the UPR, and late BiP downregulation in association with cytoskeletal and organelle disorganization. We conclude that BiP decrease is a signature of the degenerating process, as its overexpression led to an increase in MN survival after root avulsion. Besides, Bcl2 is strongly implicated in the survival pathway activated by BiP overexpression.

Research paper thumbnail of Differential motor and electrophysiological outcome in rats with mid-thoracic or high lumbar incomplete spinal cord injuries

Brain Research, 2006

We have investigated the motor changes in rats subjected to a moderate photochemical injury on mi... more We have investigated the motor changes in rats subjected to a moderate photochemical injury on mid-thoracic (T8) or high lumbar (L2) spinal cord segments. Fourteen days after surgery, L2 injured animals presented gross locomotor deficits (scored 10 ± 2.8 in the BBB scale), decreased amplitude of motor-evoked potentials (MEPs) recorded on tibialis anterior (TA) and plantar (PL) muscles (24% and 6% of the preoperative mean values, respectively), reduced M wave amplitudes (75%, 62%), and also facilitated monosynaptic reflexes evidenced by an increase of the H/M amplitude ratio (158% and 563%). On the other hand, T8 injured animals had only slight deficits in locomotion (18 ± 0.6 in the BBB scale), a minimal reduction in MEP amplitudes (78% and 71% in TA and PL muscles), normal M wave amplitudes, and a milder increase of the H/M ratio in the TA muscle (191%) but less pronounced in the PL muscle (172%). The percentage of spared tissue at the site of injury was similar in both experimental groups (L2: 79% and T8: 82%). Taken together, these results indicate that lumbar spinal injuries have more severe consequences on hindlimb motor output than injuries exerted on thoracic segments. The causes of this anatomical difference may be attributed to damage inflicted on the central pattern generator of locomotion resulting in dysfunction of lumbar motoneurons and altered spinal reflexes modulation.

Research paper thumbnail of Neuroprotection and axonal regeneration after lumbar ventral root avulsion by re-implantation and mesenchymal stem cells transplant combined therapy

Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, 2013

Ventral spinal root avulsion causes complete denervation of muscles in the limb and also progress... more Ventral spinal root avulsion causes complete denervation of muscles in the limb and also progressive death of segmental motoneurons (MN) leading to permanent paralysis. The chances for functional recovery after ventral root avulsion are very poor owing to the loss of avulsed neurons and the long distance that surviving neurons have to re-grow axons from the spinal cord to the corresponding targets. Following unilateral avulsion of L4, L5 and L6 spinal roots in adult rats, we performed an intraspinal transplant of mesenchymal stem cells (MSC) and surgical re-implantation of the avulsed roots. Four weeks after avulsion the survival of MN in the MSC-treated animals was significantly higher than in vehicle-injected rats (45% vs. 28%). Re-implantation of the avulsed roots in the injured spinal cord allowed the regeneration of motor axons. By combining root re-implantation and MSC transplant the number of surviving MN at 28 days post-injury was higher (60%) than in re-implantation alone a...

Research paper thumbnail of Network-based proteomic approaches reveal the neurodegenerative, neuroprotective and pain-related mechanisms involved after retrograde axonal damage

Scientific reports, 2015

Neurodegenerative processes are preceded by neuronal dysfunction and synaptic disconnection. Disc... more Neurodegenerative processes are preceded by neuronal dysfunction and synaptic disconnection. Disconnection between spinal motoneuron (MN) soma and synaptic target leads either to a retrograde degenerative process or to a regenerative reaction, depending injury proximity among other factors. Distinguished key events associated with one or other processes may give some clues towards new therapeutical approaches based on boosting endogenous neuroprotective mechanisms. Root mechanical traction leads to retrograde MN degeneration, but share common initial molecular mechanisms with a regenerative process triggered by distal axotomy and suture. By 7 days post-injury, key molecular events starts to diverge and sign apart each destiny. We used comparative unbiased proteomics to define these signatures, coupled to a novel network-based analysis to get biological meaning. The procedure implicated the previous generation of combined topological information from manual curated 19 associated biol...

