Abstract
Diabetes causes various macrovascular and microvascular alterations, often culminating in major clinical complications (first of all, stroke) that lack an effective therapeutic intervention. N-palmitoylethanolamide-oxazoline (PEA-OXA) possesses anti-inflammatory and potent neuroprotective effects. Although recent studies have explained the neuroprotective properties of PEA-OXA, nothing is known about its effects in treating cerebral ischemia. Methods: Focal cerebral ischemia was induced by transient middle cerebral artery occlusion (MCAo) in the right hemisphere. Middle cerebral artery (MCA) occlusion was provided by introducing a 4–0 nylon monofilament (Ethilon; Johnson & Johnson, Somerville, NJ, USA) precoated with silicone via the external carotid artery into the internal carotid artery to occlude the MCA. Results: A neurological severity score and infarct volumes were carried out to assess the neuroprotective effects of PEA-OXA. Moreover, we observed PEA-OXA-mediated improvements in tissue histology shown by a reduction in lesion size and an improvement in apoptosis level (assessed by caspases, Bax, and Bcl-2 modulation and a TUNEL assay), which further supported the efficacy of PEA-OXA therapy. We also found that PEA-OXA treatment was able to reduce mast cell degranulation and reduce the MCAo-induced expression of NF-κB pathways, cytokines, and neurotrophic factors. Conclusions: based on these findings, we propose that PEA-OXA could be useful in decreasing the risk of impairment or improving function in ischemia/reperfusion brain injury-related disorders.
Highlights
Diabetes mellitus (DM) is a metabolic disorder connected with chronic hyperglycemia, which has been identified as enhancing systemic oxidative stress, inclining patients toward diabetic complications
The PEA-OXA-administered group (Figure 1B,F) had significantly less tissue damage 24 h after transient middle cerebral artery occlusion (MCAo) compared to sham-operated animals (Figure 1B,C) and PEA-treated animals (Figure 1B,E)
We focused our attention on the neuroprotective effects of PEA-OXA in a rat model of transient middle cerebral artery occlusion (MCAo) in diabetic rats
Summary
Diabetes mellitus (DM) is a metabolic disorder connected with chronic hyperglycemia, which has been identified as enhancing systemic oxidative stress, inclining patients toward diabetic complications. Recent studies, performed using experimental animal models, have helped to identify a wide selection of neuroprotective/anti-inflammatory compounds (e.g., inhibitors of inducible nitric oxide synthase and kinases, antiepileptics, polyphenols, and antioxidants) [16,17,18,19,20] Often these molecules have shown few positive outcomes [21,22]. Recent evidence has shown that pharmacological management of NAAA with the oxazoline of PEA (2-pentadecyl-2-oxazoline (PEA-OXA)) [43] had beneficial effects on secondary neuroinflammatory events associated with the spinal cord, traumatic brain injury, and Parkinson’s disease in mice [44,45] Starting from this evidence, the aim of this study was to investigate the effects of PEA-OXA on secondary neuroinflammatory events induced by transient middle cerebral artery occlusion (MCAo) in diabetic rats
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