Design, Synthesis of Amide Derivatives of Scutellarin And Their Anti-Leukemia And Neuroprotective Activities

A unique series of amide-scutellarin derivatives were designed and synthesized in order to develop the function of scutellarin further. The antiproliferative activity of all target compounds against two human leukaemia cell lines were evaluated. Among them, compounds 6g and 7c displayed the most antitumor activities against HL-60 and THP-1. Moreover, all compounds were also assayed for their neuroprotective activity against hydrogen peroxide (H2O2)-induced PC-12 cell injury, and the majority of the compounds had moderate to good neuroprotective properties. These findings confirmed that these target compounds could be used as anti-leukaemia and neuroprotective candicates in the future.

Enantioselective Synthesis and Pharmacological Evaluation of Aza-CGP37157–Lipoic Acid Hybrids for the Treatment of Alzheimer’s Disease

Hybrids based on an aza-analogue of CGP37157, a mitochondrial Na+/Ca2+ exchanger antagonist, and lipoic acid were obtained in order to combine in a single molecule the antioxidant and NRF2 induction properties of lipoic acid and the neuroprotective activity of CGP37157. The four possible enantiomers of the hybrid structure were synthesized by using as the key step a fully diastereoselective reduction induced by Ellman’s chiral auxiliary. After computational druggability studies that predicted good ADME profiles and blood–brain permeation for all compounds, the DPPH assay showed moderate oxidant scavenger capacity. Following a cytotoxicity evaluation that proved the compounds to be non-neurotoxic at the concentrations tested, they were assayed for NRF2 induction capacity and for anti-inflammatory properties and measured by their ability to inhibit nitrite production in the lipopolysaccharide-stimulated BV2 microglial cell model. Moreover, the compounds were studied for their neuroprotective effect in a model of oxidative stress achieved by treatment of SH-SY5Y neuroblastoma cells with the rotenone–oligomycin combination and also in a model of hyperphosphorylation induced by treatment with okadaic acid. The stereocenter configuration showed a critical influence in NRF2 induction properties, and also in the neuroprotection against oxidative stress experiment, leading to the identification of the compound with S and R configuration as an interesting hit with a good neuroprotective profile against oxidative stress and hyperphosphorylation, together with a relevant anti-neuroinflammatory activity. This interesting multitarget profile will be further characterized in future work.

GINGER LOADED CHITOSAN NANOPARTICLES FOR THE MANAGEMENT OF 3–NITROPROPIONIC ACID-INDUCED HUNTINGTON’S DISEASE-LIKE SYMPTOMS IN MALE WISTAR RATS

Objective: The purpose of this research work is to enhance bioavailability and brain delivery of ginger through the development of ginger-loaded chitosan nanoparticles and evaluation of its neuroprotective potential against 3-Nitropropionic acid (3-NP) induced Huntington’s Disease model rats. Methods: Ginger-loaded chitosan nanoparticles were developed as five different formulations (F1-F5) by the ionic gelation method. Based on their release, formulations F1 and F3 were chosen for physicochemical characterization. The neuroprotective activity of formulations F1 and F3 were evaluated by behavioural (Neurological scoring, Hanging wire test, Elevated plus maze test), biochemical (estimation of lipid peroxidation, glutathione, protein, superoxide dismutase, catalase) and neurochemical (estimation of acetylcholine esterase inhibition) tests in comparison with ginger extract in Huntington’s Disease (HD) model rats. Results: Formulations F1 and F3 showed almost similar and significant controlled release. Formulation F1 showed spherical nanoparticles with optimum size range and negative zeta potential. The behavioural assessment revealed that there was an improvement in gait, movement, grip strength and memory in ginger-loaded chitosan nanoformulations administered to rats than ginger extract administered rats. Biochemical and neurochemical analyses also proved that ginger-loaded chitosan nanoformulations had greatly lowered the oxidative stress parameters such as malondialdehyde and protein carbonyls in comparison with ginger extract (p<0.05). The ginger nanoformulations had highly increased the activity of antioxidant enzymes such as superoxide dismutase, glutathione and catalase by reducing the formation of free radicals than ginger extract (p<0.05). The memory and cognition of ginger nanoformulations administered Wistar rats had highly improved than ginger extract administered Wistar rats (p<0.05 due to inhibition of acetylcholine esterase enzyme). Conclusion: The current study indicated that ginger-loaded chitosan nanoparticles have a superior neuroprotective effect than their extract due to their nano size, which facilitates their entry across the blood-brain barrier and eventually improves the bioavailability of ginger.

Protective Effects of Chlorogenic Acid on Trimethyltin Chloride-Induced Neurobehavioral Dysfunctions in Mice Relying on Gut Microbiota

Trimethyltin chloride (TMT) is acknowledged to have potent neurotoxicity. Chlorogenic acid (CGA), the most abundant polyphenol in the human diet, is well-known for its neuroprotective activity. This investigation was to...