Research paper thumbnail of Alignment of collagen and laminin-containing gels improve nerve regeneration within silicone tubes

Restorative neurology and neuroscience, 2002

Placement of extracellular matrix components has been used as a mean to enhance axonal growth acr... more Placement of extracellular matrix components has been used as a mean to enhance axonal growth across nerve long gaps repaired by tubulization. However, such matrices may impede axonal regeneration depending on its density and microgeometry. Silicone tubes were prefilled with collagen or laminin-containing gels and implanted into a 6 mm gap, a length considered limiting for regeneration, in the mouse sciatic nerve. Gels were polymerized prior to implantation either in horizontal position or subjected to gravitational (in vertical position) or to magnetic forces to induce longitudinal alignment of the fibrils. Recovery of motor, sensory and sudomotor functions in the hindpaw was evaluated during 4 months postoperation. Reinnervation started earlier and achieved slightly higher levels with aligned collagen gels than with the horizontal gel. For the three groups repaired with tubes with Matrigel, there was a gradation of the functional results, reinnervation started earlier and reached ...

Research paper thumbnail of El trasplante de células de la glía envolvente del bulbo olfatorio tras lesión de la médula espinal: Estudio experimental en ratas

Revista Española de Cirugía Ortopédica y Traumatología, 2005

Research paper thumbnail of Improved prediction of knee osteoarthritis progression by genetic polymorphisms: the Arthrotest Study

Rheumatology (Oxford, England), Jan 7, 2015

The aim of this study was to develop a genetic prognostic tool to predict radiographic progressio... more The aim of this study was to develop a genetic prognostic tool to predict radiographic progression towards severe disease in primary knee OA (KOA) patients. This investigation was a cross-sectional, retrospective, multicentric association study in 595 Spanish KOA patients. Caucasian patients aged ≥40 years at the time of diagnosis of primary KOA of Kellgren-Lawrence grade 2 or 3 were included. Patients who progressed to Kellgren-Lawrence score 4 or who were referred for total knee replacement within 8 years after diagnosis were classified as progressors to severe disease. Clinical variables of the initial stages of the disease (gender, BMI, age at diagnosis, OA in the contralateral knee, and OA in other joints) were registered as potential predictors. Single nucleotide polymorphisms and clinical variables with an association of P < 0.05 were included in the multivariate analysis using forward logistic regression. A total of 23 single nucleotide polymorphisms and the time of prima...

Research paper thumbnail of Transplanted olfactory ensheathing cells modulate the inflammatory response in the injured spinal cord

Neuron Glia Biology, 2004

Transplantation of olfactory ensheathing cells (OECs) into the injured spinal cord has been shown... more Transplantation of olfactory ensheathing cells (OECs) into the injured spinal cord has been shown to exert neuroprotective effects and promote functional recovery. In the present study, we investigated the potential modulatory effects of OECs on the inflammatory reaction developed after photochemical injury to the spinal cord. OEC cultures were obtained from olfactory bulbs of adult Sprague-Dawley rats. Photochemical spinal cord injury was induced in adult rats at T8. Thirty minutes after the insult, either a suspension of OECs (180 000 cells in 12 microl DMEM) or DMEM alone was injected into the lesioned spinal cord.At 3, 7 and 14 days post-operation (dpo), five animals from each group were processed for histology. Double-fluorescent labeling of transverse sections of the cord were made by combination of immunohistochemistry for inflammatory markers, interleukin 1b(IL-1b) and inducible nitric oxide synthase (iNOS), and for selective markers of astrocytes (glial fibrillar acidic protein; GFAP)and microglia/macrophages (tomato lectin; LEC). Differences in the intensity and time course of glial response, and IL-1band iNOS expression were found between the two groups of rats. The reactivity grade against IL-1beta, iNOS, GFAP and LEC in OEC-transplanted rats was higher at 7 dpo and lower at 14 dpo compared with DMEM-injected rats. These results indicate that the mechanisms underlying neuroprotection by OECs might be caused by earlier, higher and shorter duration of microglia/macrophage and astrocyte responses after injury.

