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Treatment with Albumin (A)-Hydroxyoleic acid (HOA) complex restores sensorimotor function in rats with spinal cord injury: Efficacy and gene expression regulation

ABSTRACT: Sensorimotor dysfunction following incomplete spinal cord injury (SCI) is often characterized by paralysis, spasticity and pain. Previously, we showed that intrathecal (i.t.) administration of the albumin-oleic acid (A-OA) complex in rats with SCI produced partial improvement of these symptoms and that oral 2-hydroxyoleic acid (HOA), a non-hydrolyzable OA analogue), was efficacious in the modulation and treatment of nociception and pain-related anxiety, respectively. Here we observed that intrathecal treatment with the complex albumin-HOA (A-HOA) every 3 days following T9 spinal contusion injury promoted significant recovery in locomotor function and marked an inhibition of TA noxious reflex activity (i.e., nociception) in Wistar rats. To investigate the mechanism of action of A-HOA, microarray analysis was carried out in the spinal cord lesion area. Representative genes involved in pain and neuroregeneration were selected to validate the changes observed in the microarray analysis by quantitative real-time RT-PCR. Comparison of the expression between healthy rats, SCI rats, and SCI treated with A-HOA rats revealed relevant changes in the expression of genes associated with neuronal morphogenesis and growth, neuronal survival, pain and inflammation. Thus, treatment with A-HOA not only induced a significant overexpression of growth and differentiation factor 10 (GDF10), tenascin C (TNC), aspirin (ASPN) and sushi-repeat-containing X-linked 2 (SRPX2), but also a significant reduction in the expression of prostaglandin E synthase (PTGES) and phospholipases A1 and A2 (PLA1/2). Currently, SCI has very important unmet clinical needs. A-HOA proved to downregulate genes involved in inflammation and upregulate genes involved in neuron growth, which balanced the important body response to medular lesion and allowed recovery from paralysis and pain.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE104317 | GEO | 2017/09/28

SECONDARY ACCESSION(S): PRJNA412335

REPOSITORIES: GEO

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Project description:Abstract Objective: Osteoarthritis (OA) is accompanied by severe and debilitating pain that current analgesics are unable to fully alleviate. A multitude of signaling molecules, pathways, and cells have been identified as regulators of OA pain. Fatty acid binding protein 5 (FABP5) regulates pain in other disease states and we hypothesized that it is involved in the regulation of OA pain. Design: This was a combined clinical and pre-clinical study. Human synovial and osteochondral tissues collected during total knee arthroplasty were subjected to immunohistochemical analyses to identify the spatial expression patterns of FAB5, COX1, COX2, and macrophages. In addition, synovial specimens were cultured the presence and absence of SBFI-103, a selective FABP5 inhibitor, and cytokines and chemokines levels were measured. The rat monoiodoacetate (MIA) model of OA was then enlisted to evaluate the efficacy of SBFI-103 in alleviating OA pain. Finally, RNAseq was performed to identify alterations in synovial gene expression in vehicle and SBFI-103 treated MIA rats. Results: FABP5 expression was present in clinical OA tissues, with higher expression seen higher grade OA and no apparent differences between genders. Furthermore, FABP5 staining colocalized with CD14+ cells, indicating a macrophage origin of FABP5. Synovial specimens secreted CCL2, IL6, IL8, CXCL1, MIF, and Serpin E1 in vitro and treatment with SBFI-103 attenuated CCL2, IL6, IL8, and CXCL1, but not MIF and Serpin E1. Twenty-eight days after MIA injection, rats exhibited histological joint degradation and significant incapacitance. Ketoprofen treatment partially reduced incapacitance and naproxen had no effect; however, SBFI-103 showed a dose dependent alleviation of incapacitance that was independent of cannabinoid or PPARα receptor activity. RNAseq analyses identified differential expression of >6,000 transcripts compared to contralateral controls in vehicle treated rats and only 513 after SBFI-103 treatment. Notably, CCL2, CCL7, CCL9, and CXCL1were upregulated in vehicle treated rats, but not those treated with SBFI-103, and this was confirmed with qPCR. Conclusions: Our results show that FABP5 is upregulated in clinical and preclinical OA tissues and that its inhibition lowers pronociceptive signaling and reduces OA pain, indicating that FABP5 inhibitors may constitute a novel class of analgesics to treat OA.

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Treatment with Albumin (A)-Hydroxyoleic acid (HOA) complex restores sensorimotor function in rats with spinal cord injury: Efficacy and gene expression regulation

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