Treatment with albumin-hydroxyoleic acid complex restores sensorimotor function in rats with spinal cord injury: Efficacy and gene expression regulation

Gerardo Avila-Martin, Manuel Mata-Roig, Iriana Galán-Arriero, Julian S Taylor, Xavier Busquets, Pablo V Escribá, Gerardo Avila-Martin, Manuel Mata-Roig, Iriana Galán-Arriero, Julian S Taylor, Xavier Busquets, Pablo V Escribá

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 improved locomotor function assessed with the Rotarod and inhibited TA noxious reflex activity 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 downregulated genes involved with inflammation and upregulated genes involved in neuronal growth, and may serve to promote recovery of function after experimental SCI.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1. A-HOA promotes early recovery of…
Fig 1. A-HOA promotes early recovery of motor function following T9 spinal cord injury.
Longitudinal analysis of the mean (±SEM) time spent on the rotarod following contusion SCI from 4 to 28 days revealed that intrathecal administration of A-HOA (SCI A-HOA, ♦) induced locomotor recovery in contrast to saline vehicle treatment (SCI Sal, ▼). Statistical analysis was performed using a two-way ANOVA. *p

Fig 2. Inhibition of Tibialis Anterior noxious…

Fig 2. Inhibition of Tibialis Anterior noxious reflex activity in rats with SCI.

Quantitative analysis…

Fig 2. Inhibition of Tibialis Anterior noxious reflex activity in rats with SCI.
Quantitative analysis of Tibialis Anterior (TA) noxious reflex temporal summation at 28 days following spinal contusion. Significant (p

Fig 3. mRNAs differentially expressed in the…

Fig 3. mRNAs differentially expressed in the spinal cord lesion region in rats with SCI.

Fig 3. mRNAs differentially expressed in the spinal cord lesion region in rats with SCI.
After contusion, total RNA was extracted from the lesion region of rats with SCI or from healthy non-injured controls (Control) 1 day or 7 days (1d and 7d, respectively) and treated with saline vehicle (S) or A-HOA (HOA). mRNA was quantified by microarray analysis. ANOVA following the false discovery rate (FDR) P value correction used to detect significant changes. The figure shows hierarchical clustering in the 5 experimental groups showing the expression levels from green (low) to red (high). Expression levels using the color code indicated at the bottom of the graph is shown for all four animals from each experimental group.

Fig 4. Relative gene expression in SCI…

Fig 4. Relative gene expression in SCI rats 7 days after lesion.

Levels of the…

Fig 4. Relative gene expression in SCI rats 7 days after lesion.
Levels of the mRNA species indicated were quantified by qRT-PCR in the spinal cord of healthy non-injured rats (open bars) and SCI rats 7 days after contusion (solid bars). The relative expression was calculated from 4 animals using triplicate samples. The samples used were the same as those used for microarray analysis. The relative expression for each gene was calculated with respect to the expression of the housekeeping gene GAPDH. *p<0.01.

Fig 5. Relative gene expression in SCI…

Fig 5. Relative gene expression in SCI rats 1 and 7 days after lesion.

Levels…

Fig 5. Relative gene expression in SCI rats 1 and 7 days after lesion.
Levels of mRNA species quantified by qRT-PCR in the spinal cord of SCI rats 7 days after contusion (solid bars) relative to 1 day expression. The relative expression was calculated from 4 animals using triplicate samples. The samples used were the same as those used for microarray analysis. The relative expression for each gene was calculated with respect to the expression of the housekeeping gene GAPDH. *p<0.01.

Fig 6. Effect of A-HOA on the…

Fig 6. Effect of A-HOA on the relative gene expression of SCI rats 7 days…

Fig 6. Effect of A-HOA on the relative gene expression of SCI rats 7 days after lesion.
Levels of the mRNA species were quantified by qRT-PCR in the spinal cord of SCI rats 7 days after contusion treated with saline vehicle (solid bars) or A-HOA. The relative expression was calculated from 4 animals using triplicate samples. The samples used were the same as those used for microarray analysis. The relative expression for each gene was calculated with respect to the expression of the housekeeping gene GAPDH. *p<0.01.
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References
    1. Hulsebosch CE (2002) Recent advances in pathophysiology and treatment of spinal cord injury. Adv Physiol Educ 26:238–255. - PubMed
    1. Rossignol S, Schwab M, Schwartz M, Fehlings MG (2007) Spinal cord injury: time to move?. J Neurosci 27:11782–11792. doi: 10.1523/JNEUROSCI.3444-07.2007 - DOI - PMC - PubMed
    1. Bareyre FM, Schwab ME (2003) Inflammation, degeneration and regeneration in the injured spinal cord: insights from DNA microarrays. Trends Neurosci 26: 555–563. doi: 10.1016/j.tins.2003.08.004 - DOI - PubMed
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This study was financed from several sources including: Mutua Madrileña Foundation (2010 and 2013) and Spanish Ministry for Science and Innovation (IPT-010000-2010-016) with co-financial support from European Union FEDER funds to Dr. Taylor and Dr. Avila-Martin. Spanish Ministry for Economy and Competition (BIO2010-21132, BIO2013-49006-C2-1-R, RTC-2015-3542, RTC-2015-4094), Govern de les Illes Balears Research Grants for Groups of Excellence and Marathon Foundation project awarded to Dr. Pablo V. Escribá.
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Fig 2. Inhibition of Tibialis Anterior noxious…
Fig 2. Inhibition of Tibialis Anterior noxious reflex activity in rats with SCI.
Quantitative analysis of Tibialis Anterior (TA) noxious reflex temporal summation at 28 days following spinal contusion. Significant (p

Fig 3. mRNAs differentially expressed in the…

Fig 3. mRNAs differentially expressed in the spinal cord lesion region in rats with SCI.