Research paper thumbnail of Acute and delayed transplantation of olfactory ensheathing cells promote partial recovery after complete transection of the spinal cord

Neurobiology of Disease, 2006

The present study was undertaken to determine whether olfactory ensheathing cells (OECs) from the... more The present study was undertaken to determine whether olfactory ensheathing cells (OECs) from the olfactory bulb were capable to promote axonal regeneration and functional recovery when transplanted either acutely or 1 week delayed into the T8 transected rat spinal cord. OEC transplants increased recovery of functional outcomes, as shown electrophysiologically by return of motor evoked potentials and by reduction of hindlimb hyperreflexia, and behaviorally by recovery of movements of hindlimb joints. Axonal regeneration was proven histologically by demonstrating long axonal outgrowth of raphespinal, coerulospinal, and corticospinal tracts within the caudal cord stump. Expression of GFAP and NG2 was down-regulated in perilesional cord segments in transplanted animals, indicating a more suitable environment for axonal regeneration. Overall, earlier recovery and better functional and histological results were observed in rats receiving acute than delayed OEC transplants. The beneficial effects obtained with transplantation after transection are encouraging for the application of OECs in the human injured spinal cord.

Research paper thumbnail of Olfactory ensheathing glia graft in combination with FK506 administration promote repair after spinal cord injury

Neurobiology of Disease, 2006

The aim of this study was to determine whether a combination of olfactory ensheathing cell (OEC) ... more The aim of this study was to determine whether a combination of olfactory ensheathing cell (OEC) graft with the administration of FK506, two experimental approaches that have been previously reported to exert protective/regenerative effects after spinal cord injury, promotes synergic restorative effects after complete or partial spinal cord injuries. In partial spinal cord injury, combination of an OEC graft and FK506 reduced functional deficits evaluated by the BBB score, motor-evoked potentials (MEPs) and H reflex tests, diminished cavitation, astrogliosis and increased sparing/regeneration of raphespinal fibers compared to untreated and single-treatment groups of rats. After complete spinal cord transection, the combined treatment significantly improved functional outcomes, promoted axonal regeneration caudal to the lesion, and diminished astrogliosis compared only to non-transplanted animals. Slightly, but nonsignificant, better functional and histological results were found in OEC-grafted animals treated with FK506 than in those given saline after spinal cord transection. Nevertheless, the combined treatment increased the percentage of rats that recovered MEPs and promoted a significant reduction in astrogliosis. In conclusion, this study demonstrates that OEC grafts combined with FK506 promote additive repair of spinal cord injuries to those exerted by single treatments, the effect being more remarkable when the spinal cord is partially lesioned.

Research paper thumbnail of Cytoskeletal and activity-related changes in spinal motoneurons after root avulsion

Journal of Neurotrauma, 2009

Compelling evidence shows that after root avulsion motoneurons attempt to survive and regenerate ... more Compelling evidence shows that after root avulsion motoneurons attempt to survive and regenerate before dying. In order to study these mechanisms, unilateral avulsion of L4-L5 spinal roots was performed in adult rats, and the ventral spinal cords were studied from 3 to 28 days post-operation (dpo). Electrophysiological results indicated complete denervation of L4-L5 muscles in the injured limb without functional effects on the contralateral hindlimb. Estimated cell counts showed progressive loss of avulsed motoneurons; at 28 dpo, the number of surviving motoneurons averaged 13% (AE3), 22% (AE0.9), and 29% (AE0.7) in samples stained with cresyl violet, immunostained for choline acetyltransferase (ChAT) and for SMI32, respectively. Regarding glial reactivity, we found an early microglial response, with the highest increase of isolectin B4 (IB4) and Iba1 expression at 3 days, and a slower and progressive response of astrocytes, shown by increasing expression of glial fibrillary acidic protein (GFAP) during the 28 days studied. Accumulation of phosphorylated (RT97þ) and non-phosphorylated (SMI32þ) neurofilaments was observed in the soma of axotomized motoneurons from 3 dpo. RT97 expression was present in approximately 80% (AE3.7) of surviving motoneurons at 7 dpo, and it was related to the regenerative response of motoneurons, as revealed by decreased ChAT expression and co-localization with GAP43. Intense SMI32 immunostaining was observed during the first week after avulsion, appearing in 37% (AE0.9) of surviving motoneurons, but it was not associated with GAP43 expression. Calcitonin gene-related peptide (CGRP) expression in motoneurons was markedly reduced from the second week after avulsion. This study presents a detailed description of motoneuron reaction after root avulsion, which suggests an early time-window during the first 2 weeks for attempts to repair the injury and promote motoneuron survival and regeneration.

