Characterization of novel kainic acid analogs as inhibitors of select microglial functions.

Alzheimer's disease (AD) is characterized by abnormal accumulation of extracellular amyloid beta protein (Aß) plaques and intracellular neurofibrillary tangles, as well as by a state of chronic inflammation in the central nervous system (CNS). Adverse activation of microglia, the brain immune cells, is believed to contribute to AD pathology including excessive neuronal death. Thus, normalizing immune functions of microglia could slow neurodegeneration, and identification of novel compounds capable of modifying microglial functions is an important goal. Since kainic acid (KA) has been shown to modulate microglial morphology and immune functions, we synthesized six new KA analogs (KAAs) and tested their effects on select microglial functions by using three different cell types as microglia models. Four of the KAAs at low micromolar concentrations inhibited secretion of cytotoxins, monocyte chemoattractant protein (MCP)-1, reactive oxygen species and nitric oxide (NO) by immune-stimulated microglia-like cells. We hypothesize that the effects of the novel KAAs on microglia-like cells are not mediated by KA receptors since their biological activity was distinct from that of KA in all assays performed. A structural similarity search identified aldose reductase (AR) as a potential target for the novel KAAs. This hypothesis was supported by use of AR inhibitor zopolrestat, which abolished the inhibitory effects of two KAAs on microglial secretion of NO. Since the newly developed KAAs inhibited pro-inflammatory and cytotoxic functions of microglia, they should be further investigated for their potential beneficial effect on neuroinflammation and neurodegeneration in AD animal models.

Aldose reductase inhibitors attenuate ß-amyloid-induced TNF-α production in microlgia via ROS-PKC-mediated NF-κB and MAPK pathways.

Microglia-mediated neuroinflammation is a key risk factor to the development of Alzheimer' disease (AD). Aldose reductase (AR) has been found to be widely involved in inflammation-related diseases; however, whether aldose reductase inhibitors (ARIs) could be used to treat neuroinflammation is rarely reported. This study aims to evaluate the anti-neuroinflammatory effects of two major ARIs of Sorbinil (Sor) and Zopolrestat (Zol) in ß-amyloid protein (Aß)-induced microglia (BV-2). We find that Sor and Zol significantly inhibit TNF-α, IL-1ß, IL-6 production from microglia in response to Aß stimulation. Mechanism study showed that Sor and Zol decreased the production of intracellular ROS which resulted in an effective inhibition on the phosphorylation of several protein kinase C (PKC) isoforms including PKCα/ß, δ, ζ/λ and mu. Moreover, Sor and Zol inactivated PCK-associated IKKß-IκB-NF-κB and mitogen-activated protein kinase (JNK, p38, ERK) inflammation pathways. In summary, our findings suggest that Sor and Zol could inhibit Aß-induced neuroinflammation by regulating ROS/PKC-dependent NF-κB and MAPK signaling pathways, indicating that ARIs could be promising agents for treating inflammation-related neurodegenerative diseases such as AD.

Ferulic acid, a natural polyphenol, alleviates insulin resistance and hypertension in fructose fed rats: Effect on endothelial-dependent relaxation.

Ferulic acid (FER) is a polyphenolic compound contained in various types of fruits. It has a substantial therapeutic effect inhibitory activity against aldose reductase (AR) inhibition. In this study, we examined the effect of FER on fructose-fed rats in comparison to a standard AR inhibitor, zopolrestat (ZOP). We determined the protective role of FER against metabolic syndrome by examining serum insulin/Glucose levels, triglycerides (TGs), cholesterol and advanced glycation end product (AGE) in rats supplied with 10% fructose drinking water. In addition, blood pressure, vascular reactivity of isolated thoracic aortas and acetylcholine-induced NO were all evaluated to estimate the cardiovascular complications of metabolic syndrome (MetS) associated with fructose feeding. Animals were randomly divided into four groups: control, (+10% fructose, Fru), zopolrestat-treated fructose fed (Fru-zop) and ferulic acid-treated fructose fed rats (Fru-Fer). After 12 weeks of FER treatment, we found significant reduction in both hyperinsulinemia and elevated diastolic blood pressure associated with fructose-fed to levels comparable to those achieved with ZOP. Both FER and ZOP significantly augmented the impaired relaxation associated with fructose-fed, whereas neither showed any significant effect on the developed vasoconstriction. Isolated aortas from fructose-fed rats incubated with either FER or ZOP, reinstated normal relaxation response to acetylcholine (ACh). Furthermore, isolated aortas showed attenuated nitric oxide (NO) production following the addition of (ACh), while both FER and ZOP restored normal induction of NO. Taken together, the current study shows that, FER alleviated insulin resistance and hypertension associated with metabolic syndrome compared to the standard AR inhibitor (ZOP). This potential protective effect is at least mediated by restoring endothelial relaxation.