In Vitro Modulation of Autophagy by New Antioxidant Nitrones as a Potential Therapeutic Approach for the Treatment of Ischemic Stroke.

Stroke is a leading cause of death worldwide, yet current therapeutic strategies remain limited. Among the neuropathological events underlying this disease are multiple cell death signaling cascades, including autophagy. Recent interest has focused on developing agents that target molecules involved in autophagy to modulate this process under pathological conditions.

A methodology to globally assess ectodomain shedding using soluble fractions from the mouse brain.

Ectodomain shedding (ES) is a fundamental process involving the proteolytic cleavage of membrane-bound proteins, leading to the release of soluble extracellular fragments (shed ectodomains) with potential paracrine and autocrine signaling functions. In the central nervous system (CNS), ES plays pivotal roles in brain development, axonal regulation, synapse formation, and disease pathogenesis, spanning from cancer to Alzheimer's disease. Recent evidence also suggests its potential involvement in neurodevelopmental conditions like autism and schizophrenia.

Design and Synthesis of Multi-Functional Ligands through Hantzsch Reaction: Targeting Ca Channels, Activating Nrf2 and Possessing Cathepsin S Inhibitory, and Antioxidant Properties.

This work relates to the design and synthesis of a series of novel multi-target directed ligands (MTDLs), i.e., compounds -, via a convenient one-pot three-component Hantzsch reaction.

Neuroprotective and Antioxidant Properties of CholesteroNitrone ChN2 and QuinolylNitrone QN23 in an Experimental Model of Cerebral Ischemia: Involvement of Necrotic and Apoptotic Cell Death.

Ischemic stroke is the leading cause of disability and the second leading cause of death worldwide. However, current therapeutic strategies are scarce and of limited efficacy. The abundance of information available on the molecular pathophysiology of ischemic stroke has sparked considerable interest in developing new neuroprotective agents that can target different events of the ischemic cascade and may be used in combination with existing treatments.

The activation of mGluR4 rescues parallel fiber synaptic transmission and LTP, motor learning and social behavior in a mouse model of Fragile X Syndrome.

Background: Fragile X syndrome (FXS), the most common inherited intellectual disability, is caused by the loss of expression of the Fragile X Messenger Ribonucleoprotein (FMRP). FMRP is an RNA-binding protein that negatively regulates the expression of many postsynaptic as well as presynaptic proteins involved in action potential properties, calcium homeostasis and neurotransmitter release. FXS patients and mice lacking FMRP suffer from multiple behavioral alterations, including deficits in motor learning for which there is currently no specific treatment.

Neuroprotective and antioxidant properties of new quinolylnitrones in in vitro and in vivo cerebral ischemia models.

Cerebral ischemia is a condition affecting an increasing number of people worldwide, and the main cause of disability. Current research focuses on the search for neuroprotective drugs for its treatment, based on the molecular targets involved in the ischemic cascade. Nitrones are potent antioxidant molecules that can reduce oxidative stress.

Nucleobase-Derived Nitrones: Synthesis and Antioxidant and Neuroprotective Activities in an In Vitro Model of Ischemia-Reperfusion.

Herein, we report the synthesis, antioxidant, and neuroprotective properties of some nucleobase-derived nitrones named -. The neuroprotective properties of nitrones, -, were measured against an oxygen-glucose-deprivation in vitro ischemia model using human neuroblastoma SH-SY5Y cells. Our results indicate that nitrones, -, have better neuroprotective and antioxidant properties than α-phenyl-N-tert-butylnitrone () and are similar to N-acetyl-L-cysteine (), a well-known antioxidant and neuroprotective agent.

Use of Radical Oxygen Species Scavenger Nitrones to Treat Oxidative Stress-Mediated Hearing Loss: State of the Art and Challenges.

Nitrones are potent antioxidant molecules able to reduce oxidative stress by trapping reactive oxygen and nitrogen species. The antioxidant potential of nitrones has been extensively tested in multiple models of human diseases. Sensorineural hearing loss has a heterogeneous etiology, genetic alterations, aging, toxins or exposure to noise can cause damage to hair cells at the organ of Corti, the hearing receptor.

Synthesis, Neuroprotection, and Antioxidant Activity of 1,1'-Biphenylnitrones as α-Phenyl--butylnitrone Analogues in In Vitro Ischemia Models.

Herein, we report the neuroprotective and antioxidant activity of 1,1'-biphenyl nitrones () - as α-phenyl---butylnitrone analogues prepared from commercially available [1,1'-biphenyl]-4-carbaldehyde and [1,1'-biphenyl]-4,4'-dicarbaldehyde. The neuroprotection of - has been measured against oligomycin A/rotenone and in an oxygen-glucose deprivation in vitro ischemia model in human neuroblastoma SH-SY5Y cells. Our results indicate that - have better neuroprotective and antioxidant properties than α-phenyl---butylnitrone (), and they are quite similar to -acetyl-L-cysteine (), which is a well-known antioxidant agent.

Homo-Tris-Nitrones Derived from α-Phenyl--butylnitrone: Synthesis, Neuroprotection and Antioxidant Properties.