Research paper thumbnail of Functional and Electrophysiological Characterization of Photochemical Graded Spinal Cord Injury in the Rat

Journal of Neurotrauma, 2003

This study characterizes by functional and electrophysiological methods changes following photoch... more This study characterizes by functional and electrophysiological methods changes following photochemically induced injuries to the spinal cord in adult rats. The spinal cord was exposed by laminectomy and bathed with 1.5% rose bengal solution for 10 min (T12-L1 vertebrae). The excess dye was removed by saline rinse and the spinal cord was irradiated with &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;cold&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; light for 0, 1, 2.5, 5, and 10 min in different groups of rats. During the first 15 days postlesion, locomotion activity, pain sensibility, motor and somatosensory evoked potentials, and motor and nerve action potentials were evaluated. Graded locomotor and nociceptive recovery was observed in irradiated rats depending on the photoinduction time. At 15 days, the amplitude of motor and sensory evoked potentials was significantly lower in irradiated groups with respect to control rats. The amplitude of compound muscle action potentials and of reflex H wave after sciatic nerve stimulation decreased significantly in irradiated animals with respect to control rats, while the latency did not show significant differences. In irradiated groups, significant differences were seen between pre- and postoperative values for most functional and electrophysiological parameters analyzed. A significant negative relationship was found between the area of cystic cavity of the spinal cord and the functional and electrophysiological impairment.

Research paper thumbnail of Increased Expression of Cyclo-Oxygenase 2 and Vascular Endothelial Growth Factor in Lesioned Spinal Cord by Transplanted Olfactory Ensheathing Cells

Journal of Neurotrauma, 2004

Olfactory ensheathing cells (OECs) were transplanted in adult rats after photochemical injury of ... more Olfactory ensheathing cells (OECs) were transplanted in adult rats after photochemical injury of the spinal cord. Rats received either 180,000 OECs suspended in DMEM or DMEM alone. Locomotor ability scored by the BBB-scale, pain sensibility, and motor and somatosensory evoked potentials were evaluated during the first 14 days post-surgery. At 3, 7, and 14 days, 5 rats per day of both groups were perfused and transverse sections from proximal, lesioned and distal spinal cord blocks were stained for COX-2, VEGF, GFAP and lectin. The BBB-score and the amplitude of motor and somatosensory evoked potentials were significantly higher in OEC- than in DMEM-injected animals throughout follow-up, whereas the withdrawal latency to heat noxious stimulus was lower in OEC- than in DMEM-injected rats. The area of preserved spinal cord and the levels of COX-2 and VEGF staining were significantly higher in OEC- than in DMEM-injected rats. GFAP- but no LEC-positive cells expressed COX-2 staining in OEC-transplanted rats. The density of blood vessels was also significantly increased in OEC- with respect to DMEM-injected rats. Our results show that OECs promote functional and morphological preservation of the spinal cord after photochemical injury, increasing neoangiogenesis and up-regulation of COX-2 and VEGF expression in astrocytes.

Research paper thumbnail of Morphological Characterization of Photochemical Graded Spinal Cord Injury in the Rat

