Abstract
The PPAR-α agonist, oleoylethanolamide (OEA) has neuroprotective properties in stroke models. However, its rapid degradation represents a limitation for an effective therapeutic approach. In this study, we evaluated the effects of a stable OEA-modeled compound, octadecylpropyl sulfamide (SUL) on the cognitive, behavioral, cellular and molecular alterations associated with hypoxia-ischemia (HI) in mice. Mice subjected to HI were treated with the PPAR-α antagonist GW6471 (GW) (1 mg/kg) followed 15 min later by SUL (3 and 10 mg/kg). Behavioral, motor, and cognitive tests were carried out 24 h and 7 days after the HI. The levels of microglia, reactive astrocytes and neuronal nuclei were studied using immunofluorescence, and the expression of genes related to the N-acyl-ethanolamides/endocannabinoid signaling systems was determined by qRT-PCR at the end of the experimental sequence. HI induced brain damage in the ipsilateral hippocampus and cortex, which lead to severe memory impairments, and motor coordination deficits. Significant neuronal loss, increased microglia and reactive astrocytes, and compensatory changes in genes associated with the inflammation/immune and endocannabinoid systems were observed in these brain structures of lesioned mice. SUL reversed the memory and motor deficits, decreased the overexpression of microglia and astrocytes, and reduced neurodegeneration induced by HI. Cnr1 and Cnr2 gene expression was modulated by SUL in both sham and HI mice, while Pparα and Faah expression was regulated in HI mice. GW completely blocked the beneficial actions of SUL. These findings suggest that treatment with SUL reduces brain damage and the associated motor and memory deficits induced by HI probably by normalizing the changes in neuroinflammation/immune system mediators.
Highlights
Cerebral ischemia is one of the leading causes of mortality and severe disability worldwide (Mathers et al, 2006; Flynn et al, 2008)
To understand the cellular and molecular mechanisms involved in the effects of SUL, we examined neurodegeneration processes, the levels of microglia and reactive astrocytes, as well as, changes in gene expression related to the N-acylethanolamides (NAEs)/endocannabinoid signaling systems in different brain areas following the HI insult
SUL normalized the changes in the expression of genes associated with HI-induced neuroinflammatory response in these brain structures, especially those of the NAEs/endocannabinoid signaling systems, and those related to activation of astrocytes and microglial phenotypes M1 and M2
Summary
Cerebral ischemia is one of the leading causes of mortality and severe disability worldwide (Mathers et al, 2006; Flynn et al, 2008). This condition is usually caused by a reduction in blood oxygen content, and if the blood flow is not rapidly restored, there is a risk of damage to brain tissues that can lead to severe neurological deficits depending on the duration, location, and size of the insult. The peroxisome proliferator-activated receptor alpha (PPAR-α) is a nuclear receptor involved in different processes including modulation of cellular differentiation, metabolism of carbohydrates, lipids and proteins, and tumorigenesis (Lee et al, 2003; Marx et al, 2004). Modeling OEA analog drugs with high affinity for the PPAR-α might solve this issue and facilitate the development of more stable neuroprotectant drugs
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