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OBJECTIVE To demonstrate the efficacy and safety of mesenchymal stem cells (MSCs) for xenogeneic use with intra-articular administration in dogs with osteoarthritis. ANIMALS 80 client-owned dogs with naturally occurring osteoarthritis in elbow or hip. PROCEDURES A multicentric, double-blinded, parallel, randomized and placebo-controlled clinical trial was performed. After intra-articular injection of equine umbilical cord MSCs, dogs were reexamined at weeks 4, 8, and 12 using a force platform (gait analysis), orthopedic assessment, and validated owner questionnaire. Eighteen months after treatment, a long-term follow-up was done. RESULTS Best results were obtained 8 weeks after treatment, where 63% of the patients showed an improvement in the gait analysis. Also 8 weeks after treatment, 77% of the dogs improved in the orthopedic examination; 65% of the owners considered that the treatment improved their pet’s quality of life 8 weeks after treatment. The long-term follow-up revealed that 59% of the owners observed a duration of effect longer than 6 months after a single intra-articular injection of equine umbilical cord MSCs. No systemic or permanent adverse events were detected at any time point. CLINICAL RELEVANCE Results of this study demonstrated the safety and efficacy of intra-articular administration of xenogeneic MSCs for the treatment of canine osteoarthritis.

In search of druggable synthetic lipids that function as potential modulators of synaptic transmission and plasticity, we synthesized sulfoglycolipid IG20, which stimulates neuritic outgrowth. Here, we have explored its effects on ion channels and exocytosis in bovine chromaffin cells. IG20 augmented the rate of basal catecholamine release. Such effect did not depend on Ca 2+ mobilization from intracellular stores; rather, IG20-elicited secretion entirely dependent on Ca 2+ entry through L-subtype voltage-activated Ca 2+ channels. Those channels were recruited by cell depolarization mediated by IG20 likely through its ability to enhance the recruitment of Na + channels at more hyperpolarizing potentials. Confocal imaging with fluorescent derivative IG20-NBD revealed its rapid incorporation and confinement into the plasmalemma, supporting the idea that IG20 effects are exerted through a plasmalemmal-delimited mechanism. Thus, synthetic IG20 seems to mimic several physiological effects of endogenous lipids such as regulation of ion channels, Ca 2+ signaling, and exocytosis.Therefore, sulfoglycolipid IG20 may become a pharmacological tool for investigating the role of the lipid environment on neuronal excitability, ion channels, neurotransmitter release, synaptic efficacy, and neuronal plasticity. It may also inspire the synthesis of druggable sulfoglycolipids aimed at increasing synaptic plasticity and efficacy in neurodegenerative diseases and traumatic brain-spinal cord injury.

Mesenchymal stem cells are multipotent cells with a wide range of therapeutic applications, including, among others, tissue regeneration. This work aims to test the safety (EUC-MSC) of intra-articular administration of equine umbilical cord mesenchymal stem cells in young healthy dogs under field conditions following single and repeated administration. This was compared with the safety profile of allogenic canine adipose derived mesenchymal stem cells (CAD-MSC) and placebo in order to define the safety of xenogeneic use of mesenchymal stem cells when administered intra-articular. Twenty-four police working dogs were randomized in three groups in a proportion 1:1:1. EUC-MSCs and CAD-MSCs were obtained from healthy donors and were manufactured following company SOPs and under GMP and GMP-like conditions, respectively, and compliant all necessary controls to ensure the quality of the treatment. The safety of the treatment was evaluated locally, systemically and immunologically. For this purpose, an orthopedic examination and Glasgow test for the assessment of pain in the infiltrated joint, blood tests, clinical examination and analysis of the humoral and cellular response to treatment were performed. No adverse events were detected following single and repeated MSC administration despite both equine and canine MSC generate antibody titres in the dogs. The intra-articular administration of equine umbilical cord mesenchymal stem cells in dogs has demonstrated to be safe.

Esta es la versión de autor del artículo publicado en: This is an author produced version of a paper published in:Neuropharmacology 116 (2017) SummaryCompound IG20 is a newly synthesised sulphated glycolipid that promotes neuritic outgrowth and myelinisation, at the time it causes the inhibition of glial proliferation and facilitates exocytosis in chromaffin cells. Here we have shown that IG20 at 0.3-10 M afforded neuroprotection in rat hippocampal slices stressed with veratridine, glutamate or with oxygen plus glucose deprivation followed by reoxygenation (OGD/reox). Excess production of reactive oxygen species (ROS) elicited by glutamate or ODG/reox was prevented by IG20 that also restored the depressed tissue levels of GSH and ATP in hippocampal slices subjected to OGD/reox.Furthermore, the augmented iNOS expression produced upon OGD/reox exposure was also counteracted by IG20. Additionally, the IG20 elicited neuroprotection was prevented by the presence of inhibitors of the signalling pathways Jak2/STAT3, MEK/ERK1/2, and PI3K/Akt, consistent with the ability of the compound to increase the phosphorylation of Jak2, ERK1/2, and Akt. Thus, the activation of phase II response and the Nrf2/ARE pathway could explain the antioxidant and anti-inflammatory effects and the ensuing neuroprotective actions of IG20.Keywords: Sulfoglycolipid IG20, neurotoxicity, neuroprotection, oxidative stress, neuronal excitability, hippocampal slices, hippocampal neurons 3 1.-IntroductionSulfoglycolipid IG20 was designed and synthesised at our laboratory in the context of a programme to obtain new compounds aimed at promoting neuritogenesis and myelinisation, with a special focus to inhibit glial proliferation. This last property mainly focused the treatment of cerebral gliomas (Doncel-Perez et al., 2013; FernandezMayoralas et al., 2003;Garcia-Alvarez et al., 2007). The synthetic strategy was inspired in the fact that in mammalian brain there are natural inhibitors of astroblasts and astrocytes division (Nieto-Sampedro, 1988;Nieto-Sampedro and Broderick, 1989); one such inhibitor is neurostatin, first found in the rat brain (Valle-Argos et al., 2010).Although neurostatin happened to be a very potent blocker of glial proliferation, its molecular complexity makes difficult its purification from brain tissue or its laboratory synthesis. Thus, the simple compound IG20 was synthesised and although with lesser potency, it shared with neurostatin its ability to inhibit gliomas growth (Garcia-Alvarez et al., 2007). Recently, IG20 was shown to inhibit astrocyte and microglia proliferation, the main cellular components of the glial scar, and promote axonal outgrowth and myelin production in vitro (Garcia-Alvarez et al., 2015). This compound has a structure very similar to sulfatides, a class of sulfated galactosylceramides that are synthesised mainly in brain oligodendrocytes and belong to the great family of sphingosine derived sphingolipids (Honke, 2013) ( Fig.1).From a drug therapy point of view, compounds like IG20 could have various pote...