Journal of Neurotrauma, 2003

This study characterizes the histological and immunohistochemical changes in the adult rat spinal... more This study characterizes the histological and immunohistochemical changes in the adult rat spinal cord following photochemically induced spinal cord lesions. The spinal cord was exposed by laminectomy (T12-L1 vertebrae) and bathed with 1.5% rose bengal solution for 10 min. The excess dye was removed by saline rinse and the spinal cord was irradiated with &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;cold&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; light for 0, 1, 2.5, 5, and 10 min in different groups of rats. After 15 days a graded loss of spinal tissue was observed according to photoinduction times. Animals irradiated for 1 min showed spinal cavities involving the dorsal funiculi. The cavity became progressively larger, involving dorsal horns in animals irradiated for 2.5 min, together with the dorsolateral funiculi in animals irradiated for 5 min and the ventrolateral funiculi in those irradiated for 10 min, with loss of gray matter in these three groups. Changes in GFAP-, CGRP-, proteoglycan- and calbindin-immunoreactivity were observed in all lesioned groups when compared with control spinal cords. Hypertrophied and heavily GFAP- and proteoglycan-stained astrocytes were seen in irradiated spinal cords. Reactive microglial cells were also found. Both astroglial and microglial reactions paralleled the severity of the spinal cord lesion. A significant loss of CGRP-immunoreactive somas was seen in animals irradiated for 10 min, whereas the wider distribution of calbindin-positive neurons was found in lesioned rats. In spinal cord sections from animals illuminated for 5 min and perfused 60 min postillumination, light and electron microscopy showed cytotoxic edema with astrocytic swelling, red blood cell extravasation, and myelin degradation.

Research paper thumbnail of FK506 reduces tissue damage and prevents functional deficit after spinal cord injury in the rat

Journal of Neuroscience Research, 2005

We examined the efficacy of FK 506 in reducing tissue damage after spinal cord injury in comparis... more We examined the efficacy of FK 506 in reducing tissue damage after spinal cord injury in comparison to methylprednisolone (MP) treatment. Rats were subjected to a photochemical injury (T8) and were given a bolus of MP (30 mg/kg), FK 506 (2 mg/kg), or saline. An additional group received an initial bolus of FK 506 (2 mg/kg) followed by daily injections (0.2 mg/kg intraperitoneally). Functional recovery was evaluated using open-field walking, inclined plane tests, motor evoked potentials (MEPs), and the H-reflex response during 14 days postoperation (dpo). Tissue sparing and glial fibrillary acidic protein (GFAP), biotinylated tomato lectin LEC, cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and interleukin 1 beta (IL-1 beta) immunoreactivity were quantified in the injured spinal cord. FK 506-treated animals demonstrated significantly better neurologic outcome, higher MEP amplitudes, and lower H-wave amplitude compared to that of saline-treated rats. In contrast, administration of MP did not result in significant differences with respect to the saline-treated group. Histologic examination revealed that tissue sparing was largest in FK 506-treated compared to saline and MP-treated animals. GFAP and COX-2 reactivity was decreased in animals treated with FK 506 compared to that in animals given MP or saline, whereas IL-1 beta expression was similarly reduced in both FK 506- and MP-treated groups. Microglia/macrophage response was reduced in FK 506 and MP-injected animals at 3 dpo, but only in MP-treated animals at 7 dpo with respect to saline-injected rats. Repeated administrations of FK 506 improved functional and histologic results to a greater degree than did a single bolus of FK 506. The results indicate that FK 506 administration protects the damaged spinal cord and should be considered as potential therapy for treating spinal cord injuries.

Research paper thumbnail of Spinal cord injury induces endoplasmic reticulum stress with different cell-type dependent response

Journal of Neurochemistry, 2007

The mechanisms of injury-induced apoptosis of neurons within the spinal cord are poorly understoo... more The mechanisms of injury-induced apoptosis of neurons within the spinal cord are poorly understood. In this study, we show that spinal cord injury (SCI) induces endoplasmic reticulum stress revealed by the activation of an unbalanced unfolded protein response (UPR). Using a weight-drop contusion model of SCI, the UPR activation was characterized by a quick transient phosphorylation of alpha subunit of eukaryotic initiation factor 2 soon restored by the up-regulation of its regulator Gadd34; an effective cleavage/activation of the ATF6a transcription factor leading to up-regulation of the canonical UPR target genes Chop, Xbp1 and Grp78; the presence of the processing of Xbp1 mRNA indicative of inositol requiring kinase 1 activation, and a gradual accumulation of C/EBP homologous transcription factor protein (CHOP) with concomitant caspase-12 activation. Interestingly, the subcellular distribution of CHOP was found in the nucleus of neurons and oligodendrocytes but in the cytoplasm of astrocytes. Considering the pro-apoptotic action attributed to this transcription factor, this phenomenon might account for the different susceptibility of cell types to dye after SCI.