The Role of p53 Protein in the Realization of the Exogenous Heat Shock Protein 70 Anti-Apoptotic Effect during Axotomy

The search for effective neuroprotective agents for the treatment of neurotrauma has always been of great interest to researchers around the world. Extracellular heat shock protein 70 (eHsp70) is considered a promising agent to study, as it has been demonstrated to exert a significant neuroprotective activity against various neurodegenerative diseases. We showed that eHsp70 can penetrate neurons and glial cells when added to the incubation medium, and can accumulate in the nuclei of neurons and satellite glial cells after axotomy. eHsp70 reduces apoptosis and necrosis of the glial cells, but not the neurons. At the same time, co-localization of eHsp70 with p53 protein, one of the key regulators of apoptosis, was noted. eHsp70 reduces the level of the p53 protein apoptosis promoter both in glial cells and in the nuclei and cytoplasm of neurons, which indicates its neuroprotective effect. The ability of eHsp70 to reverse the proapoptotic effect of the p53 activator WR1065 may indicate its ability to regulate p53 activity or its proteosome-dependent degradation.

Evaluation of the neuroprotective activity of a new allylmorpholine derivative in a rat model of traumatic brain injury

Introduction. The search for and development of new drugs capable of reducing the severity of neurological deficit in traumatic brain injury are a critical task for investigational pharmacology. Chromone-containing allylmorpholines are a new group of neuroprotective drug candidates that have been shown to inhibit acetylcholinesterase and butyrylcholinesterase, and block N-methyl-D-aspartate receptors in vitro.Aim. This study aimed to evaluate the neuroprotective activity of the allylmorpholine derivative (E)-4-[3-(8-bromo-6-methyl-4-oxo-4H-chromen- 3-yl)-1-cyclohexylallyl]morpholin-4-ium chloride (33b) in vivo using a rat model of traumatic brain injury.Materials and methods. Traumatic brain injury was induced using the controlled cortical impact model. The allylmorpholine derivative was administered intraperitoneally at 1, 10, or 50 mg × kg-1 b.w. at 1 h after trauma induction, and then daily for the next 6 d. The neurological deficit was assessed using the Limb Placing, Open Field, Elevated Plus Maze, Beam Walking, and Cylinder tests.Results and discussion. At all doses administered, the allylmorpholine derivative had no positive effect on the motor function or exploratory behavior following traumatic brain injury. In the Elevated Plus Maze, 10 mg × kg-1 b.w. of the compound further suppressed exploratory behaviour in the injured animals, which appears to be consistent with its sedative properties observed previously in zebrafish.Conclusion. Despite the previously described in vitro affinity of allylmorpholines towards several molecular targets crucial for the pathogenesis of brain trauma and posttraumatic functional recovery, an allylmorpholine derivative had no neuroprotective effect in a rat model of traumatic brain injury in this study. These results further emphasize the importance of in vivo evaluation of potential neuroprotective drug candidates.

CNTF enhances aerobic glycolysis and anabolic activities in degenerating retinas

Ciliary neurotrophic factor (CNTF) has potent neuroprotective activity in retinal degeneration animal models, yet the cellular mechanisms underlying its broad neuronal survival effects remain unclear. Here, we investigated the impact of CNTF on retinal metabolism in a mouse model of human retinitis pigmentosa. CNTF treatment resulted in improved mitochondrial morphology in mutant rod photoreceptors, but also led to reduced oxygen consumption and suppression of respiratory chain complex activities. Metabolomics analyses detected significantly higher levels of ATP and the energy currency phospho-creatine post CNTF exposure. In addition, CNTF-treated retinas contained elevated glycolytic metabolites and showed increased expression of genes and active enzymes of the glycolytic pathway. Metabolomics analyses also revealed increased TCA cycle products, lipid biosynthetic pathway intermediates, nucleotides, and amino acids, indicating an overall CNTF-dependent augmentation of anabolic activities. Moreover, CNTF treatment restored the key antioxidant glutathione to the wild type level in the degenerating retina. Taken together, these results demonstrate that CNTF profoundly impacts the metabolic status of degenerating retinas by promoting aerobics glycolysis and anabolism, enhancing energy supply, and restoring redox homeostasis. Our study thus reveals important cellular mechanisms underlying CNTF-mediated neuroprotection and provides novel insight for the on-going CNTF clinical trials treating blinding diseases.

Baicalein ameliorated cerebral ischemia-reperfusion injury dependent on calpain 1/AIF pathway

Cerebral ischemia-reperfusion (CIR) has become the leading cause of death and disability. Baicalein is a natural bioactive ingredient extracted from Scutellaria baicalensis Georgi and has neuroprotective activity. In our work, baicalein was found to reduce neurological deficits, brain water content, infarct area and neuronal death of rats induced by middle cerebral artery occlusion/reperfusion. In vitro, oxygen-glucose deprivation/reperfusion induced inordinate ROS production and apoptosis that could be reversed by baicalein. Our study revealed for the first time that baicalein has the potential to binds and inhibits the activity of calpain 1, thereby inhibiting AIF nuclear translocation. These findings demonstrated that baicalein protected against CIR injury via inhibiting AIF nuclear translocation by inhibiting calpain 1 activity.