Docosahexaenoic Acid Increases the Potency of Soluble Epoxide Hydrolase Inhibitor in Alleviating Streptozotocin-Induced Alzheimer’s Disease-Like Complications of Diabetes

Abstract

Diabetes is a risk factor for Alzheimer’s disease and it is associated with significant memory loss. In the present study, we hypothesized that the soluble epoxide hydrolase (sEH) inhibitor N-[1-(1-oxopropyl)-4-piperidinyl]-N’-[4-(trifluoromethoxy)phenyl)-urea (also known as TPPU) could alleviate diabetes-aggravated Alzheimer’s disease-like symptoms by improving memory and cognition, and reducing the oxidative stress and inflammation associated with this condition. Also, we evaluated the effect of edaravone, an antioxidant on diabetes-induced Alzheimer’s-like complications and the additive effect of docosahexaenoic acid (DHA) on the efficacy of TPPU. Diabetes was induced in male Sprague-Dawley rats by intraperitoneally administering streptozotocin (STZ). Six weeks after induction of diabetes, animals were either treated with vehicle, edaravone (3 or 10 mg/kg), TPPU (1 mg/kg) or TPPU (1 mg/kg) + DHA (100 mg/kg) for 2 weeks. The results demonstrate that the treatments increased the memory response of diabetic rats, in comparison to untreated diabetic rats. Indeed, DHA + TPPU were more effective than TPPU alone in reducing the symptoms monitored. All drug treatments reduced oxidative stress and minimized inflammation in the brain of diabetic rats. Expression of the amyloid precursor protein (APP) was increased in the brain of diabetic rats. Treatment with edaravone (10 mg/kg), TPPU or TPPU + DHA minimized the level of APP. The activity of acetylcholinesterase (AChE) which metabolizes acetylcholine was increased in the brain of diabetic rats. All the treatments except edaravone (3 mg/kg) were effective in decreasing the activity of AChE and TPPU + DHA was more efficacious than TPPU alone. Intriguingly, the histological changes in hippocampus after treatment with TPPU + DHA showed significant protection of neurons against STZ-induced neuronal damage. Overall, we found that DHA improved the efficacy of TPPU in increasing neuronal survival and memory, decreasing oxidative stress and inflammation possibly by stabilizing anti-inflammatory and neuroprotective epoxides of DHA. In the future, further evaluating the detailed mechanisms of action of sEH inhibitor and DHA could help to develop a strategy for the management of Alzheimer’s-like complications in diabetes.

Serum metabolomic biomarkers of perceptual speed in cognitively normal and mildly impaired subjects with fasting state stratification

“…Recent studies of mice and men have implicated sEH in neurodegenerative diseases of the brain 59 . Moreover, DHA feeding enhances the therapeutic efficacy of sEH inhibitors in reducing neurocognitive complications in rodent models of diabetes 60 . Together, these studies provide strong evidence that the identified shifts in sEH metabolism in association with cognitive decline may be linked to the underlying pathology of this process.…”

Docosahexaenoic acid modulates oxidative stress and monoamines levels in brain of streptozotocin-induced diabetic rats

“…In the present study, diabetes mellitus successful induction was reflected by a significant rise in blood glucose levels and low insulin levels, which is in line with El-Yamany et al (17) and Mohamed et al (18). DM was reported to be accompanied with altered memory function, cardiac stress, endothelial disturbed function and many complications (1,19) could be linked to impaired insulin as insulin signaling affects synaptogenesis and neuronal survival, which leads to memory loss (1).…”

“…Diabetes mellitus (DM) is a complex metabolic disorder which affects multiple physiological systems including the central nervous system (1). According to WHO, more than 180 million people worldwide have DM and this may double by 2030.…”

SMTP‐44D improves diabetic neuropathy symptoms in mice through its antioxidant and anti‐inflammatory activities

“…The EDR dose was selected as reported previously. [44‐46] PGN is the first line agent for the treatment of painful DN. It binds to the α 2 δ subunit of the voltage dependent calcium channel in the central nervous system indicating an anti‐hyperalgesic and anti‐allodynic effect specific for its action at the CaVα 2 δ‐1 subunit.…”