Herein we report the synthesis, antioxidant and neuroprotective power of homo-tris-nitrones () , designed on the hypothesis that the incorporation of a third nitrone motif into our previously identified homo-bis-nitrone () would result in an improved and stronger neuroprotection. The neuroprotection of , measured against oligomycin A/rotenone, showed that was the best neuroprotective agent at a lower dose (EC = 51.63 ± 4.

Synthesis, antioxidant properties and neuroprotection of α-phenyl-tert-butylnitrone derived HomoBisNitrones in in vitro and in vivo ischemia models.

We herein report the synthesis, antioxidant power and neuroprotective properties of nine homo-bis-nitrones HBNs 1-9 as alpha-phenyl-N-tert-butylnitrone (PBN) analogues for stroke therapy. In vitro neuroprotection studies of HBNs 1-9 against Oligomycin A/Rotenone and in an oxygen-glucose-deprivation model of ischemia in human neuroblastoma cell cultures, indicate that (1Z,1'Z)-1,1'-(1,3-phenylene)bis(N-benzylmethanimine oxide) (HBN6) is a potent neuroprotective agent that prevents the decrease in neuronal metabolic activity (EC = 1.24 ± 0.

Neuroprotection by Phytoestrogens in the Model of Deprivation and Resupply of Oxygen and Glucose In Vitro: The Contribution of Autophagy and Related Signaling Mechanisms.

Phytoestrogens can have a neuroprotective effect towards ischemia-reperfusion-induced neuronal damage. However, their mechanism of action has not been well described. In this work, we investigate the type of neuronal cell death induced by oxygen and glucose deprivation (OGD) and resupply (OGDR) and pinpoint some of the signaling mechanisms whereby the neuroprotective effects of phytoestrogens occur in these conditions.

Synthesis of new ferulic/lipoic/comenic acid-melatonin hybrids as antioxidants and Nrf2 activators via Ugi reaction.

Oxidative stress has been implicated in the pathogenesis of many neurodegenerative diseases, and particularly in Alzheimer's disease. This work describes the Ugi multicomponent synthesis, antioxidant power and Nrf2 pathway induction in antioxidant response element cells of ()--(2-((2-(1-indol-3-yl)ethyl)amino)-2-oxoethyl)--(2-(5-(benzyloxy)-1-indol-3-yl)ethyl)-3-(4-hydroxy-3-methoxyphenyl)acryl amides , -(2-((2-(1-indol-3-yl)ethyl)amino)-2-oxoethyl)--(2-(5-(benzyloxy)-1-indol-3-yl)ethyl)-5-(1,2-dithiolan-3-yl)pentanamides and -(2-((2-(1-indol-3-yl)ethyl)amino)-2-oxoethyl)--(2-(5-(benzyloxy)-1-indol-3-yl)ethyl)-5-hydroxy-4-oxo-4-pyran-2-carboxamides . We have identified compounds and , showing a potent antioxidant capacity, a remarkable neuroprotective effect against the cell death induced by HO in SH-SY5Y cells, and a performing activation of the Nrf2 signaling pathway, as very interesting new antioxidant agents for pathologies that curse with oxidative stress.

Synthesis and Neuroprotective Properties of N-Substituted -Dialkoxyphosphorylated Nitrones.

Herein, we report the synthesis and neuroprotective power of some N-substituted -(dialkoxy)phosphorylated nitrones -, by studying their ability to increase the cell viability, as well as their capacity to reduce necrosis and apoptosis. We have identified ()---butyl-1-(diethoxyphosphoryl)methanimine oxide () as the most potent, nontoxic, and neuroprotective agent, with a high activity against neuronal necrotic cell death, a result that correlates very well with its great capacity for the inhibition of the superoxide production (72%), as well as with the inhibition of lipid peroxidation (62%), and the 5-lipoxygenase activity (45%) at 100 μM concentrations. Thus, nitrone could be a convenient promising compound for further investigation.

The loss of β adrenergic receptor mediated release potentiation in a mouse model of fragile X syndrome.

In fragile X syndrome, the absence of Fragile X Mental Retardation Protein (FMRP) is known to alter postsynaptic function, although alterations in presynaptic function also occur. We found that the potentiation of glutamate release induced by the β adrenergic receptor (βAR) agonist isoproterenol is absent in cerebrocortical nerve terminals (synaptosomes) from mice lacking FMRP (Fmr1 KO), despite the normal cAMP generation. The glutamate release induced by moderate stimulation of synaptosomes with 5 mM KCl was not potentiated in Fmr1 KO synaptosomes by isoproterenol, nor by stimulating the receptor associated signaling pathway with the adenylyl cyclase activator forskolin or with the Epac activator 8-pCPT.

Synthesis, neuroprotective and antioxidant capacity of PBN-related indanonitrones.

In this work six PBN-related indanonitrones 1-6 have been designed, synthesized, and their neuroprotection capacity tested in vitro, under OGD conditions, in SH-SY5Y human neuroblastoma cell cultures. As a result, we have identified indanonitrones 1, 3 and 4 (EC = 6.64 ± 0.