Research paper thumbnail of Chronic transplantation of olfactory ensheathing cells promotes partial recovery after complete spinal cord transection in the rat

Glia, 2007

The goal of this study was to ascertain whether olfactory ensheathing cells (OECs) were able to p... more The goal of this study was to ascertain whether olfactory ensheathing cells (OECs) were able to promote axonal regeneration and functional recovery when transplanted 45 days after complete transection of the thoracic spinal cord in adult rats. OECs promoted partial restitution of supraspinal pathways evaluated by motor evoked potentials and modest recovery of hindlimb movements. In addition, OEC grafts reduced lumbar reflex hyperexcitability from the first month after transplantation. Histological results revealed that OECs facilitated corticospinal and raphespinal axons regrowth through the injury site and into the caudal spinal cord segments. Interestingly, raphespinal but not corticospinal fibers regenerated long distances through the gray matter and reached the lower lumbar segments (L5) of the spinal cord. However, delayed OEC grafts failed to reduce posttraumatic astrogliosis. In conclusion, the beneficial effects found in the present study further support the use of OECs for treating chronic spinal cord injuries.

Research paper thumbnail of Olfactory ensheathing cells transplanted in lesioned spinal cord prevent loss of spinal cord parenchyma and promote functional recovery

Glia, 2003

We studied the effects of olfactory ensheathing cells (OECs) transplanted in a photochemical spin... more We studied the effects of olfactory ensheathing cells (OECs) transplanted in a photochemical spinal cord injury in adult rats. After dorsal laminectomy at T8 vertebra, subjacent spinal cord was bathed with rose Bengal for 10 min and illuminated with visible light by means of an optic fiber connected to a halogen lamp for 2.5 min at maximal intensity of 8 kLux. Eight injured rats received a suspension of OECs in DMEM, and another eight rats received DMEM alone. Locomotor ability scored by the BBB scale, pain sensibility by the plantar algesimetry test, and motor-and somatosensory-evoked potentials by electrophysiological techniques were evaluated for 3 months postsurgery. Finally, all rats were perfused with paraformaldehyde and transverse sections from the spinal cord segment at the lesion site were immunostained against GFAP. Area of the preserved spinal cord parenchyma was measured from the GFAPimmunolabeled cord sections. The BBB score and the amplitude of motor-and somatosensory-evoked potentials were higher in OECs-transplanted rats than in DMEMinjected animals throughout follow-up, whereas the withdrawal response to heat noxious stimulus was lower in OEC-than in DMEM-injected rats. The area of preserved spinal cord was significantly larger in OECs-transplanted rats than in DMEM-injected animals. These results indicate that OECs promote functional and morphological preservation of the spinal cord after photochemical injury. GLIA 42: [275][276][277][278][279][280][281][282][283][284][285][286] 2003.

Research paper thumbnail of Influence of Physical Parameters of Nerve Chambers on Peripheral Nerve Regeneration and Reinnervation

Experimental Neurology, 1996

We compared reinnervation of target organs after sciatic nerve section leaving gaps of 2, 4, 6, o... more We compared reinnervation of target organs after sciatic nerve section leaving gaps of 2, 4, 6, or 8 mm or gaps repaired with silicone tubes in different groups of mice. Functional reinnervation was assessed by noninvasive methods to determine recovery of sweating, nociceptive, and muscular functions in the hindpaw repeatedly during 3 months postoperation. The increase of gap length between nerve stumps delayed the beginning and reduced the degree of functional recovery achieved either with or without repair. When lesions were left unrepaired, functional reinnervation was only noticeable with a 2-mm gap and practically absent with longer gaps. With tube repair, reinnervation started earlier and achieved higher values than in the corresponding unrepaired groups. Tubulization was most effective with 4-mm gaps and comparatively less with shorter and longer gaps. With 4-mm gaps, recovery was higher when the silicone tube had a cross-sectional area 2.5 times that of the sciatic nerve than with narrower or wider tubes and when the wall was the thinnest available. In all cases muscle reinnervation showed a lower progression than sweating and nociceptive recovery.