Fig 3. mRNAs differentially expressed in the spinal cord lesion region in rats with SCI.
After contusion, total RNA was extracted from the lesion region of rats with SCI or from healthy non-injured controls (Control) 1 day or 7 days (1d and 7d, respectively) and treated with saline vehicle (S) or A-HOA (HOA). mRNA was quantified by microarray analysis. ANOVA following the false discovery rate (FDR) P value correction used to detect significant changes. The figure shows hierarchical clustering in the 5 experimental groups showing the expression levels from green (low) to red (high). Expression levels using the color code indicated at the bottom of the graph is shown for all four animals from each experimental group.

Fig 4. Relative gene expression in SCI…

Fig 4. Relative gene expression in SCI rats 7 days after lesion.

Levels of the…

Fig 4. Relative gene expression in SCI rats 7 days after lesion.
Levels of the mRNA species indicated were quantified by qRT-PCR in the spinal cord of healthy non-injured rats (open bars) and SCI rats 7 days after contusion (solid bars). The relative expression was calculated from 4 animals using triplicate samples. The samples used were the same as those used for microarray analysis. The relative expression for each gene was calculated with respect to the expression of the housekeeping gene GAPDH. *p<0.01.

Fig 5. Relative gene expression in SCI…

Fig 5. Relative gene expression in SCI rats 1 and 7 days after lesion.

Levels…

Fig 5. Relative gene expression in SCI rats 1 and 7 days after lesion.
Levels of mRNA species quantified by qRT-PCR in the spinal cord of SCI rats 7 days after contusion (solid bars) relative to 1 day expression. The relative expression was calculated from 4 animals using triplicate samples. The samples used were the same as those used for microarray analysis. The relative expression for each gene was calculated with respect to the expression of the housekeeping gene GAPDH. *p<0.01.

Fig 6. Effect of A-HOA on the…

Fig 6. Effect of A-HOA on the relative gene expression of SCI rats 7 days…

Fig 6. Effect of A-HOA on the relative gene expression of SCI rats 7 days after lesion.
Levels of the mRNA species were quantified by qRT-PCR in the spinal cord of SCI rats 7 days after contusion treated with saline vehicle (solid bars) or A-HOA. The relative expression was calculated from 4 animals using triplicate samples. The samples used were the same as those used for microarray analysis. The relative expression for each gene was calculated with respect to the expression of the housekeeping gene GAPDH. *p<0.01.
Fig 3. mRNAs differentially expressed in the…
Fig 3. mRNAs differentially expressed in the spinal cord lesion region in rats with SCI.
After contusion, total RNA was extracted from the lesion region of rats with SCI or from healthy non-injured controls (Control) 1 day or 7 days (1d and 7d, respectively) and treated with saline vehicle (S) or A-HOA (HOA). mRNA was quantified by microarray analysis. ANOVA following the false discovery rate (FDR) P value correction used to detect significant changes. The figure shows hierarchical clustering in the 5 experimental groups showing the expression levels from green (low) to red (high). Expression levels using the color code indicated at the bottom of the graph is shown for all four animals from each experimental group.
Fig 4. Relative gene expression in SCI…
Fig 4. Relative gene expression in SCI rats 7 days after lesion.
Levels of the mRNA species indicated were quantified by qRT-PCR in the spinal cord of healthy non-injured rats (open bars) and SCI rats 7 days after contusion (solid bars). The relative expression was calculated from 4 animals using triplicate samples. The samples used were the same as those used for microarray analysis. The relative expression for each gene was calculated with respect to the expression of the housekeeping gene GAPDH. *p<0.01.
Fig 5. Relative gene expression in SCI…
Fig 5. Relative gene expression in SCI rats 1 and 7 days after lesion.
Levels of mRNA species quantified by qRT-PCR in the spinal cord of SCI rats 7 days after contusion (solid bars) relative to 1 day expression. The relative expression was calculated from 4 animals using triplicate samples. The samples used were the same as those used for microarray analysis. The relative expression for each gene was calculated with respect to the expression of the housekeeping gene GAPDH. *p<0.01.
Fig 6. Effect of A-HOA on the…
Fig 6. Effect of A-HOA on the relative gene expression of SCI rats 7 days after lesion.
Levels of the mRNA species were quantified by qRT-PCR in the spinal cord of SCI rats 7 days after contusion treated with saline vehicle (solid bars) or A-HOA. The relative expression was calculated from 4 animals using triplicate samples. The samples used were the same as those used for microarray analysis. The relative expression for each gene was calculated with respect to the expression of the housekeeping gene GAPDH. *p<0.01.

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