Donepezil + chromone + melatonin hybrids as promising agents for Alzheimer's disease therapy.

We describe herein the design, multicomponent synthesis and biological studies of new donepezil + chromone + melatonin hybrids as potential agents for Alzheimer's disease (AD) therapy. We have identified compound 14n as promising multitarget small molecule showing strong BuChE inhibition (IC = 11.90 ± 0.

Synthesis, antioxidant and Aβ anti-aggregation properties of new ferulic, caffeic and lipoic acid derivatives obtained by the Ugi four-component reaction.

We report herein the synthesis antioxidant and Aβ anti-aggregation capacity of (E)-N-benzyl-N-[2-(benzylamino)-2-oxoethyl]-3-(aryl)acrylamides and related (R)-N-benzyl-N-(2-(benzylamino)-2-oxoethyl)-5-(1,2-dithiolan-3-yl)pentanamides 1-12. These compounds have been obtained, via Ugi four-component reaction, from modest to good yields. Their antioxidant analysis, using the DPPH and ORAC assays, allowed us to identify compounds 8 and 9, as potent antioxidant agents, showing also strong Aβ self-aggregation inhibition, two biological properties of interest in pathologies linked to the oxidative stress, such as Alzheimer's disease.

Tacrine-Natural-Product Hybrids for Alzheimer's Disease Therapy.

Alzheimer's disease (AD) is a complex, neurodegenerative pathology showing, among others, high cholinergic and neurotransmitter deficits, oxidative stress, inflammation, Aβ-aggregation resulting in senile plaques formation, and hyperphosphorylation of tau-protein leading to neurofibrillary tangles. Due to its multifactorial and complex nature, multitarget directed small-molecules able to simultaneously inhibit or bind diverse biological targets involved in the progress and development of AD are considered now the best therapeutic strategy to design new compounds for AD therapy. Among them, tacrine is a very well known standard-gold ligand, and natural products have been a traditional source of new agents for diverse therapeutic treatments.

Alzheimer's Disease, the "One-Molecule, One-Target" Paradigm, and the Multitarget Directed Ligand Approach.

No selective drugs exist, and we have been designing, synthesizing, and evaluating multitarget-directed ligands since the beginning of modern medicinal chemistry, without knowing it, most possibly. The challenge to discover the efficient Multi-Target Small Molecules (MTSMs) for Alzheimer's disease (AD) therapy implies to identify the key combination of biological targets to modulate them, thus including in the design the corresponding pharmacophoric groups able to do it. Universal and polyvalent pharmacophoric groups, able to modulate diverse receptors or enzymatic systems, would simplify the drug discovery process leading to new and more efficient MTSMs for AD.

New Tacrines as Anti-Alzheimer's Disease Agents. The (Benzo)Chromeno- PyranoTacrines.

Tacrine was the first drug approved by FDA (US) for the treatment of Alzheimer's disease suffering patients. Nowadays, this agent has been withdrawn from the clinics due to secondary effects, which, most importantly, include hepatotoxicity. However, the research on new tacrine analogues devoid of these therapeutically undesirable effects, but benefiting of their high and well known positive cholinergic power, has produced a number of new non-hepatotoxic tacrines.

Corrigendum: Melatonin and Nitrones As Potential Therapeutic Agents for Stroke.

[This corrects the article on p. 281 in vol. 8, PMID: 27932976.

Vesicular glutamate transporters play a role in neuronal differentiation of cultured SVZ-derived neural precursor cells.

The role of glutamate in the regulation of neurogenesis is well-established, but the role of vesicular glutamate transporters (VGLUTs) and excitatory amino acid transporters (EAATs) in controlling adult neurogenesis is unknown. Here we investigated the implication of VGLUTs in the differentiation of subventricular zone (SVZ)-derived neural precursor cells (NPCs). Our results show that NPCs express VGLUT1-3 and EAAT1-3 both at the mRNA and protein level.

Melatonin and Nitrones As Potential Therapeutic Agents for Stroke.

Stroke is a disease of aging affecting millions of people worldwide, and recombinant tissue-type plasminogen activator (r-tPA) is the only treatment approved. However, r-tPA has a low therapeutic window and secondary effects which limit its beneficial outcome, urging thus the search for new more efficient therapies. Among them, neuroprotection based on melatonin or nitrones, as free radical traps, have arisen as drug candidates due to their strong antioxidant power.

Avarol derivatives as competitive AChE inhibitors, non hepatotoxic and neuroprotective agents for Alzheimer's disease.

Avarol is a marine sesquiterpenoid hydroquinone, previously isolated from the marine sponge Dysidea avara Schmidt (Dictyoceratida), with antiinflammatory, antitumor, antioxidant, antiplatelet, anti-HIV, and antipsoriatic effects. Recent findings indicate that some thio-avarol derivatives exhibit acetylcholinesterase (AChE) inhibitory activity. The multiple pharmacological properties of avarol, thio-avarol and/or their derivatives prompted us to continue the in vitro screening, focusing on their AChE inhibitory and neuroprotective effects.