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Interactions between essential fatty acid, prostanoid, polyol pathway and nitric oxide mechanisms in the
N E Cameron1, M A Cotter, T C Hohman
1Department of Biomedical Sciences, University of Aberdeen, Scotland, UK.
Abstract:
Impaired omega-6 essential fatty acid metabolism and exaggerated polyol pathway flux contribute to the neurovascular abnormalities in streptozotocin-diabetic rats. The potential interactions between these mechanisms were examined by comparing the effects of threshold doses of aldose reductase inhibitors and evening primrose oil, alone and in combination, on neurovascular deficits. In addition, high-dose aldose reductase inhibitor and evening primrose oil treatment effects were challenged by co-treatment with the cyclo-oxygenase inhibitor, flurbiprofen, or the nitric oxide synthase inhibitor, NG-nitro-L-arginine. Eight weeks of diabetes caused an 18.9% reduction in sciatic motor conduction velocity (p < 0.001). This was only modestly ameliorated by a 0.1% dietary supplement of evening primrose oil or the aldose reductase inhibitors ZD5522 (0.25 mg.kg-1.day-1 and WAY121 509 (0.2 mg.kg-1.day-1 for the final 2 weeks. However, joint treatment with primrose oil and ZD5522 or WAY121 509 caused marked 71.5 and 82.4% corrections, respectively, of the conduction deficit. Sciatic nutritive blood flow was 43.1% reduced by diabetes (p < 0.001) and this was corrected by 67.8% with joint ZD5522 and primrose oil treatment (p < 0.001). High-dose WAY121 509 (10 mg. kg-1.day-1 and primrose oil (10% dietary supplement) prevented sciatic conduction velocity and nutritive blood flow deficits in 1-month diabetic rats (p < 0.001). However, these effects were abolished by flurbiprofen (5 mg.kg(-1).day-1 and NG-nitro-L-arginine (10 mg.kg-1.day-1) co-treatment (p < 0.001). Thus, the data provide evidence for synergistic interactions between polyol pathway/nitric oxide and essential fatty acid/cyclo-oxygenase systems in the control of neurovascular function in diabetic rats, from which a potential therapeutic advantage could be derived.
Insights
Diabetic neurovascular deficits are improved by combining evening primrose oil with aldose reductase inhibitors. These treatments show synergistic effects, highlighting potential therapeutic strategies for diabetic complications.
Area of Science:
- Biochemistry
- Neuroscience
- Pharmacology
Background:
- Diabetes mellitus is associated with neurovascular abnormalities.
- Impaired omega-6 essential fatty acid metabolism and polyol pathway flux are implicated in these deficits.
- Understanding the interplay between these pathways is crucial for therapeutic development.
Purpose of the Study:
- To investigate the synergistic effects of aldose reductase inhibitors (ARIs) and evening primrose oil (EPO) on neurovascular deficits in diabetic rats.
- To examine the roles of cyclo-oxygenase (COX) and nitric oxide synthase (NOS) pathways in mediating these effects.
Main Methods:
- Streptozotocin-induced diabetic rats were treated with varying doses of EPO and ARIs (ZD5522, WAY121509), alone and in combination.
- Neurovascular function was assessed by measuring sciatic motor conduction velocity and nutritive blood flow.
- Co-treatment with COX inhibitor (flurbiprofen) and NOS inhibitor (NG-nitro-L-arginine) was used to probe underlying mechanisms.
Main Results:
- Combined low-dose EPO and ARIs significantly corrected sciatic motor conduction velocity and nutritive blood flow deficits.
- High-dose EPO and WAY121509 prevented diabetes-induced neurovascular impairments.
- These protective effects were abolished by co-administration of flurbiprofen or NG-nitro-L-arginine.
Conclusions:
- Synergistic interactions exist between the polyol pathway/nitric oxide system and the essential fatty acid/cyclo-oxygenase system in regulating neurovascular function in diabetes.
- Combined therapeutic strategies targeting these pathways may offer significant advantages for managing diabetic neurovascular complications.