The Slow-Releasing and Mitochondria-Targeted Hydrogen Sulfide (H2S) Delivery Molecule AP39 Induces Brain Tolerance to Ischemia

Ischemic stroke is the third leading cause of death in the world, which accounts for almost 12% of the total deaths worldwide. Despite decades of research, the available and effective pharmacotherapy is limited. Some evidence underlines the beneficial properties of hydrogen sulfide (H2S) donors, such as NaSH, in an animal model of brain ischemia and in in vitro research; however, these data are ambiguous. This study was undertaken to verify the neuroprotective activity of AP39, a slow-releasing mitochondria-targeted H2S delivery molecule. We administered AP39 for 7 days prior to ischemia onset, and the potential to induce brain tolerance to ischemia was verified. To do this, we used the rat model of 90-min middle cerebral artery occlusion (MCAO) and used LC-MS/MS, RT-PCR, LuminexTM assays, Western blot and immunofluorescent double-staining to determine the absolute H2S levels, inflammatory markers, neurotrophic factor signaling pathways and apoptosis marker in the ipsilateral frontal cortex, hippocampus and in the dorsal striatum 24 h after ischemia onset. AP39 (50 nmol/kg) reduced the infarct volume, neurological deficit and reduced the microglia marker (Iba1) expression. AP39 also exerted prominent anti-inflammatory activity in reducing the release of Il-1β, Il-6 and TNFα in brain areas particularly affected by ischemia. Furthermore, AP39 enhanced the pro-survival pathways of neurotrophic factors BDNF-TrkB and NGF-TrkA and reduced the proapoptotic proNGF-p75NTR-sortilin pathway activity. These changes corresponded with reduced levels of cleaved caspase 3. Altogether, AP39 treatment induced adaptative changes within the brain and, by that, developed brain tolerance to ischemia.

Preparation of Cadmium Telluride Quantum Dots and Its Effects on Cyclic Adenosine Monophosphate-cAMP Response Element-Binding Proteins-Brain-Derived Neurotrophic Factor Signaling Pathway in Mouse Hippocampus

N-acetyl-L-cysteine-modified CdTe QDs (Cadmium Telluride Quantum Dots) were obtained by hydrothermal method, and DA (amino deoxyglucose), PEG (polyethylene glycol), and 9-p-D (9 polyamine acid) were obtained by ligand substitution, which were used for remodifying CdTe QDs. Successively, a novel CdTe QDs nanoma-terial, CdTe-NALC, was obtained. This composite nanometer material was characterized by ultraviolet, fluorescence spectrum, nuclear magnetic resonance hydrogen-spectrum, and other methods to study further its biocompatibility and toxic effect on the primary cultured mouse hippocampus neurons. PC12 cells were vitro-cultured and dissolved in the CdTe-NALC solution with different concentrations. After 24 h, the expression levels of proteins related to the cAMP (cyclic adenosine monophosphate)-CREB (cAMP response element-binding proteins)-BDNF (brain-derived neurotrophic factor) signaling pathway in the cells were detected by ELISA (enzyme-linked immunosorbent assay) kit. In the experiment, the DA/9-p-D/PEG-modified CdTe QDs composite nanometer material was successfully manufactured by ligand replacement. The nanoparticles had good dis-persibility with an average particle size of about 9.2 nm. DA/9-p-D/PEG modification improved the biocompatibil-ity of the QDs. CdTe composite nanomaterials could significantly reduce the cell activity of mouse hippocampal neurons and promote their apoptosis, with an evident dose-apoptosis relationship. With the increase of CDTE-NALC solution concentration, cAMP, pCREB (phosphorylated CREB), and BDNF protein content decreased (P < 0.05).

Pharmacological Strategies to Improve Dendritic Spines in Alzheimer’s Disease

To deeply understand late onset Alzheimer’s disease (LOAD), it may be necessary to change the concept that it is a disease exclusively driven by aging processes. The onset of LOAD could be associated with a previous peripheral stress at the level of the gut (changes in the gut microbiota), obesity (metabolic stress), and infections, among other systemic/environmental stressors. The onset of LOAD, then, may result from the generation of mild peripheral inflammatory processes involving cytokine production associated with peripheral stressors that in a second step enter the brain and spread out the process causing a neuroinflammatory brain disease. This hypothesis could explain the potential efficacy of Sodium Oligomannate (GV–971), a mixture of acidic linear oligosaccharides that have shown to remodel gut microbiota and slowdown LOAD. However, regardless of the origin of the disease, the end goal of LOAD–related preventative or disease modifying therapies is to preserve dendritic spines and synaptic plasticity that underlay and support healthy cognition. Here we discuss how systemic/environmental stressors impact pathways associated with the regulation of spine morphogenesis and synaptic maintenance, including insulin receptor and the brain derived neurotrophic factor signaling. Spine structure remodeling is a plausible mechanism to maintain synapses and provide cognitive resilience in LOAD patients. Importantly, we also propose a combination of drugs targeting such stressors that may be able to modify the course of LOAD by acting on preventing dendritic spines and synapsis loss.

Glutamate Attenuates the Survival Property of IGFR through NR2B Containing N-Methyl-D-aspartate Receptors in Cortical Neurons

Glutamate-induced neurotoxicity is involved in various neuronal diseases, such as Alzheimer’s disease. We have previously reported that glutamate attenuated the survival signaling of insulin-like growth factor-1 (IGF-1) by N-methyl-D-aspartate receptors (NMDARs) in cultured cortical neurons, which is viewed as a novel mechanism of glutamate-induced neurotoxicity. However, the phosphorylation sites of IGF-1 receptor (IGF-1R) affected by glutamate remain to be elucidated, and importantly, which subtype of NMDARs plays a major role in attenuating the prosurvival effect of IGF-1 is still unknown. In the present study, glutamate was found to attenuate the tyrosine phosphorylation of the IGF-1R and the prosurvival effect of IGF-1 in primary cultured cortical neurons. NMDAR inhibitors, MK801 and AP-5, blocked the inhibitory effect of glutamate on the phosphorylation of IGF-1R and increased cell survival, while DNQX, LY341495, and CPCCOEt had no effect. Interestingly, we found that glutamate decreased the phosphorylation of tyrosine residues 1131, 1135/1136, 1250/1251, and 1316, while it had no effect on tyrosine 950 in cortical neurons. Moreover, using specific antagonists and siRNA to downregulate individual NMDAR subunits, we found that the activation of NR2B-containing NMDARs was essential for glutamate to inhibit IGF-1 signaling. These findings indicate that the glutamate-induced attenuation of IGF-1 signaling is mediated by NR2B-containing NMDARs. Our study also proposes a novel mechanism of altering neurotrophic factor signaling by the activation of NMDARs.