Research paper thumbnail of Autophagy, and BiP level decrease are early key events in retrograde degeneration of motoneurons

Cell Death and Differentiation, 2011

Disconnection of the axon from the soma of spinal motoneurons (MNs) leads either to a retrograde ... more Disconnection of the axon from the soma of spinal motoneurons (MNs) leads either to a retrograde degenerative process or to a regenerative reaction, depending on the severity and the proximity to the soma of the axonal lesion. The endoplasmic reticulum (ER) is a continuous membranous network that extends from the nucleus to the entire cytoplasm of the neuronal soma, axon and dendrites. We investigated whether axonal injury is sensed by the ER and triggers the activation of protective mechanisms, such as the unfolded protein response (UPR) and autophagy. We found early (at 3 days) accumulation of beclin1, LC3II and Lamp-1, hallmarks of autophagy, in both degenerating MNs after spinal root avulsion and in non-degenerating MNs after distal nerve section, although Lamp-1 disappeared by 5 days only in the former. In contrast, only degenerating MNs presented early activation of IRE1a, revealed by an increase of the spliced isoform of Xbp1 and accumulation of ATF4 in their nucleus, two branches of the UPR, and late BiP downregulation in association with cytoskeletal and organelle disorganization. We conclude that BiP decrease is a signature of the degenerating process, as its overexpression led to an increase in MN survival after root avulsion. Besides, Bcl2 is strongly implicated in the survival pathway activated by BiP overexpression.

Research paper thumbnail of Differential motor and electrophysiological outcome in rats with mid-thoracic or high lumbar incomplete spinal cord injuries

Brain Research, 2006

We have investigated the motor changes in rats subjected to a moderate photochemical injury on mi... more We have investigated the motor changes in rats subjected to a moderate photochemical injury on mid-thoracic (T8) or high lumbar (L2) spinal cord segments. Fourteen days after surgery, L2 injured animals presented gross locomotor deficits (scored 10 ± 2.8 in the BBB scale), decreased amplitude of motor-evoked potentials (MEPs) recorded on tibialis anterior (TA) and plantar (PL) muscles (24% and 6% of the preoperative mean values, respectively), reduced M wave amplitudes (75%, 62%), and also facilitated monosynaptic reflexes evidenced by an increase of the H/M amplitude ratio (158% and 563%). On the other hand, T8 injured animals had only slight deficits in locomotion (18 ± 0.6 in the BBB scale), a minimal reduction in MEP amplitudes (78% and 71% in TA and PL muscles), normal M wave amplitudes, and a milder increase of the H/M ratio in the TA muscle (191%) but less pronounced in the PL muscle (172%). The percentage of spared tissue at the site of injury was similar in both experimental groups (L2: 79% and T8: 82%). Taken together, these results indicate that lumbar spinal injuries have more severe consequences on hindlimb motor output than injuries exerted on thoracic segments. The causes of this anatomical difference may be attributed to damage inflicted on the central pattern generator of locomotion resulting in dysfunction of lumbar motoneurons and altered spinal reflexes modulation.

Research paper thumbnail of Neuroprotection and axonal regeneration after lumbar ventral root avulsion by re-implantation and mesenchymal stem cells transplant combined therapy

Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, 2013

Ventral spinal root avulsion causes complete denervation of muscles in the limb and also progress... more Ventral spinal root avulsion causes complete denervation of muscles in the limb and also progressive death of segmental motoneurons (MN) leading to permanent paralysis. The chances for functional recovery after ventral root avulsion are very poor owing to the loss of avulsed neurons and the long distance that surviving neurons have to re-grow axons from the spinal cord to the corresponding targets. Following unilateral avulsion of L4, L5 and L6 spinal roots in adult rats, we performed an intraspinal transplant of mesenchymal stem cells (MSC) and surgical re-implantation of the avulsed roots. Four weeks after avulsion the survival of MN in the MSC-treated animals was significantly higher than in vehicle-injected rats (45% vs. 28%). Re-implantation of the avulsed roots in the injured spinal cord allowed the regeneration of motor axons. By combining root re-implantation and MSC transplant the number of surviving MN at 28 days post-injury was higher (60%) than in re-implantation alone a...